Base de dados : MEDLINE
Pesquisa : D12.776.157.530.400.150.740.500 [Categoria DeCS]
Referências encontradas : 728 [refinar]
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[PMID]:29225169
[Au] Autor:Yu BX; Yuan JN; Zhang FR; Liu YY; Zhang TT; Li K; Lv XF; Zhou JG; Huang LY; Shang JY; Liang SJ
[Ad] Endereço:Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Guangzhou, China; Center for Translational Medicine, The First Affiliated Hospital, Guangzhou, China.
[Ti] Título:Inhibition of Orai1-mediated Ca entry limits endothelial cell inflammation by suppressing calcineurin-NFATc4 signaling pathway.
[So] Source:Biochem Biophys Res Commun;495(2):1864-1870, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Orai1-dependent Ca entry plays an essential role in inflammatory response through regulating T cell and macrophage activation and neutrophil infiltration. However, whether Orai1 Ca entry contributes to endothelial activation, one of the early steps of vascular inflammation, remains elusive. In the present study, we observed that knockdown of Orai1 reduced, whereas overexpression of Orai1 potentiated, TNFα-induced expression of adhesion molecules such as ICAM-1 and VCAM-1 in HUVECs, and subsequently blocked adhesion of monocyte to HUVECs. In vivo, Orai1 downregulation attenuated TNFα-induced ICAM-1 and VCAM-1 expression in mouse aorta and the levels of pro-inflammatory cytokines in the serum. In addition, Orai1 knockdown also dramatically decreased the expression of pro-inflammatory cytokines and neutrophil infiltration in the lung after TNFα treatment, and thus protected lung tissue injury. Notably, among all isoforms of nuclear factor of activated T cells (NFATs), TNFα only triggered NFATc4 nuclear accumulation in HUVECs. Knockdown of Orai1 or inhibition of calcineurin prevented TNFα-induced NFATc4 nuclear translocation and reduced ICAM-1 and VCAM-1 expression in HUVECs. Overexpression of NFATc4 further enhanced ICAM-1 and VCAM-1 expression induced by TNFα. Our study demonstrates that Orai1-Ca -calcineurin-NFATc4 signaling is an essential inflammatory pathway required for TNFα-induced endothelial cell activation and vascular inflammation. Therefore, Orai1 may be a potential therapeutic target for treatment of inflammatory diseases.
[Mh] Termos MeSH primário: Aortite/imunologia
Calcineurina/imunologia
Cálcio/imunologia
Moléculas de Adesão Celular/imunologia
Endotélio Vascular/imunologia
Fatores de Transcrição NFATC/imunologia
Proteína ORAI1/imunologia
[Mh] Termos MeSH secundário: Animais
Aortite/patologia
Células Cultivadas
Regulação para Baixo/imunologia
Seres Humanos
Mediadores da Inflamação/imunologia
Redes e Vias Metabólicas/imunologia
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cell Adhesion Molecules); 0 (Inflammation Mediators); 0 (NFATC Transcription Factors); 0 (Nfatc4 protein, mouse); 0 (ORAI1 Protein); 0 (Orai1 protein, mouse); EC 3.1.3.16 (Calcineurin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:29305862
[Au] Autor:Li Y; Lou C; Wang W
[Ad] Endereço:Department of Pediatrics, Huaihe Hospital, Henan University, Kaifeng 475000, China. Electronic address: liyanyanghuaihe@qq.com.
[Ti] Título:STIM1 deficiency protects the liver from ischemia/reperfusion injury in mice.
