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  1 / 16680 MEDLINE  
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[PMID]:28968395
[Au] Autor:Chua TH; Manin BO; Daim S; Vythilingam I; Drakeley C
[Ad] Endereço:Department of Pathobiology and Medical Diagnostics, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia.
[Ti] Título:Phylogenetic analysis of simian Plasmodium spp. infecting Anopheles balabacensis Baisas in Sabah, Malaysia.
[So] Source:PLoS Negl Trop Dis;11(10):e0005991, 2017 Oct.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Anopheles balabacensis of the Leucospyrus group has been confirmed as the primary knowlesi malaria vector in Sabah, Malaysian Borneo for some time now. Presently, knowlesi malaria is the only zoonotic simian malaria in Malaysia with a high prevalence recorded in the states of Sabah and Sarawak. METHODOLOGY/PRINCIPAL FINDINGS: Anopheles spp. were sampled using human landing catch (HLC) method at Paradason village in Kudat district of Sabah. The collected Anopheles were identified morphologically and then subjected to total DNA extraction and polymerase chain reaction (PCR) to detect Plasmodium parasites in the mosquitoes. Identification of Plasmodium spp. was confirmed by sequencing the SSU rRNA gene with species specific primers. MEGA4 software was then used to analyse the SSU rRNA sequences and bulid the phylogenetic tree for inferring the relationship between simian malaria parasites in Sabah. PCR results showed that only 1.61% (23/1,425) of the screened An. balabacensis were infected with one or two of the five simian Plasmodium spp. found in Sabah, viz. Plasmodium coatneyi, P. inui, P. fieldi, P. cynomolgi and P. knowlesi. Sequence analysis of SSU rRNA of Plasmodium isolates showed high percentage of identity within the same Plasmodium sp. group. The phylogenetic tree based on the consensus sequences of P. knowlesi showed 99.7%-100.0% nucleotide identity among the isolates from An. balabacensis, human patients and a long-tailed macaque from the same locality. CONCLUSIONS/SIGNIFICANCE: This is the first study showing high molecular identity between the P. knowlesi isolates from An. balabacensis, human patients and a long-tailed macaque in Sabah. The other common simian Plasmodium spp. found in long-tailed macaques and also detected in An. balabacensis were P. coatneyi, P. inui, P. fieldi and P. cynomolgi. The high percentage identity of nucleotide sequences between the P. knowlesi isolates from the long-tailed macaque, An. balabacensis and human patients suggests a close genetic relationship between the parasites from these hosts.
[Mh] Termos MeSH primário: Anopheles/parasitologia
Doenças dos Macacos/parasitologia
Plasmodium knowlesi/classificação
Plasmodium knowlesi/genética
[Mh] Termos MeSH secundário: Animais
DNA de Protozoário/genética
Genes de RNAr
Macaca fascicularis/parasitologia
Malária/epidemiologia
Malária/parasitologia
Malária/transmissão
Malária/veterinária
Malásia/epidemiologia
Filogenia
Reação em Cadeia da Polimerase
RNA de Protozoário/genética
RNA Ribossômico/genética
Zoonoses/epidemiologia
Zoonoses/parasitologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Protozoan); 0 (RNA, Protozoan); 0 (RNA, Ribosomal)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171002
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005991


  2 / 16680 MEDLINE  
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[PMID]:28381665
[Au] Autor:Nakayama S; Koie H; Kanayama K; Katakai Y; Ito-Fujishiro Y; Sankai T; Yasutomi Y; Ageyama N
[Ad] Endereço:Nihon University, Collage of Bioresource Science, Kanagawa 252-0880, Japan.
[Ti] Título:Establishment of reference values for complete blood count and blood gases in cynomolgus monkeys (Macaca fascicularis).
[So] Source:J Vet Med Sci;79(5):881-888, 2017 May 18.
[Is] ISSN:1347-7439
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Cynomolgus monkeys are closely related to humans phylogenetically, and this has resulted in their widespread use as a preclinical model. Hematological data with regard to these monkeys are thus important. Although reference values for blood components and sex hormones have been established for cynomolgus monkeys, those for arterial blood gases have not. The arterial blood gases quickly reflect respiratory and circulatory dynamics, and are thus useful for animal management and safe general anesthesia and surgical operations. Furthermore, since O is transported by RBC, CBC and blood gases are closely related. The present study aimed to establish reference values for arterial blood gases and CBC in cynomolgus monkeys over a wide age range. Blood gases and CBC of arterial blood, collected from 41 female and 21 male anesthetized monkeys, were measured. Age correlated with RBC, HGB and HCT in the CBC. Values differed significantly between males and females in pCO , CO concentration, MCV and MCH. The pH of blood was equivalent to that of humans and pCO was more stable, whereas MCV and MCH were lower than those in humans. Erythrocytes were smaller and less pigmented than in other Macaca species. Several relationships between gender and age, and blood gases and CBC were identified in cynomolgus monkeys. In conclusion, these reference values will be useful as markers for veterinary applications and in the care and maintenance of these animals.
[Mh] Termos MeSH primário: Contagem de Células Sanguíneas/veterinária
Gasometria/veterinária
Macaca fascicularis/sangue
[Mh] Termos MeSH secundário: Envelhecimento/sangue
Animais
Feminino
Masculino
Valores de Referência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1292/jvms.16-0638


