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[PMID]:28624579
[Au] Autor:Nano J; Ghanbari M; Wang W; de Vries PS; Dhana K; Muka T; Uitterlinden AG; van Meurs JBJ; Hofman A; Franco OH; Pan Q; Murad SD; Dehghan A; BIOS consortium
[Ad] Endereço:Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
[Ti] Título:Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis.
[So] Source:Gastroenterology;153(4):1096-1106.e2, 2017 Oct.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Epigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis. METHODS: We conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non-overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs. RESULTS: Eight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 × 10 ). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 × 10 ). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism. CONCLUSIONS: Our results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagnostic and therapeutic applications.
[Mh] Termos MeSH primário: Alanina Transaminase/sangue
Sistema y+ de Transporte de Aminoácidos/genética
Aspartato Aminotransferases/sangue
Metilação de DNA
Epigênese Genética
Fígado Gorduroso/genética
Metabolismo dos Lipídeos/genética
gama-Glutamiltransferase/sangue
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Sistema ASC de Transporte de Aminoácidos/genética
Sistema ASC de Transporte de Aminoácidos/metabolismo
Sistema y+ de Transporte de Aminoácidos/metabolismo
Sistema y+L de Transporte de Aminoácidos/genética
Sistema y+L de Transporte de Aminoácidos/metabolismo
Biomarcadores/sangue
Linhagem Celular Tumoral
Ilhas de CpG
Fígado Gorduroso/sangue
Fígado Gorduroso/enzimologia
Fígado Gorduroso/prevenção & controle
Feminino
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Análise da Randomização Mendeliana
Meia-Idade
Antígenos de Histocompatibilidade Menor/genética
Antígenos de Histocompatibilidade Menor/metabolismo
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Países Baixos
Razão de Chances
Fenótipo
Fosfoglicerato Desidrogenase/genética
Fosfoglicerato Desidrogenase/metabolismo
Fatores de Proteção
Interferência de RNA
Medição de Risco
Fatores de Risco
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Amino Acid Transport System y+); 0 (Amino Acid Transport System y+L); 0 (Biomarkers); 0 (Minor Histocompatibility Antigens); 0 (Neoplasm Proteins); 0 (SLC1A5 protein, human); 0 (SLC43A1 protein, human); 0 (SLC7A11 protein, human); EC 1.1.1.95 (Phosphoglycerate Dehydrogenase); EC 2.3.2.2 (gamma-Glutamyltransferase); EC 2.3.2.2 (gamma-glutamyltransferase, human); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase)
[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:170619
[St] Status:MEDLINE


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[PMID]:27780818
[Au] Autor:Jiang X; Zhang Y; Yang Y; Yang J; Asico LD; Chen W; Felder RA; Armando I; Jose PA; Yang Z
[Ad] Endereço:Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Centre, Peking Union Medical, Beijing, China.
[Ti] Título:Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA.
[So] Source:Am J Physiol Endocrinol Metab;312(1):E1-E10, 2017 Jan 01.
[Is] ISSN:1522-1555
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension.
[Mh] Termos MeSH primário: Pressão Sanguínea/efeitos dos fármacos
Dopamina/biossíntese
Gastrinas/farmacologia
Córtex Renal/efeitos dos fármacos
Túbulos Renais Proximais/efeitos dos fármacos
Levodopa/metabolismo
RNA Mensageiro/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sistema y+L de Transporte de Aminoácidos/efeitos dos fármacos
Sistema y+L de Transporte de Aminoácidos/metabolismo
Animais
Pressão Sanguínea/fisiologia
Células Cultivadas
Dopamina/urina
Regulação para Baixo
Gastrinas/genética
Gastrinas/metabolismo
Inativação Gênica
Seres Humanos
Immunoblotting
Rim/efeitos dos fármacos
Rim/metabolismo
Córtex Renal/metabolismo
Túbulos Renais Proximais/citologia
Túbulos Renais Proximais/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
RNA Mensageiro/metabolismo
RNA Interferente Pequeno
Reação em Cadeia da Polimerase em Tempo Real
Receptor de Colecistocinina B/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (Gastrins); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Receptor, Cholecystokinin B); 46627O600J (Levodopa); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE
[do] DOI:10.1152/ajpendo.00116.2016


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[PMID]:26201052
[Au] Autor:Yamane S; Nomura R; Yanagihara M; Nakamura H; Fujino H; Matsumoto K; Horie S; Murayama T
[Ad] Endereço:Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan.