[So] Source:Biochem Biophys Res Commun;496(2):422-428, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hepatic ischemia reperfusion (I/R) injury is unavoidable in various clinical conditions. Despite considerable investigation, the underlying molecular mechanism revealing liver I/R injury remains elusive. Stromal interaction molecule 1 (STIM1) plays essential role in regulating the induction of cellular responses to a number of stress conditions, including temperature changes, elevated ROS, and hypoxia. Here, to explore if STIM1 is involved in hepatic injury, wild type (WT) and STIM1-knockout (STIM1 ) mice were subjected to I/R. Our results indicated that the WT mice with hepatic I/R injury showed higher STIM1 expressions from gene and protein levels in liver tissue samples. Similar results were observed in hypoxia-exposed cells in vitro. Significantly, STIM1 attenuated hepatic injury compared to the WT mice after I/R, as evidenced by the improved pathological alterations in liver sections. WT mice subjected to liver I/R showed higher serum alanine aminotransferase (ALT) and aminotransferase (AST) levels, as well as pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß, which were significantly reduced by STIM1 . In addition, STIM1 also decreased the liver mRNA levels of pro-inflammatory cytokines in mice after I/R injury. Furthermore, significantly decreased oxidative stress was found in STIM1 mice after I/R injury compared to the WT group of mice, evidenced by the enhanced superoxide dismutase (SOD) activity and the reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels in liver tissue samples. Moreover, STIM1 mice with hepatic I/R injury displayed the down-regulated nuclear factor of activated T cell (NFAT1), Orai1 and cleaved Caspase-3 levels in liver, contributing to apoptosis suppression. The results above were confirmed in hypoxia-treated cells lacking of STIM1 expression. Together, the findings suggested that STIM1-deletion protects the liver from I/R injury in mice through inhibiting inflammation, oxidative stress and apoptosis. STIM1 could be considered as a potential therapeutic target to ameliorate I/R injury.
[Mh] Termos MeSH primário: Macrófagos do Fígado/metabolismo
Fígado/metabolismo
Traumatismo por Reperfusão/genética
Molécula 1 de Interação Estromal/genética
[Mh] Termos MeSH secundário: Alanina Transaminase/sangue
Animais
Apoptose/genética
Aspartato Aminotransferases/sangue
Caspase 3/genética
Caspase 3/metabolismo
Regulação da Expressão Gênica
Interleucina-1beta/genética
Interleucina-1beta/metabolismo
Interleucina-6/genética
Interleucina-6/metabolismo
Macrófagos do Fígado/patologia
Fígado/patologia
Masculino
Malondialdeído/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fatores de Transcrição NFATC/genética
Fatores de Transcrição NFATC/metabolismo
Proteína ORAI1/genética
Proteína ORAI1/metabolismo
Estresse Oxidativo
Cultura Primária de Células
Espécies Reativas de Oxigênio/metabolismo
Traumatismo por Reperfusão/metabolismo
Traumatismo por Reperfusão/patologia
Traumatismo por Reperfusão/prevenção & controle
Molécula 1 de Interação Estromal/deficiência
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL1B protein, mouse); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (NFATC Transcription Factors); 0 (Nfatc2 protein, mouse); 0 (ORAI1 Protein); 0 (Orai1 protein, mouse); 0 (Reactive Oxygen Species); 0 (Stim1 protein, mouse); 0 (Stromal Interaction Molecule 1); 0 (Tumor Necrosis Factor-alpha); 4Y8F71G49Q (Malondialdehyde); EC 1.15.1.1 (Superoxide Dismutase); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); EC 3.4.22.- (Casp3 protein, mouse); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180107
[St] Status:MEDLINE


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[PMID]:28845932
[Au] Autor:Apolikhin OI; Sivkov AV; Konstantinova OV; Slominskii PA; Tupitsyna TV; Kalinichenko DN
[Ad] Endereço:N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology branch of National Medical Radiological Research Center of Minzdrav of Russia, Moscow, Russia.
[Ti] Título:[Early diagnosis of risk for developing calcium oxalate urolithiasis].
[So] Source:Urologiia;(3):5-8, 2017 Jul.