  3 / 16680 MEDLINE  
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[PMID]:28929759
[Au] Autor:Patel S; Meilandt WJ; Erickson RI; Chen J; Deshmukh G; Estrada AA; Fuji RN; Gibbons P; Gustafson A; Harris SF; Imperio J; Liu W; Liu X; Liu Y; Lyssikatos JP; Ma C; Yin J; Lewcock JW; Siu M
[Ti] Título:Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.
[So] Source:J Med Chem;60(19):8083-8102, 2017 Oct 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.
[Mh] Termos MeSH primário: Doença de Alzheimer/quimioterapia
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/farmacologia
MAP Quinase Quinase Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/biossíntese
Precursor de Proteína beta-Amiloide/genética
Animais
Encéfalo/efeitos de drogas
Encéfalo/metabolismo
Desenho de Drogas
Humanos
Macaca fascicularis
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Enzyme Inhibitors); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (mitogen-activated protein kinase kinase kinase 12)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00843


  4 / 16680 MEDLINE  
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[PMID]:28607482
[Au] Autor:Kobayashi T; Zhang H; Tang WWC; Irie N; Withey S; Klisch D; Sybirna A; Dietmann S; Contreras DA; Webb R; Allegrucci C; Alberio R; Surani MA
[Ad] Endereço:Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
[Ti] Título:Principles of early human development and germ cell program from conserved model systems.
[So] Source:Nature;546(7658):416-420, 2017 06 15.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during weeks 2-3 of early post-implantation development. Using in vitro models of hPGC induction, recent studies have suggested that there are marked mechanistic differences in the specification of human and mouse PGCs. This may be due in part to the divergence in their pluripotency networks and early post-implantation development. As early human embryos are not accessible for direct study, we considered alternatives including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs originate from the posterior pre-primitive-streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. We use this model together with human and monkey in vitro models simulating peri-gastrulation development to show the conserved principles of epiblast development for competency for primordial germ cell fate. This process is followed by initiation of the epigenetic program and regulated by a balanced SOX17-BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models provides synthetic insights into early human development.
[Mh] Termos MeSH primário: Diferenciação Celular
Desenvolvimento Embrionário
Células Germinativas/citologia
Macaca fascicularis/embriologia
Modelos Biológicos
Células-Tronco Pluripotentes/citologia
Suínos/embriologia
[Mh] Termos MeSH secundário: Animais
Proteínas Morfogenéticas Ósseas/metabolismo
Linhagem da Célula
Corpos Embrioides/citologia
Epigênese Genética
Feminino
Gastrulação
Dosagem de Genes
Células Germinativas/metabolismo
Camadas Germinativas/citologia
Humanos
Técnicas In Vitro
Masculino
Modelos Animais
Linha Primitiva/citologia
Proteínas Repressoras/genética
Fatores de Transcrição SOXF/genética
Via de Sinalização Wnt
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Repressor Proteins); 0 (SOX17 protein, human); 0 (SOXF Transcription Factors); 138415-26-6 (PRDM1 protein, human)
[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:170613
[St] Status:MEDLINE
[do] DOI:10.1038/nature22812