[Ti] Título:L-Cysteine/D,L-homocysteine-regulated ileum motility via system L and B°(,+) transporter: Modification by inhibitors of hydrogen sulfide synthesis and dietary treatments.
[So] Source:Eur J Pharmacol;764:471-9, 2015 Oct 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Previous studies including ours demonstrated that L-cysteine treatments decreased motility in gastrointestinal tissues including the ileum via hydrogen sulfide (H2S), which is formed from sulfur-containing amino acids such as L-cysteine and L-homocysteine. However, the amino acid transport systems involved in L-cysteine/L-homocysteine-induced responses have not yet been elucidated in detail; therefore, we investigated these systems pharmacologically by measuring electrical stimulation (ES)-induced contractions with amino acids in mouse ileum preparations. The treatments with L-cysteine and D,L-homocysteine inhibited ES-induced contractions in ileum preparations from fasted mice, and these responses were decreased by the treatment with 2-aminobicyclo[2.2.1]heptane-2-carboxylate (BCH), an inhibitor of systems L and B°(,+). The results obtained using ileum preparations and a model cell line (PC12 cells) with various amino acids and BCH showed that not only L-cysteine, but also aminooxyacetic acid and D,L-propargylglycine, which act as H2S synthesis inhibitors, appeared to be taken up by these preparations/cells in L and B°(,+) system-dependent manners. The L-cysteine and D,L-homocysteine responses were delayed and abolished, respectively, in ileum preparations from fed mice. Our results suggested that the regulation of ileum motility by L-cysteine and D,L-homocysteine was dependent on BCH-sensitive systems, and varied depending on feeding in mice. Therefore, the effects of aminooxyacetic acid and D,L-propargylglycine on transport systems need to be considered in pharmacological analyses.
[Mh] Termos MeSH primário: Sistema y+L de Transporte de Aminoácidos/metabolismo
Sistemas de Transporte de Aminoácidos Neutros/metabolismo
Cisteína/farmacologia
Ingestão de Alimentos
Jejum
Motilidade Gastrointestinal/efeitos dos fármacos
Homocisteína/farmacologia
Sulfeto de Hidrogênio/metabolismo
Íleo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sistema y+L de Transporte de Aminoácidos/antagonistas & inibidores
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores
Aminoácidos Cíclicos/farmacologia
Animais
Cisteína/metabolismo
Dieta
Estimulação Elétrica
Íleo/inervação
Íleo/metabolismo
Técnicas In Vitro
Masculino
Camundongos
Células PC12
Período Pós-Prandial
Ratos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (Amino Acid Transport Systems, Neutral); 0 (Amino Acids, Cyclic); 0LVT1QZ0BA (Homocysteine); 20448-79-7 (2-aminobicyclo(2,2,1)heptane-2-carboxylic acid); K848JZ4886 (Cysteine); YY9FVM7NSN (Hydrogen Sulfide)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151009
[Lr] Data última revisão:
151009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150723
[St] Status:MEDLINE


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[PMID]:26054677
[Au] Autor:Wang J; Chen X; Su L; Li P; Cai Q; Liu B; Wu W; Zhu Z
[Ad] Endereço:Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197, Rui Jin Er Road, Shanghai 20025, People's Republic of China; Shanghai Key Laboratory of Gastric Neoplasms, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197, Rui Jin Er Road, Shangha
[Ti] Título:MicroRNA-126 inhibits cell proliferation in gastric cancer by targeting LAT-1.