[Is] ISSN:1728-2985
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:AIM: To identify risk groups for calcium oxalate urolithiasis among healthy individuals and patients with urolithiasis in the Russian population using molecular genetics. MATERIALS AND METHODS: The study comprised 72 patients with calcium oxalate urolithiasis (study group) and 189 healthy adults from the general Russian population (control group). The study group consisted of 39 (54.2%) men and 33 (45.8%) women. The mean age of urolithiasis patients was 41.5+/-12.4 years. Analysis of polymorphic variants of 8 candidate urolithiasis genes: tumor necrosis factor 11B (TNFRSF11B, rs3134057), -subunit of the nuclear estrogen receptor (ESR1, rs851982), Cloto gene (KL, rs526906), vitamin D receptor (VDR, rs1540339 ), an extracellular calcium-sensing receptor (CASR, rs2202127), membrane anion transporter family 26 (SLC26A6, rs2310996), tumor necrosis factor 11 (TNFSF11, rs9525641), the calcium release-activated calcium modulator 1 (ORAI1, rs7135617) in two groups was performed by real-time PCR using Applied Biosystems test. Statistical analysis was performed using Fishers angular transformation and 2. RESULTS: In the polymorphism of the ORAI1 gene (rs7135617), the differences in the frequencies of the GG genotype and the G allele in the control sample and in the sample of patients with calcium oxalate urolithiasis were significant: p=0.0004 and p=0.001, respectively. No statistically significant differences in the genotype and allele frequencies were found in the remaining seven gene polymorphisms. CONCLUSIONS: Healthy individuals and patients with urolithiasis in the Russian population who have the GG genotype and/or the G allele of the polymorphism of the ORAI1 gene (rs7135617) represent risk groups for the formation of calcium oxalate stones.
[Mh] Termos MeSH primário: Nefrolitíase/diagnóstico
Nefrolitíase/genética
Proteína ORAI1/genética
[Mh] Termos MeSH secundário: Adulto
Alelos
Diagnóstico Precoce
Feminino
Glucuronidase/genética
Seres Humanos
Masculino
Meia-Idade
Nefrolitíase/epidemiologia
Osteoprotegerina/genética
Polimorfismo Genético
Reação em Cadeia da Polimerase em Tempo Real
Receptores de Calcitriol/genética
Receptores de Detecção de Cálcio/genética
Fatores de Risco
Federação Russa/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ORAI1 Protein); 0 (ORAI1 protein, human); 0 (Osteoprotegerin); 0 (Receptors, Calcitriol); 0 (Receptors, Calcium-Sensing); 0 (TNFRSF11B protein, human); 0 (VDR protein, human); EC 3.2.1.31 (Glucuronidase); EC 3.2.1.31 (klotho protein)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28704809
[Au] Autor:Stagno MJ; Zacharopoulou N; Bochem J; Tsapara A; Pelzl L; Al-Maghout T; Kallergi G; Alkahtani S; Alevizopoulos K; Dimas K; Calogeropoulou T; Warmann SW; Lang F; Schmid E; Stournaras C
[Ad] Endereço:Department of Pediatric Surgery & Pediatric Urology, Children's Hospital, Eberhard-Karls-University Tuebingen, Tuebingen, Germany.
[Ti] Título:Istaroxime Inhibits Motility and Down-Regulates Orai1 Expression, SOCE and FAK Phosphorylation in Prostate Cancer Cells.
