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Pesquisa : D12.776.157.530.450.250.812 [Categoria DeCS]
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[PMID]:29346429
[Au] Autor:Ferrigno A; Di Pasqua LG; Berardo C; Siciliano V; Rizzo V; Adorini L; Richelmi P; Vairetti M
[Ad] Endereço:Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
[Ti] Título:The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury.
[So] Source:PLoS One;13(1):e0191430, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
[Mh] Termos MeSH primário: Antiporters/metabolismo
Arginina/análogos & derivados
Sistema Biliar/efeitos dos fármacos
Ácido Quenodesoxicólico/análogos & derivados
Hepatopatias/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
Traumatismo por Reperfusão/metabolismo
Regulação para Cima/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Arginina/sangue
Arginina/metabolismo
Arginina/secreção
Sistema Biliar/metabolismo
Sistema Biliar/secreção
Western Blotting
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Ácido Quenodesoxicólico/farmacologia
Masculino
Óxido Nítrico Sintase/metabolismo
Proteína-Arginina N-Metiltransferases/genética
RNA Mensageiro/genética
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiporters); 0 (Carrier Proteins); 0 (MATE1 protein, rat); 0 (Organic Cation Transport Proteins); 0 (RNA, Messenger); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 0462Z4S4OZ (obeticholic acid); 0GEI24LG0J (Chenodeoxycholic Acid); 63CV1GEK3Y (N,N-dimethylarginine); 94ZLA3W45F (Arginine); EC 1.14.13.39 (Nitric Oxide Synthase); EC 2.1.1.319 (PRMT1 protein, rat); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191430


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[PMID]:29342199
[Au] Autor:Chung H; Oh J; Yoon SH; Yu KS; Cho JY; Chung JY
[Ad] Endereço:Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.
[Ti] Título:A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study.
[So] Source:PLoS One;13(1):e0191258, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. METHODS: A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. RESULTS: The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·µg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. CONCLUSIONS: This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. TRIAL REGISTRATION: ClinicalTrials.gov NCT02712619.
[Mh] Termos MeSH primário: Hipoglicemiantes/farmacologia
Hipoglicemiantes/farmacocinética
Metformina/farmacologia
Metformina/farmacocinética
[Mh] Termos MeSH secundário: Adulto
Glicemia/metabolismo
Relação Dose-Resposta a Droga
Teste de Tolerância a Glucose
Voluntários Saudáveis
Seres Humanos
Hipoglicemiantes/administração & dosagem
Masculino
Metformina/administração & dosagem
Modelos Biológicos
Dinâmica não Linear
Proteínas de Transporte de Cátions Orgânicos/genética
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Transportador 2 de Cátion Orgânico/genética
Transportador 2 de Cátion Orgânico/metabolismo
Variantes Farmacogenômicos
Polimorfismo de Nucleotídeo Único
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Hypoglycemic Agents); 0 (MATE1 protein, human); 0 (MATE2-K protein, human); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 9100L32L2N (Metformin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191258


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[PMID]:29318274
[Ti] Título:Lesinurad/Allopurinol (Duzallo) for Gout-Associated Hyperuricemia.
[So] Source:JAMA;319(2):188-189, 2018 01 09.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Alopurinol/administração & dosagem
Supressores da Gota/uso terapêutico
Gota/tratamento farmacológico
Hiperuricemia/tratamento farmacológico
Tioglicolatos/administração & dosagem
Tioglicolatos/uso terapêutico
Triazóis/administração & dosagem
[Mh] Termos MeSH secundário: Alopurinol/efeitos adversos
Alopurinol/uso terapêutico
Combinação de Medicamentos
Interações Medicamentosas
Gota/complicações
Supressores da Gota/efeitos adversos
Seres Humanos
Hiperuricemia/complicações
Transportadores de Ânions Orgânicos/antagonistas & inibidores
Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores
Tioglicolatos/efeitos adversos
Triazóis/efeitos adversos
Xantina Oxidase/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drug Combinations); 0 (Duzallo); 0 (Gout Suppressants); 0 (Organic Anion Transporters); 0 (Organic Cation Transport Proteins); 0 (SLC22A12 protein, human); 0 (Thioglycolates); 0 (Triazoles); 09ERP08I3W (lesinurad); 63CZ7GJN5I (Allopurinol); EC 1.17.3.2 (Xanthine Oxidase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180123
[Lr] Data última revisão:
180123
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.20189


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[PMID]:27777271
[Au] Autor:Lee HH; Leake BF; Kim RB; Ho RH
[Ad] Endereço:Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (H.H.L., B.F.L., R.H.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Can
[Ti] Título:Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance.