[So] Source:Biomed Pharmacother;72:66-73, 2015 May.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:MicroRNA-126 (miR-126) is a pivotal post-transcriptional regulator, which has been validated as a suppressor in gastric cancer (GC). However, the downstream of its tumor inhibiting function has not been totally clear. L-type amino-acid transporter 1 (LAT-1) is a novel member of system L-type transporters involving in cell proliferation, and we have previously validated that LAT-1 played a role of promotor in GC. In this study, we further detected and confirmed that LAT-1 was exactly targeted by miR-126 in GC. We found LAT-1 was significantly downregulated in GC MKN-45 cell lines by using miR-126 mimics, along with an impairment on cell proliferation and cell cycle. Additionally, by overexpressing LAT-1 in MKN-45 cells which was firstly treated with miR-126 mimics, the ability of cell proliferation in MKN-45 cells was definitely rescued. Thus, our results suggests and consolidates the standpoint that miR-126 plays a pivotal role in GC suppressing the process of GC cell, and this function is at least partly taken to implement by miR-126s's post-transcriptional effect on LAT-1. This might provide us likely potential biomarkers and targets for GC prevention, diagnosis and therapeutic treatment.
[Mh] Termos MeSH primário: Sistema y+L de Transporte de Aminoácidos/genética
Transportador 1 de Aminoácidos Neutros Grandes/genética
MicroRNAs/metabolismo
Neoplasias Gástricas/genética
Neoplasias Gástricas/patologia
[Mh] Termos MeSH secundário: Sistema y+L de Transporte de Aminoácidos/metabolismo
Sequência de Bases
Pontos de Checagem do Ciclo Celular/genética
Linhagem Celular Tumoral
Proliferação Celular
Regulação Neoplásica da Expressão Gênica
Genes Reporter
Seres Humanos
Transportador 1 de Aminoácidos Neutros Grandes/metabolismo
Luciferases/metabolismo
MicroRNAs/genética
Dados de Sequência Molecular
Fenótipo
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (Large Neutral Amino Acid-Transporter 1); 0 (MIRN126 microRNA, human); 0 (MicroRNAs); EC 1.13.12.- (Luciferases)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150609
[Lr] Data última revisão:
150609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150610
[St] Status:MEDLINE


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[PMID]:25959825
[Au] Autor:Rossi F; Casano AM; Henke K; Richter K; Peri F
[Ad] Endereço:Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidbelberg, Germany.
[Ti] Título:The SLC7A7 Transporter Identifies Microglial Precursors prior to Entry into the Brain.
[So] Source:Cell Rep;11(7):1008-17, 2015 May 19.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During development, macrophages invade organs to establish phenotypically and transcriptionally distinct tissue-resident populations. How they invade and colonize these organs is unclear. In particular, it remains to be established whether they arise from naive equivalents that colonize organs randomly or whether there are committed macrophages that follow pre-determined migration paths. Here, by using a combination of genetics and imaging approaches in the zebrafish embryo, we have addressed how macrophages colonize the brain to become microglia. Identification and cloning of a mutant that lacks microglia has shown that Slc7a7, a Leucine/Arginine transporter, defines a restricted macrophage sub-lineage and is necessary for brain colonization. By taking a photoconversion approach, we show that these macrophages give rise to microglia. This study provides direct experimental evidence for the existence of sub-lineages among embryonic macrophages.
[Mh] Termos MeSH primário: Sistema y+L de Transporte de Aminoácidos/metabolismo
Encéfalo/embriologia
Macrófagos/citologia
Microglia/citologia
Células-Tronco Neurais/citologia
Proteínas de Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Diferenciação Celular/fisiologia
Embrião não Mamífero
Hibridização In Situ
Macrófagos/metabolismo
Microglia/metabolismo
Células-Tronco Neurais/metabolismo
Neurogênese/fisiologia
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (SLC7A7 protein, zebrafish); 0 (Zebrafish Proteins)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150521
[Lr] Data última revisão:
150521
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150512
[St] Status:MEDLINE


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[PMID]:25455457
[Au] Autor:Silva R; Carmo H; Vilas-Boas V; Barbosa DJ; Monteiro M; de Pinho PG; de Lourdes Bastos M; Remião F
[Ad] Endereço:REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, Porto 4050-313, Portugal. Electronic address: rsilva@ff.up.pt.
[Ti] Título:Several transport systems contribute to the intestinal uptake of Paraquat, modulating its cytotoxic effects.