[So] Source:Cell Physiol Biochem;42(4):1366-1376, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Istaroxime is a validated inotropic Na+/K+ ATPase inhibitor currently in development for the treatment of various cardiac conditions. Recent findings established that this steroidal drug exhibits potent apoptotic responses in prostate tumors in vitro and in vivo, by affecting key signaling orchestrating proliferation and apoptosis, such as c-Myc and caspase 3, Rho GTPases and actin cytoskeleton dynamics. In the present study we examined whether istaroxime is affecting cell motility and analyzed the underlying mechanism in prostate tumor cells. METHODS: Migration was assessed by transwell and wound healing assays, Orai1 and Stim1 abundance by RT-PCR and confocal immunofluorescence microscopy, Fura-2 fluorescence was utilized to determine intracellular Ca2+ and Western blotting for FAK/pFAK measurements. RESULTS: We observed strong inhibition of cell migration in istaroxime treated DU-145 prostate cancer cells. Istaroxime further decreased Orai1 and Stim1 transcript levels and downregulated Orai1 protein expression. Moreover, SOCE was significantly decreased upon istaroxime treatment. Furthermore, istaroxime strikingly diminished phosphorylated FAK levels. Interestingly, the efficacy of istaroxime on the inhibition of DU-145 cell migration was further enhanced by blocking Orai1 with 2-APB and FAK with the specific inhibitor PF-00562271. These results provide strong evidence that istaroxime prevents cell migration and motility of DU-145 prostate tumor cells, an effect at least partially attributed to Orai1 downregulation and FAK de-activation. CONCLUSION: Collectively our results indicate that this enzyme inhibitor, besides its pro-apoptotic action, affects motility of cancer cells, supporting its potential role as a strong candidate for further clinical cancer drug development.
[Mh] Termos MeSH primário: Movimento Celular/efeitos dos fármacos
Células Epiteliais/efeitos dos fármacos
Etiocolanolona/análogos & derivados
Quinase 1 de Adesão Focal/genética
Regulação Neoplásica da Expressão Gênica
Proteína ORAI1/genética
Bloqueadores dos Canais de Sódio/farmacologia
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Canais de Cálcio/genética
Canais de Cálcio/metabolismo
Linhagem Celular Tumoral
Células Epiteliais/metabolismo
Células Epiteliais/patologia
Etiocolanolona/farmacologia
Corantes Fluorescentes/química
Quinase 1 de Adesão Focal/antagonistas & inibidores
Quinase 1 de Adesão Focal/metabolismo
Fura-2/química
Seres Humanos
Masculino
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Proteína ORAI1/antagonistas & inibidores
Proteína ORAI1/metabolismo
Fosforilação/efeitos dos fármacos
Próstata/efeitos dos fármacos
Próstata/metabolismo
Próstata/patologia
Inibidores de Proteínas Quinases/farmacologia
Pirimidinas/farmacologia
Transdução de Sinais
Molécula 1 de Interação Estromal/antagonistas & inibidores
Molécula 1 de Interação Estromal/genética
Molécula 1 de Interação Estromal/metabolismo
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels); 0 (Fluorescent Dyes); 0 (Neoplasm Proteins); 0 (ORAI1 Protein); 0 (ORAI1 protein, human); 0 (PF-00562271); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (STIM1 protein, human); 0 (Sodium Channel Blockers); 0 (Stromal Interaction Molecule 1); 0 (Sulfonamides); 97CGB1M48I (Etiocholanolone); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (PTK2 protein, human); SY7Q814VUP (Calcium); TSN3DL106G (Fura-2); W8I9H2TPPL (Istaroxime)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1159/000479200


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[PMID]:28637791
[Au] Autor:Chaudhari S; Li W; Wang Y; Jiang H; Ma Y; Davis ME; Zuckerman JE; Ma R
[Ad] Endereço:Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, Texas.
[Ti] Título:Store-operated calcium entry suppressed the TGF-ß1/Smad3 signaling pathway in glomerular mesangial cells.
[So] Source:Am J Physiol Renal Physiol;313(3):F729-F739, 2017 Sep 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-ß1 (TGF-ß1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-ß1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-ß1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La ; 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca channels, significantly augmented TGF-ß1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-ß1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-ß1/Smad3 signaling pathway.