[So] Source:Mol Pharmacol;91(1):14-24, 2017 Jan.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2 mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.
[Mh] Termos MeSH primário: Doxorrubicina/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Transportadores de Ânions Orgânicos/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Animais
Transporte Biológico
Membrana Celular/metabolismo
Cães
Células HeLa
Seres Humanos
Cinética
Fígado/metabolismo
Células Madin Darby de Rim Canino
Masculino
Camundongos
Modelos Biológicos
Proteínas Mutantes/metabolismo
Ratos
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Mutant Proteins); 0 (Oatp1a1 protein, mouse); 0 (Organic Anion Transporters); 0 (Organic Anion Transporters, Sodium-Independent); 0 (Organic Cation Transport Proteins); 0 (SLCO1A2 protein, human); 0 (Slco1b2 protein, mouse); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:28864226
[Au] Autor:Saito Y; Okamoto K; Kobayashi M; Narumi K; Furugen A; Yamada T; Iseki K
[Ad] Endereço:Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo 060-8648, Japan.
[Ti] Título:Magnesium co-administration decreases cisplatin-induced nephrotoxicity in the multiple cisplatin administration.
[So] Source:Life Sci;189:18-22, 2017 Nov 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Pretreatment with magnesium (Mg) has been reported to attenuate cisplatin (CDDP)-induced nephrotoxicity (CIN). This attenuation involves modulation of the expression of renal transporters, resulting in reduced renal platinum accumulation after a single round of CDDP treatment. In this study, we investigated whether Mg co-administration ameliorates CIN after multiple doses of CDDP as effectively as after a single dose. METHODS: Rats were divided into control, Mg alone, CDDP alone, and CDDP with Mg groups. Rats received CDDP (2.5mg/kg), MgSO (40mg/kg), or saline once per week for three weeks. Seven days after the third round of treatment, the kidneys were excised, and the expression of renal transporters and renal platinum accumulation were analyzed. RESULTS: CDDP significantly elevated serum creatinine levels, which were significantly reduced by Mg co-administration. Renal platinum accumulation was significantly lower in the CDDP-Mg group than in the CDDP group. Expression of renal organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1), which are involved in CDDP transport, did not differ between the groups. However, the expression of copper transporter 1 (rCtr1) was significantly downregulated after Mg co-administration. CONCLUSION: Mg co-administration significantly attenuated CIN by reducing renal platinum accumulation even after multiple rounds of treatment with CDDP as effectively as in a model of a single CDDP administration. However, the specific underlying mechanism was different between single and multiple administrations, further studies will be needed to identify what contributes to this difference and to elucidate how Mg regulates the expression of renal transporters.
[Mh] Termos MeSH primário: Antineoplásicos/toxicidade
Cisplatino/toxicidade
Nefropatias/prevenção & controle
Sulfato de Magnésio/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Cisplatino/administração & dosagem
Creatinina/sangue
Nefropatias/induzido quimicamente
Sulfato de Magnésio/administração & dosagem
Masculino
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Transportador 2 de Cátion Orgânico
Platina/metabolismo
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (Slc22a2 protein, rat); 49DFR088MY (Platinum); 7487-88-9 (Magnesium Sulfate); AYI8EX34EU (Creatinine); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


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[PMID]:28844485
[Au] Autor:He Z; Xu B; Lee S; Ionita-Laza I
[Ad] Endereço:Department of Biostatistics, Columbia University, New York, NY 10032, USA.