[So] Source:Toxicol Lett;232(1):271-83, 2015 Jan 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Paraquat (PQ) is an extremely toxic herbicide upon oral ingestion that lacks a specific antidote. In case of intoxication, treatment primarily relies on limiting its intestinal absorption. In this study, we elucidate the intestinal transport mechanisms of PQ uptake using Caco-2 cells as a model of the human intestinal epithelium. The cells were incubated with a wide range of PQ concentrations (0-5000µM) for 24h with or without simultaneous exposure to different transporters substrates/inhibitors including, choline or hemicolinium-3 (for choline carrier-mediated transport system inhibition) and putrescine, trifluoperazine, valine, lysine, arginine or N-ethylmaleimide (for basic amino acid transport systems inhibition). PQ cytotoxicity was evaluated by the MTT reduction assay and correlated with PQ intracellular levels quantified by gas chromatography-ion trap-mass spectrometry (GC-IT/MS). Potential interactions of PQ with the substrates/inhibitors of the transport systems were investigated and discarded by infrared spectroscopy. Our results showed a significant reduction in PQ intracellular accumulation and, consequently, in PQ cytotoxicity, in the presence of both choline and hemicolinium-3, demonstrating that the choline carrier-mediated transport system is partially involved in PQ intestinal uptake. Likewise, PQ cytotoxicity and intracellular accumulation were significantly attenuated by simultaneous exposure to putrescine, trifluoperazine, valine, lysine, arginine and N-ethylmaleimide. These data suggested the involvement of more than one of the basic amino acids transport systems, including the y(+), b(0,+) or y(+)L systems. In conclusion, this study demonstrated that several transport systems mediate PQ intestinal absorption and, therefore, their modulation may provide alternative efficient pathways for limiting PQ toxicity in intoxication scenarios.
[Mh] Termos MeSH primário: Herbicidas/metabolismo
Absorção Intestinal
Mucosa Intestinal/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Paraquat/metabolismo
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Sistema y+ de Transporte de Aminoácidos/metabolismo
Sistema y+L de Transporte de Aminoácidos/metabolismo
Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Cromatografia Gasosa-Espectrometria de Massas
Herbicidas/toxicidade
Seres Humanos
Mucosa Intestinal/efeitos dos fármacos
Mucosa Intestinal/patologia
Cinética
Moduladores de Transporte de Membrana/farmacologia
Proteínas de Membrana Transportadoras/efeitos dos fármacos
Antígenos de Histocompatibilidade Menor/metabolismo
Paraquat/toxicidade
Espectrofotometria Infravermelho
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Amino Acid Transport System y+); 0 (Amino Acid Transport System y+L); 0 (Herbicides); 0 (Membrane Transport Modulators); 0 (Membrane Transport Proteins); 0 (Minor Histocompatibility Antigens); 0 (SLC1A5 protein, human); 0 (choline transporter); PLG39H7695 (Paraquat)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


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[PMID]:25454221
[Au] Autor:Kharlyngdoh JB; Pradhan A; Asnake S; Walstad A; Ivarsson P; Olsson PE
[Ad] Endereço:Biology, Örebro Life Science Center, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
[Ti] Título:Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters.
[So] Source:Environ Int;74:60-70, 2015 Jan.
[Is] ISSN:1873-6750
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5α-reductases and ß-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Andrógenos/farmacologia
Retardadores de Chama/farmacologia
Hidrocarbonetos Bromados/farmacologia
[Mh] Termos MeSH secundário: Sistema y+L de Transporte de Aminoácidos/biossíntese
Sistema y+L de Transporte de Aminoácidos/genética
Antagonistas de Receptores de Andrógenos/química
Antagonistas de Receptores de Andrógenos/metabolismo
Barreira Hematoencefálica/metabolismo
Linhagem Celular Tumoral
Disruptores Endócrinos/química
Retardadores de Chama/metabolismo
Seres Humanos
Hidrocarbonetos Bromados/química
Hidrocarbonetos Bromados/metabolismo
Masculino
Simulação de Acoplamento Molecular
Antígeno Prostático Específico/genética
Neoplasias da Próstata/genética
Neoplasias da Próstata/metabolismo
Receptores Androgênicos/química
Receptores Androgênicos/metabolismo
Ativação Transcricional/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2,3-dibromopropyl-2,4,6-tribromophenyl ether); 0 (AR protein, human); 0 (Amino Acid Transport System y+L); 0 (Androgen Receptor Antagonists); 0 (Endocrine Disruptors); 0 (Flame Retardants); 0 (Hydrocarbons, Brominated); 0 (Receptors, Androgen); EC 3.4.21.77 (Prostate-Specific Antigen)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:141203
[Lr] Data última revisão:
141203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


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[PMID]:25305508
[Au] Autor:Rautio J; Kärkkäinen J; Huttunen KM; Gynther M
[Ad] Endereço:School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: jarkko.rautio@uef.fi.