[Mh] Termos MeSH primário: Sinalização do Cálcio
Células Mesangiais/efeitos dos fármacos
Proteína ORAI1/metabolismo
Proteína Smad3/metabolismo
Fator de Crescimento Transformador beta1/farmacologia
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Animais
Bloqueadores dos Canais de Cálcio/farmacologia
Células Cultivadas
Colágeno Tipo IV/metabolismo
Inibidores Enzimáticos/farmacologia
Fibronectinas/metabolismo
Seres Humanos
Masculino
Células Mesangiais/metabolismo
Camundongos Endogâmicos C57BL
Proteína ORAI1/antagonistas & inibidores
Proteína ORAI1/genética
Fosforilação
Interferência de RNA
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Collagen Type IV); 0 (Enzyme Inhibitors); 0 (Fibronectins); 0 (ORAI1 Protein); 0 (ORAI1 protein, human); 0 (Orai1 protein, mouse); 0 (SMAD3 protein, human); 0 (Smad3 Protein); 0 (Smad3 protein, mouse); 0 (TGFB1 protein, human); 0 (Transforming Growth Factor beta1); EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00483.2016


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[PMID]:28634110
[Au] Autor:Zeng M; Szymczak M; Ahuja M; Zheng C; Yin H; Swaim W; Chiorini JA; Bridges RJ; Muallem S
[Ad] Endereço:Molecular Physiology and Therapeutics Branch, National Institutes of Health, National Institute of Dental and Craniofacial Research, Bethesda, Maryland; North Sichuan Medical College, Sichuan, China.
[Ti] Título:Restoration of CFTR Activity in Ducts Rescues Acinar Cell Function and Reduces Inflammation in Pancreatic and Salivary Glands of Mice.
[So] Source:Gastroenterology;153(4):1148-1159, 2017 Oct.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Sjögren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl channel essential for ductal fluid and HCO secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function? METHODS: We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini. RESULTS: In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR. CONCLUSIONS: Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren's syndrome and pancreatitis.
[Mh] Termos MeSH primário: Células Acinares/efeitos dos fármacos
Aminofenóis/farmacologia
Doenças Autoimunes/prevenção & controle
Agonistas dos Canais de Cloreto/farmacologia
Ciclopropanos/farmacologia
Regulador de Condutância Transmembrana em Fibrose Cística/agonistas
Terapia Genética
Pâncreas/efeitos dos fármacos
Pancreatite/prevenção & controle
Quinolonas/farmacologia
Glândulas Salivares/efeitos dos fármacos
Síndrome de Sjogren/prevenção & controle
[Mh] Termos MeSH secundário: Células Acinares/imunologia
Células Acinares/metabolismo
Células Acinares/patologia
Animais
Aquaporina 5/metabolismo
Doenças Autoimunes/imunologia
Doenças Autoimunes/metabolismo
Doenças Autoimunes/patologia
Proteína Morfogenética Óssea 6/genética
Proteína Morfogenética Óssea 6/metabolismo
Sinalização do Cálcio/efeitos dos fármacos
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo
Modelos Animais de Doenças
Feminino
Receptores de Inositol 1,4,5-Trifosfato/metabolismo
Camundongos Endogâmicos MRL lpr
Camundongos Endogâmicos NOD
Proteína ORAI1/metabolismo
Pâncreas/imunologia
Pâncreas/metabolismo
Pâncreas/patologia
Pancreatite/imunologia
Pancreatite/metabolismo
Pancreatite/patologia
Recuperação de Função Fisiológica
Glândulas Salivares/imunologia
Glândulas Salivares/metabolismo
Glândulas Salivares/patologia
Salivação/efeitos dos fármacos
Síndrome de Sjogren/imunologia
Síndrome de Sjogren/metabolismo
Síndrome de Sjogren/patologia
Fatores de Tempo
Técnicas de Cultura de Tecidos
Transdução Genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminophenols); 0 (Aqp5 protein, mouse); 0 (Aquaporin 5); 0 (Bone Morphogenetic Protein 6); 0 (Chloride Channel Agonists); 0 (Cyclopropanes); 0 (Inositol 1,4,5-Trisphosphate Receptors); 0 (ORAI1 Protein); 0 (Orai1 protein, mouse); 0 (Quinolones); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 1Y740ILL1Z (ivacaftor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE


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[PMID]:28600435
[Au] Autor:Chen YJ; Chang CL; Lee WR; Liou J
[Ad] Endereço:Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX.