[Ti] Título:Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data.
[So] Source:Am J Hum Genet;101(3):340-352, 2017 Sep 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease-associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. Here, we have developed unified tests that can utilize multiple functional annotations simultaneously for integrative association analysis with efficient computational techniques. We show that the proposed tests significantly improve power when variant risk status can be predicted by functional annotations. Importantly, when functional annotations are not predictive of risk status, the proposed tests incur only minimal loss of power in relation to existing dispersion and burden tests, and under certain circumstances they can even have improved power by learning a weight that better approximates the underlying disease model in a data-adaptive manner. The tests can be constructed with summary statistics of existing dispersion and burden tests for sequencing data, therefore allowing meta-analysis of multiple studies without sharing individual-level data. We applied the proposed tests to a meta-analysis of noncoding rare variants in Metabochip data on 12,281 individuals from eight studies for lipid traits. By incorporating the Eigen functional score, we detected significant associations between noncoding rare variants in SLC22A3 and low-density lipoprotein and total cholesterol, associations that are missed by standard dispersion and burden tests.
[Mh] Termos MeSH primário: Genoma Humano
Estudo de Associação Genômica Ampla/métodos
Metabolômica
Anotação de Sequência Molecular/métodos
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Doenças Cardiovasculares/genética
Doenças Cardiovasculares/metabolismo
Doenças Cardiovasculares/patologia
Simulação por Computador
Predisposição Genética para Doença
Seres Humanos
Lipídeos/análise
Proteínas de Transporte de Cátions Orgânicos/genética
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipids); 0 (Organic Cation Transport Proteins); 0 (solute carrier family 22 (organic cation transporter), member 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28811134
[Au] Autor:Pan X; Iyer KA; Liu H; Sweet DH; Dukat M
[Ad] Endereço:Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
[Ti] Título:A new chemotype inhibitor for the human organic cation transporter 3 (hOCT3).
[So] Source:Bioorg Med Chem Lett;27(18):4440-4445, 2017 09 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Human organic cation transporters (OCTs) represent an understudied neurotransmitter uptake mechanism for which no selective agents have yet been identified. Several neurotransmitters (e.g. serotonin, norepinephrine) are low-affinity substrates for these transporters, but possess higher affinity for other transporters (e.g. the serotonin or norepinephrine transporters; SERT and NET, respectively). We have identified a new class of OCT inhibitors with a phenylguanidine structural scaffold. Here, we examine the actions of a series of such compounds and report preliminary structure-activity relationships (SARs) - the first dedicated SAR study of OCT3 action. Initial results showed that the presence of a substituent on the phenyl ring, as well as its position, contributes to the phenylguanidines' inhibitory potency (IC values ranging from 2.2 to >450µM) at hOCT3. There is a trend towards enhanced inhibitory potency of phenylguanidines with increased lipophilic character and the size of the substituent at the phenyl 4-position, with the latter reaching a ceiling effect. The first PiPT-based hOCT3 homology models were generated and are in agreement with our biological data.
[Mh] Termos MeSH primário: Guanidinas/farmacologia
Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Guanidinas/síntese química
Guanidinas/química
Seres Humanos
Estrutura Molecular
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Guanidines); 0 (Organic Cation Transport Proteins); 0 (solute carrier family 22 (organic cation transporter), member 3); 2002-16-6 (phenylguanidine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE


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[PMID]:28786996
[Au] Autor:Nakano T; Kanai Y; Amano Y; Yoshimoto T; Matsubara D; Shibano T; Tamura T; Oguni S; Katashiba S; Ito T; Murakami Y; Fukayama M; Murakami T; Endo S; Niki T
[Ad] Endereço:Division of General Thoracic Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.
[Ti] Título:Establishment of highly metastatic KRAS mutant lung cancer cell sublines in long-term three-dimensional low attachment cultures.