[Ti] Título:Amino acid ester prodrugs conjugated to the α-carboxylic acid group do not display affinity for the L-type amino acid transporter 1 (LAT1).
[So] Source:Eur J Pharm Sci;66:36-40, 2015 Jan 23.
[Is] ISSN:1879-0720
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:L-type amino acid transporter (LAT1) is an intriguing target for carrier-mediated transport of drugs as it is highly expressed in the blood-brain barrier and also in various types of cancer. Several studies have proposed that in order for compounds to act as LAT1 substrates they should possess both negatively charged α-carboxyl and positively charged α-amino groups. However, in some reports, such as in two recent publications describing an isoleucine-quinidine ester prodrug (1), compounds having no free α-carboxyl group have been reported to exhibit high affinity for LAT1 in vitro. In the present study, 1 was synthesized and its affinity for LAT1 was evaluated both with an in situ rat brain perfusion technique and in the human breast cancer cell line MCF-7 in vitro. 1 showed no affinity for LAT1 in either model nor did it show any affinity for LAT2 in an in vitro study. Our results confirm the earlier reported requirements for LAT1 substrates. Thus drugs or prodrugs with substituted α-carboxyl group cannot bind to LAT with high affinity.
[Mh] Termos MeSH primário: Sistema y+L de Transporte de Aminoácidos/metabolismo
Aminoácidos/química
Isoleucina/química
Transportador 1 de Aminoácidos Neutros Grandes/química
Quinidina/química
[Mh] Termos MeSH secundário: Sistema y+L de Transporte de Aminoácidos/química
Animais
Transporte Biológico
Encéfalo/metabolismo
Desenho de Drogas
Ésteres
Seres Humanos
Isoleucina/metabolismo
Transportador 1 de Aminoácidos Neutros Grandes/metabolismo
Células MCF-7
Masculino
Pró-Fármacos
Ligação Proteica
Quinidina/metabolismo
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (Amino Acids); 0 (Esters); 0 (Large Neutral Amino Acid-Transporter 1); 0 (Prodrugs); 04Y7590D77 (Isoleucine); ITX08688JL (Quinidine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170313
[Lr] Data última revisão:
170313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141012
[St] Status:MEDLINE


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[PMID]:23817987
[Au] Autor:Yang J; Tan Q; Zhu W; Chen C; Liang X; Pan L
[Ad] Endereço:Fisheries College, Huazhong Agricultural University, Wuhan, 430070, China.
[Ti] Título:Cloning and molecular characterization of cationic amino acid transporter y⁺LAT1 in grass carp (Ctenopharyngodon idellus).
[So] Source:Fish Physiol Biochem;40(1):93-104, 2014 Feb.
[Is] ISSN:1573-5168
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The solute carrier family 7A, member 7 gene encodes the light chain- y⁺L amino acid transporter-1 (y⁺LAT1) of the heterodimeric carrier responsible for cationic amino acid (CAA) transport across the basolateral membranes of epithelial cells in intestine and kidney. Rising attention has been given to y⁺LAT1 involved in CAA metabolic pathways and growth control. The molecular characterization and function analysis of y⁺LAT1 in grass carp (Ctenopharyngodon idellus) is currently unknown. In the present study, full-length cDNA (2,688 bp), which encodes y⁺LAT1 and contains a 5'-untranslated region (319 bp), an open reading frame (1,506 bp) and a 3'-untranslated region (863 bp), has been cloned from grass carp. Amino acid sequence of grass carp y⁺LAT1 contains 11 transmembrane domains and shows 95 %, 80 % and 75 % sequence similarity to zebra fish, amphibian and mammalian y⁺LAT1, respectively. The tissue distribution and expression regulation by fasting of y⁺LAT1 mRNA were analyzed using real-time PCR. Our results showed that y⁺LAT1 mRNA was highly expressed in midgut, foregut and spleen while weakly expressed in hindgut, kidney, gill, brain, heart, liver and muscle. Nutritional status significantly influenced y⁺LAT1 mRNA expression in fish tissues, such as down-regulation of y⁺LAT1 mRNA expression after fasting (14 days).