[Ti] Título:RASSF4 controls SOCE and ER-PM junctions through regulation of PI(4,5)P .
[So] Source:J Cell Biol;216(7):2011-2025, 2017 Jul 03.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RAS association domain family 4 (RASSF4) is involved in tumorigenesis and regulation of the Hippo pathway. In this study, we identify new functional roles of RASSF4. First, we discovered that RASSF4 regulates store-operated Ca entry (SOCE), a fundamental Ca signaling mechanism, by affecting the translocation of the endoplasmic reticulum (ER) Ca sensor stromal interaction molecule 1 (STIM1) to ER-plasma membrane (PM) junctions. It was further revealed that RASSF4 regulates the formation of ER-PM junctions and the ER-PM tethering function of extended synaptotagmins E-Syt2 and E-Syt3. Moreover, steady-state PM phosphatidylinositol 4,5-bisphosphate (PI[4,5]P ) levels, important for localization of STIM1 and E-Syts at ER-PM junctions, were reduced in -knockdown cells. Furthermore, we demonstrated that RASSF4 interacts with and regulates the activity of adenosine diphosphate ribosylation factor 6 (ARF6), a small G protein and upstream regulator of type I phosphatidylinositol phosphate kinases (PIP5Ks) and PM PI(4,5)P levels. Overall, our study suggests that RASSF4 controls SOCE and ER-PM junctions through ARF6-dependent regulation of PM PI(4,5)P levels, pivotal for a variety of physiological processes.
[Mh] Termos MeSH primário: Sinalização do Cálcio
Membrana Celular/metabolismo
Retículo Endoplasmático/metabolismo
Proteínas de Neoplasias/metabolismo
Proteína ORAI1/metabolismo
Fosfatidilinositol 4,5-Difosfato/metabolismo
Molécula 1 de Interação Estromal/metabolismo
Proteínas Supressoras de Tumor/metabolismo
[Mh] Termos MeSH secundário: Fatores de Ribosilação do ADP/genética
Fatores de Ribosilação do ADP/metabolismo
Feminino
Células HeLa
Seres Humanos
Microscopia de Fluorescência
Microscopia de Vídeo
Proteínas de Neoplasias/genética
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Transporte Proteico
Interferência de RNA
Molécula 1 de Interação Estromal/genética
Sinaptotagmina II/genética
Sinaptotagmina II/metabolismo
Sinaptotagminas/genética
Sinaptotagminas/metabolismo
Fatores de Tempo
Imagem com Lapso de Tempo
Transfecção
Proteínas Supressoras de Tumor/genética
Neoplasias do Colo do Útero/genética
Neoplasias do Colo do Útero/metabolismo
Neoplasias do Colo do Útero/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (ORAI1 Protein); 0 (ORAI1 protein, human); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (RASSF4 protein, human); 0 (STIM1 protein, human); 0 (SYT2 protein, human); 0 (SYT3 protein, human); 0 (Stromal Interaction Molecule 1); 0 (Synaptotagmin II); 0 (Tumor Suppressor Proteins); 134193-27-4 (Synaptotagmins); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.68 (1-phosphatidylinositol-4-phosphate 5-kinase); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ADP-ribosylation factor 6)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170611
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201606047


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[PMID]:28446591
[Au] Autor:Sahu I; Pelzl L; Sukkar B; Fakhri H; Al-Maghout T; Cao H; Hauser S; Gutti R; Gawaz M; Lang F
[Ad] Endereço:Department of Cardiology and Vascular Medicine and Physiology, University of Tübingen, Tübingen, Germany.