[So] Source:PLoS One;12(8):e0181342, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Decreased cell-substratum adhesion is crucially involved in metastasis. Previous studies demonstrated that lung cancer with floating cell clusters in histology is more likely to develop metastasis. In the present study, we investigated whether cancer cells in long-term, three-dimensional low attachment cultures acquire high metastatic potential; these cells were then used to examine the mechanisms underlying metastasis. Two KRAS-mutated adenocarcinoma cell lines (A549 and H441) were cultured and selected on ultra-low attachment culture dishes, and the resulting cells were defined as FL (for floating) sublines. Cancer cells were inoculated into NOD/SCID mice via an intracardiac injection, and metastasis was evaluated using luciferase-based imaging and histopathology. In vitro cell growth (in attachment or suspension cultures), migration, and invasion were assayed. A whole genomic analysis was performed to identify key molecular alterations in FL sublines. Upon detachment on low-binding dishes, parental cells initially formed rounded spheroids with limited growth activity. However, over time in cultures, cells gradually formed smaller spheroids that grew slowly, and, after 3-4 months, we obtained FL sublines that regained prominent growth potential in suspension cultures. On ordinary dishes, FL cells reattached and exhibited a more spindle-shaped morphology than parental cells. No marked differences were observed in cell growth with attachment, migration, or invasion between FL sublines and parental cell lines; however, FL cells exhibited markedly increased growth potential under suspended conditions in vitro and stronger metastatic abilities in vivo. A genomic analysis identified epithelial-mesenchymal transition (EMT) and c-Myc amplification in A549-FL and H441-FL cells, respectively, as candidate mechanisms for metastasis. The growth potential of FL cells was markedly inhibited by lentiviral ZEB1 knockdown in A549-FL cells and by the inhibition of c-Myc through lentiviral knockdown or the pharmacological inhibitor JQ1 in H441-FL cells. Long-term three-dimensional low attachment cultures may become a useful method for investigating the mechanisms underlying metastasis mediated by decreased cell-substratum adhesion.
[Mh] Termos MeSH primário: Adenocarcinoma/patologia
Técnicas de Cultura de Células
Linhagem Celular Tumoral
Neoplasias Pulmonares/patologia
Metástase Neoplásica
Proteínas Proto-Oncogênicas p21(ras)/genética
[Mh] Termos MeSH secundário: Células A549
Adenocarcinoma/genética
Adenocarcinoma/fisiopatologia
Adenocarcinoma/secundário
Animais
Apoptose/fisiologia
Adesão Celular
Técnicas de Cultura de Células/instrumentação
Linhagem Celular Tumoral/patologia
Linhagem Celular Tumoral/fisiologia
Movimento Celular
Proliferação Celular
Feminino
Genes myc
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/fisiopatologia
Camundongos Endogâmicos NOD
Camundongos SCID
Mutação
Metástase Neoplásica/genética
Metástase Neoplásica/patologia
Metástase Neoplásica/fisiopatologia
Transplante de Neoplasias
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Esferoides Celulares/patologia
Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); 0 (Organic Cation Transport Proteins); 0 (ZEB1 protein, human); 0 (Zinc Finger E-box-Binding Homeobox 1); 0 (solute carrier family 22 (organic cation transporter), member 3); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181342


  9 / 1758 MEDLINE  
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[PMID]:28714373
[Au] Autor:Gaudelot K; Gibier JB; Pottier N; Hémon B; Van Seuningen I; Glowacki F; Leroy X; Cauffiez C; Gnemmi V; Aubert S; Perrais M
[Ad] Endereço:1 Université de Lille, Inserm, CHU Lille, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis," Jean-Pierre Aubert Research Center (JPARC), Lille, France.
[Ti] Título:Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.
[So] Source:Tumour Biol;39(7):1010428317707372, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.