  5 / 16680 MEDLINE  
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[PMID]:28009435
[Au] Autor:Fuh FK; Looney C; Li D; Poon KA; Dere RC; Danilenko DM; McBride J; Reed C; Chung S; Zheng B; Mathews WR; Polson A; Prabhu S; Williams M
[Ad] Endereço:Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.
[Ti] Título:Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells.
[So] Source:Br J Pharmacol;174(8):628-640, 2017 Apr.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: CD22 and CD79b are cell-surface receptors expressed on B-cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody-drug conjugates (ADCs) were investigated in cynomolgus monkeys. EXPERIMENTAL APPROACH: Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro. KEY RESULTS: Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity. CONCLUSIONS AND IMPLICATIONS: The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti-mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics.
[Mh] Termos MeSH primário: Anticorpos/imunologia
Antígenos CD79/imunologia
Linfócitos B/citologia
Linfócitos B/efeitos de drogas
Oligopeptídeos/farmacologia
Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
[Mh] Termos MeSH secundário: Animais
Reações Antígeno-Anticorpo
Linfócitos B/imunologia
Proliferação de Células/efeitos de drogas
Relação Dose-Resposta a Droga
Humanos
Macaca fascicularis
Masculino
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Antigens, CD79); 0 (CD22 protein, human); 0 (CD79B protein, human); 0 (Oligopeptides); 0 (Sialic Acid Binding Ig-like Lectin 2); 0 (monomethyl auristatin E)
[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:161223
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13697


  6 / 16680 MEDLINE  
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[PMID]:28027971
[Au] Autor:Soltys KA; Setoyama K; Tafaleng EN; Soto Gutiérrez A; Fong J; Fukumitsu K; Nishikawa T; Nagaya M; Sada R; Haberman K; Gramignoli R; Dorko K; Tahan V; Dreyzin A; Baskin K; Crowley JJ; Quader MA; Deutsch M; Ashokkumar C; Shneider BL; Squires RH; Ranganathan S; Reyes-Mugica M; Dobrowolski SF; Mazariegos G; Elango R; Stolz DB; Strom SC; Vockley G; Roy-Chowdhury J; Cascalho M; Guha C; Sindhi R; Platt JL; Fox IJ
[Ad] Endereço:Thomas E. Starzl Transplant Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
[Ti] Título:Host conditioning and rejection monitoring in hepatocyte transplantation in humans.
[So] Source:J Hepatol;66(5):987-1000, 2017 May.
[Is] ISSN:1600-0641
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67 hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.
[Mh] Termos MeSH primário: Rejeição de Enxerto
Hepatócitos/transplante
Fígado/efeitos de radiação
Condicionamento Pré-Transplante
[Mh] Termos MeSH secundário: Adulto
Animais
Feminino
Humanos
Hepatopatias/terapia
Macaca fascicularis
Masculino
Suínos
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161228
[St] Status:MEDLINE


  7 / 16680 MEDLINE  
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[PMID]:28922357
[Au] Autor:Diez Benavente E; Florez de Sessions P; Moon RW; Holder AA; Blackman MJ; Roper C; Drakeley CJ; Pain A; Sutherland CJ; Hibberd ML; Campino S; Clark TG
[Ad] Endereço:Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
[Ti] Título:Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations.
[So] Source:PLoS Genet;13(9):e1007008, 2017 Sep.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The macaque parasite Plasmodium knowlesi is a significant concern in Malaysia where cases of human infection are increasing. Parasites infecting humans originate from genetically distinct subpopulations associated with the long-tailed (Macaca fascicularis (Mf)) or pig-tailed macaques (Macaca nemestrina (Mn)). We used a new high-quality reference genome to re-evaluate previously described subpopulations among human and macaque isolates from Malaysian-Borneo and Peninsular-Malaysia. Nuclear genomes were dimorphic, as expected, but new evidence of chromosomal-segment exchanges between subpopulations was found. A large segment on chromosome 8 originating from the Mn subpopulation and containing genes encoding proteins expressed in mosquito-borne parasite stages, was found in Mf genotypes. By contrast, non-recombining organelle genomes partitioned into 3 deeply branched lineages, unlinked with nuclear genomic dimorphism. Subpopulations which diverged in isolation have re-connected, possibly due to deforestation and disruption of wild macaque habitats. The resulting genomic mosaics reveal traits selected by host-vector-parasite interactions in a setting of ecological transition.
[Mh] Termos MeSH primário: Interações Hospedeiro-Patógeno/genética
Malária/genética
Organelas/genética
Plasmodium knowlesi/genética
[Mh] Termos MeSH secundário: Animais
Culicidae/genética
Culicidae/parasitologia
Genoma
Humanos
Insetos Vetores/genética
Macaca fascicularis/genética
Macaca fascicularis/parasitologia
Macaca nemestrina/genética
Macaca nemestrina/parasitologia
Malária/parasitologia
Malária/transmissão
Organelas/parasitologia
Plasmodium knowlesi/patogenicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170918
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007008