[Ti] Título:NFAT5-sensitive Orai1 expression and store-operated Ca entry in megakaryocytes.
[So] Source:FASEB J;31(8):3439-3448, 2017 Aug.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The transcription factor nuclear factor of activated T cells 5 (NFAT5) is up-regulated in several clinical disorders, including dehydration. NFAT5-sensitive genes include serum and glucocorticoid-inducible kinase 1 (SGK1). The kinase is a powerful regulator of Orai1, a Ca channel accomplishing store-operated Ca entry (SOCE). Orai1 is stimulated after intracellular store depletion by the Ca sensors stromal interaction molecule 1 (STIM1), or STIM2, or both. In the present study, we explored whether nuclear factor of activated T cell (NFAT)-5 influences Ca signaling in megakaryocytes. To this end, human megakaryocytic (MEG-01) cells were transfected with NFAT5 or with siNFAT5. Platelets and megakaryocytes were isolated from wild-type mice with either access to water or dehydration by 36 h of water deprivation. Transcript levels were determined with quantitative RT-PCR and protein abundance by Western blot analysis and flow cytometry, cytosolic (intracellular) Ca concentration ([Ca ] ) by fura-2-fluorescence. SOCE was estimated from the increase of [Ca ] following readdition of extracellular Ca after store depletion with thapsigargin (1 µM). Platelet degranulation was estimated from P-selectin abundance and integrin activation from α ß integrin abundance determined by flow cytometry. As a result, NFAT5 transfection or exposure to hypertonicity (+40 mM NaCl) of MEG-01 cells increased Orai1, Orai2, STIM1, and STIM2 transcript levels. Orai1 transcript levels were decreased by NFAT5 silencing. NFAT5 transfection and IκB inhibitor BMS 345541 (5 µM) increased SOCE, whereas NFAT5 silencing and SGK1 inhibitor GSK650394 (10 µM) decreased SOCE. In the mice, dehydration increased NFAT5 and Orai1 protein abundance in megakaryocytes and NFAT5, Orai1, and Orai2 abundance in platelets. Dehydration further augmented the degranulation and integrin activation by thrombin and collagen-related peptide. In summary, NFAT5 is a powerful regulator of Orai1-expression and SOCE in megakaryocytes.-Sahu, I., Pelzl, L., Sukkar, B., Fakhri, H., al-Maghout, T., Cao, H., Hauser, S., Gutti, R., Gawaz, M., Lang, F. NFAT5-sensitive Orai1 expression and store-operated Ca entry in megakaryocytes.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Megacariócitos/metabolismo
Proteína ORAI1/metabolismo
Proteína ORAI2/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Plaquetas
Linhagem Celular
Feminino
Regulação da Expressão Gênica/fisiologia
Seres Humanos
Masculino
Camundongos
Proteína ORAI1/genética
Proteína ORAI2/genética
Molécula 1 de Interação Estromal/genética
Molécula 1 de Interação Estromal/metabolismo
Molécula 2 de Interação Estromal/genética
Molécula 2 de Interação Estromal/metabolismo
Fatores de Transcrição/genética
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nfat5 protein, mouse); 0 (ORAI1 Protein); 0 (ORAI2 Protein); 0 (Orai1 protein, mouse); 0 (Orai2 protein, mouse); 0 (Stim1 protein, mouse); 0 (Stim2 protein, mouse); 0 (Stromal Interaction Molecule 1); 0 (Stromal Interaction Molecule 2); 0 (Transcription Factors); SY7Q814VUP (Calcium)
[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:170428
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601211R


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[PMID]:28325835
[Au] Autor:Rubaiy HN; Ludlow MJ; Henrot M; Gaunt HJ; Miteva K; Cheung SY; Tanahashi Y; Hamzah N; Musialowski KE; Blythe NM; Appleby HL; Bailey MA; McKeown L; Taylor R; Foster R; Waldmann H; Nussbaumer P; Christmann M; Bon RS; Muraki K; Beech DJ
[Ad] Endereço:From the Schools of Medicine and.