[Mh] Termos MeSH primário: Carcinoma de Células Renais/tratamento farmacológico
Proteínas de Transporte de Cátions/biossíntese
MicroRNAs/genética
Proteínas de Transporte de Cátions Orgânicos/biossíntese
Transportador 1 de Cátions Orgânicos/biossíntese
[Mh] Termos MeSH secundário: Antagomirs/genética
Apoptose/efeitos dos fármacos
Benzimidazóis/administração & dosagem
Carcinoma de Células Renais/genética
Carcinoma de Células Renais/patologia
Linhagem Celular Tumoral
Proliferação Celular/genética
Resistência a Medicamentos Antineoplásicos/genética
Fluoruracila/administração & dosagem
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Transportador 2 de Cátion Orgânico
Compostos Organoplatínicos/administração & dosagem
Paclitaxel/administração & dosagem
Quinolonas/administração & dosagem
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one); 0 (Antagomirs); 0 (Benzimidazoles); 0 (Cation Transport Proteins); 0 (MIRN21 microRNA, human); 0 (MicroRNAs); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 1); 0 (Organic Cation Transporter 2); 0 (Organoplatinum Compounds); 0 (Quinolones); 0 (SLC22A2 protein, human); 0 (SLC31A1 protein, human); 04ZR38536J (oxaliplatin); P88XT4IS4D (Paclitaxel); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317707372


  10 / 1758 MEDLINE  
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[PMID]:28625319
[Au] Autor:Mahrooz A; Alizadeh A; Hashemi-Soteh MB; Ghaffari-Cherati M; Hosseyni-Talei SR
[Ad] Endereço:Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran; Diabetes Research Center, Imam Teaching Hospital, Mazandaran University of Medical Sciences, Sari, Iran; Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Scien
[Ti] Título:Polymorphic Variants rs3088442 and rs2292334 in the Organic Cation Transporter 3 (OCT3) Gene and Susceptibility Against Type 2 Diabetes: Role of their Interaction.
[So] Source:Arch Med Res;48(2):162-168, 2017 Feb.
[Is] ISSN:1873-5487
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: In this study, we investigated whether two common variants (rs3088442G>A and rs2292334G>A) in the organic cation transporter 3 (OCT3) gene, a high-capacity transporter widely expressed in various tissues, affect susceptibility to type 2 diabetes (T2D) in patients newly diagnosed with T2D. METHODS: We performed a study with 150 newly diagnosed patients with T2D and 152 controls. The genetic analyses were performed using the restricted fragment length polymorphism (RFLP) after PCR amplification. RESULTS: For the rs3088442G>A variant, A allele carriers had a significantly lower odds ratio (OR) vs. GG homozygotes in the BMI <30 kg/m group (OR = 0.23, p <0.001) compared with the BMI ≥30 kg/m group (OR = 0.67, p = 0.34). When ORs were adjusted for BMI, age, sex, and blood pressure, our findings showed that the overexpression of the A allele of the rs3088442G>A variant was associated with a decreased risk of T2D (OR = 0.016, p <0.001). A Bayesian logistic model revealed that the interaction of two variants studied were significantly associated with a decreased risk of T2D (OR = 0.61, p = 0.03). CONCLUSIONS: The present study has identified the protective effect of the variant rs3088442G>A in the 3'-untranslated region of the OCT3 gene in susceptibility to T2D, and that the protective role is maintained in the presence of risky alleles of the variant rs2292334G>A. The association of the A allele of rs3088442G>A with T2D become weaker in obese people than that of non-obese. If confirmed in other populations, the rs3088442G>A variant as a genetic marker may potentially assist in the identification of individuals at an increased risk of T2D.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/genética
Proteínas de Transporte de Cátions Orgânicos/genética
[Mh] Termos MeSH secundário: Alelos
Teorema de Bayes
Estudos de Casos e Controles
Feminino
Estudos de Associação Genética
Marcadores Genéticos
Predisposição Genética para Doença
Heterozigoto
Homozigoto
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Obesidade/genética
Razão de Chances
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Genetic Markers); 0 (Organic Cation Transport Proteins); 0 (solute carrier family 22 (organic cation transporter), member 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE



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