  8 / 16680 MEDLINE  
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[PMID]:28218919
[Au] Autor:Wang PX; Ji YX; Zhang XJ; Zhao LP; Yan ZZ; Zhang P; Shen LJ; Yang X; Fang J; Tian S; Zhu XY; Gong J; Zhang X; Wei QF; Wang Y; Li J; Wan L; Xie Q; She ZG; Wang Z; Huang Z; Li H
[Ad] Endereço:Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
[Ti] Título:Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates.
[So] Source:Nat Med;23(4):439-449, 2017 Apr.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.
[Mh] Termos MeSH primário: Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética
Fígado/metabolismo
MAP Quinase Quinase Quinase 5/metabolismo
Proteína Quinase 8 Ativada por Mitógeno/metabolismo
Hepatopatia Gordurosa não Alcoólica/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Animais
Biópsia
Glicemia/metabolismo
Dependovirus
Dimerização
Feminino
Técnicas de Introdução de Genes
Vetores Genéticos
Hepatócitos/metabolismo
Humanos
Imuno-Histoquímica
Imunoprecipitação
Resistência à Insulina/genética
Interleucina-6/metabolismo
Fígado/diagnóstico por imagem
Fígado/patologia
Macaca fascicularis
Masculino
Camundongos
Meia-Idade
Hepatopatia Gordurosa não Alcoólica/metabolismo
Hepatopatia Gordurosa não Alcoólica/patologia
Tomografia por Emissão de Pósitrons
Reação em Cadeia da Polimerase em Tempo Real
Transdução de Sinal
Fator de Necrose Tumoral alfa/metabolismo
Ultrassonografia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (CASP8 and FADD-Like Apoptosis Regulating Protein); 0 (Interleukin-6); 0 (Tumor Necrosis Factor-alpha); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8); EC 2.7.11.25 (MAP Kinase Kinase Kinase 5)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170220
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4290


  9 / 16680 MEDLINE  
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[PMID]:28869611
[Au] Autor:Mire CE; Cross RW; Geisbert JB; Borisevich V; Agans KN; Deer DJ; Heinrich ML; Rowland MM; Goba A; Momoh M; Boisen ML; Grant DS; Fullah M; Khan SH; Fenton KA; Robinson JE; Branco LM; Garry RF; Geisbert TW
[Ad] Endereço:Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
[Ti] Título:Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever.
[So] Source:Nat Med;23(10):1146-1149, 2017 Oct.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Anticorpos Neutralizantes/uso terapêutico
Anticorpos Antivirais/uso terapêutico
Febre Lassa/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Reações Cruzadas
Ensaio de Imunoadsorção Enzimática
Humanos
Evasão da Resposta Imune/genética
Imuno-Histoquímica
Vírus Lassa/genética
Macaca fascicularis
RNA Viral/sangue
Distribuição Aleatória
Taxa de Sobrevida
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antibodies, Neutralizing); 0 (Antibodies, Viral); 0 (RNA, Viral)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170904
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4396


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[PMID]:28846098
[Au] Autor:Emmerson PJ; Wang F; Du Y; Liu Q; Pickard RT; Gonciarz MD; Coskun T; Hamang MJ; Sindelar DK; Ballman KK; Foltz LA; Muppidi A; Alsina-Fernandez J; Barnard GC; Tang JX; Liu X; Mao X; Siegel R; Sloan JH; Mitchell PJ; Zhang BB; Gimeno RE; Shan B; Wu X
[Ad] Endereço:Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly &Company, Indianapolis, Indiana, USA.
[Ti] Título:The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.
[So] Source:Nat Med;23(10):1215-1219, 2017 Oct.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-ß (TGF-ß) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.
[Mh] Termos MeSH primário: Área Postrema/metabolismo
Ingestão de Alimentos/efeitos de drogas
Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética
Fator 15 de Diferenciação de Crescimento/farmacologia
Obesidade/metabolismo
Perda de Peso/efeitos de drogas
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Ingestão de Alimentos/genética
Citometria de Fluxo
Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo
Células HEK293
Humanos
Immunoblotting
Macaca fascicularis
Masculino
Camundongos
Camundongos Knockout
RNA Mensageiro/metabolismo
Ratos
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase em Tempo Real
Ressonância de Plasmônio de Superfície
Perda de Peso/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GDF15 protein, human); 0 (Glial Cell Line-Derived Neurotrophic Factor Receptors); 0 (Growth Differentiation Factor 15); 0 (RNA, Messenger)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4393



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