[Mh] Termos MeSH primário: Sistema y+L de Transporte de Aminoácidos/metabolismo
Carpas/metabolismo
Proteínas de Peixes/metabolismo
Transportador 1 de Aminoácidos Neutros Grandes/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sistema y+L de Transporte de Aminoácidos/química
Sistema y+L de Transporte de Aminoácidos/genética
Animais
Sequência de Bases
Carpas/genética
Jejum/metabolismo
Proteínas de Peixes/química
Proteínas de Peixes/genética
Transportador 1 de Aminoácidos Neutros Grandes/química
Transportador 1 de Aminoácidos Neutros Grandes/genética
Dados de Sequência Molecular
Filogenia
Distribuição Aleatória
Reação em Cadeia da Polimerase em Tempo Real
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (Fish Proteins); 0 (Large Neutral Amino Acid-Transporter 1)
[Em] Mês de entrada:1410
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130703
[St] Status:MEDLINE
[do] DOI:10.1007/s10695-013-9827-1


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[PMID]:23345264
[Au] Autor:Gorelik J; Wright PT; Lyon AR; Harding SE
[Ad] Endereço:Department of Cardiovascular Medicine, National Heart and Lung Institute, Imperial College, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. j.gorelik@ic.ac.uk
[Ti] Título:Spatial control of the ßAR system in heart failure: the transverse tubule and beyond.
[So] Source:Cardiovasc Res;98(2):216-24, 2013 May 01.
[Is] ISSN:1755-3245
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The beta1-adrenoceptors (ß(1)AR) and beta-2 (ß(2)AR) adrenoceptors represent the predominant pathway for sympathetic control of myocardial function. Diverse mechanisms have evolved to translate signalling via these two molecules into differential effects on physiology. In this review, we discuss how the functions of the ßAR are organized from the level of secondary messengers to the whole heart to achieve this. Using novel microscopy and bio-imaging methods researchers have uncovered subtle organization of the control of cyclic adenosine monophosphate (cAMP), the predominant positively inotropic pathway for the ßAR. The ß(2)AR in particular is demonstrated to give rise to highly compartmentalized, spatially confined cAMP signals. Organization of ß(2)AR within the T-tubule and caveolae of cardiomyocytes concentrates this receptor with molecules which buffer and shape its cAMP signal to give fine control. This situation is undermined in various forms of heart failure. Human and animal models of heart failure demonstrate disruption of cellular micro-architecture which contributes to the change in response to cardiac ßARs. Loss of cellular structure has proved key to the observed loss of confined ß(2)AR signalling. Some pharmacological and genetic treatments have been successful in returning failing cells to a more structured phenotype. Within these cells it has been possible to observe the partial restoration of normal ß(2)AR signalling. At the level of the organ, the expression of the two ßAR subtypes varies between regions with the ß(2)AR forming a greater proportion of the ßAR population at the apex. This distribution may contribute to regional wall motion abnormalities in Takotsubo cardiomyopathy, a syndrome of high sympathetic activity, where the phosphorylated ß(2)AR can signal via Gi protein to produce negatively inotropic effects.
[Mh] Termos MeSH primário: Insuficiência Cardíaca/fisiopatologia
Miócitos Cardíacos/fisiologia
Receptores Adrenérgicos beta/fisiologia
Retículo Sarcoplasmático/fisiologia
[Mh] Termos MeSH secundário: Sistema y+L de Transporte de Aminoácidos/fisiologia
Animais
Cavéolas/fisiologia
AMP Cíclico/fisiologia
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia
Modelos Animais de Doenças
Seres Humanos
Contração Miocárdica
Proteínas de Neoplasias/fisiologia
Retículo Sarcoplasmático/ultraestrutura
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Amino Acid Transport System y+L); 0 (Neoplasm Proteins); 0 (Receptors, Adrenergic, beta); 0 (SLC43A1 protein, human); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1311
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130125
[St] Status:MEDLINE
[do] DOI:10.1093/cvr/cvt005



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