[Ti] Título:Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels.
[So] Source:J Biol Chem;292(20):8158-8173, 2017 May 19.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The concentration of free cytosolic Ca and the voltage across the plasma membrane are major determinants of cell function. Ca -permeable non-selective cationic channels are known to regulate these parameters, but understanding of these channels remains inadequate. Here we focus on transient receptor potential canonical 4 and 5 proteins (TRPC4 and TRPC5), which assemble as homomers or heteromerize with TRPC1 to form Ca -permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested, including in epilepsy, innate fear, pain, and cardiac remodeling, but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools that are high-quality, reliable, easy to use, and readily accessible for all investigators. Here, through chemical synthesis and studies of native and overexpressed channels by Ca and patch-clamp assays, we describe compound 31, a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pm, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8, and store-operated Ca entry mediated by Orai1. These findings suggest identification of an important experimental tool compound, which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.
[Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/química
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cátion TRPC/antagonistas & inibidores
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Células HEK293
Seres Humanos
Proteína ORAI1/antagonistas & inibidores
Proteína ORAI1/genética
Proteína ORAI1/metabolismo
Canais de Cátion TRPC/genética
Canais de Cátion TRPC/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (ORAI1 Protein); 0 (ORAI1 protein, human); 0 (TRPC Cation Channels); 0 (TRPC4 ion channel); 0 (TRPC5 protein, human); 0 (transient receptor potential cation channel, subfamily C, member 1); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170608
[Lr] Data última revisão:
170608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.773556


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[PMID]:28301744
[Au] Autor:Saheki Y; De Camilli P
[Ad] Endereço:Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore; email: yasunori.saheki@ntu.edu.sg.
[Ti] Título:Endoplasmic Reticulum-Plasma Membrane Contact Sites.
[So] Source:Annu Rev Biochem;86:659-684, 2017 Jun 20.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The endoplasmic reticulum (ER) has a broad localization throughout the cell and forms direct physical contacts with all other classes of membranous organelles, including the plasma membrane (PM). A number of protein tethers that mediate these contacts have been identified, and study of these protein tethers has revealed a multiplicity of roles in cell physiology, including regulation of intracellular Ca dynamics and signaling as well as control of lipid traffic and homeostasis. In this review, we discuss the cross talk between the ER and the PM mediated by direct contacts. We review factors that tether the two membranes, their properties, and their dynamics in response to the functional state of the cell. We focus in particular on the role of ER-PM contacts in nonvesicular lipid transport between the two bilayers mediated by lipid transfer proteins.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Proteínas de Transporte/metabolismo
Membrana Celular/metabolismo
Retículo Endoplasmático/metabolismo
Proteínas de Membrana/metabolismo
Proteína ORAI1/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico
Sinalização do Cálcio
Proteínas de Transporte/genética
Membrana Celular/ultraestrutura
Retículo Endoplasmático/ultraestrutura
Células Eucarióticas/metabolismo
Células Eucarióticas/ultraestrutura
Expressão Gênica
Homeostase
Seres Humanos
Proteínas de Membrana/genética
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Proteína ORAI1/genética
Receptores de Esteroides/genética
Receptores de Esteroides/metabolismo
Molécula 1 de Interação Estromal/genética
Molécula 1 de Interação Estromal/metabolismo
Sinaptotagminas/genética
Sinaptotagminas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Membrane Proteins); 0 (Neoplasm Proteins); 0 (ORAI1 Protein); 0 (Receptors, Steroid); 0 (STIM1 protein, human); 0 (Stromal Interaction Molecule 1); 0 (lipid transfer protein); 0 (oxysterol binding protein); 134193-27-4 (Synaptotagmins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-061516-044932



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