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Suzuki, Akemi
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[PMID]:27773703
[Au] Autor:Hirano M; Totani K; Fukuda T; Gu J; Suzuki A
[Ad] Endereço:Institute of Glycoscience, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan; Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, 3-3-1 Kichijoji-kita, Musashino, Tokyo 180-8633, Japan. Electronic address: mhirano@st.seikei.ac.jp.
[Ti] Título:N-Glycoform-dependent interactions of megalin with its ligands.
[So] Source:Biochim Biophys Acta;1861(1 Pt A):3106-3118, 2017 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Megalin is a 600-kDa single-spanning transmembrane glycoprotein and functions as an endocytic receptor, distributed not only in the kidney but also in other tissues. Structurally and functionally distinct ligands for megalin have been identified. Megalin has 30 potential N-glycosylation sites in its extracellular domain. We found that megalin interacts with its ligands in a glycoform-dependent manner. METHODS: Distribution of megalin and glycans was histochemically analyzed in mouse kidneys. Kidney absorption of Cy5-labeled ligands was examined in vivo. Megalin-ligand interactions were analyzed using ligand blotting and ELISA. RESULTS: Megalins expressed on renal proximal convoluted tubules (PCTs) and proximal straight tubules (PSTs) have different N-glycans. PCT megalin stained with Lens culinaris agglutinin (LCA), which recognizes core-fucosyl N-glycans catalyzed by α1,6-fucosyltransferase (Fut8). In contrast, PST megalin stained with wheat germ agglutinin (WGA), which recognizes hybrid-type N-glycans. Retinol-binding protein-Cy5 (RBP-Cy5) was endocytosed by megalin on PCTs but minimally endocytosed by PSTs. BSA-Cy5 was endocytosed nearly equally by both tubules. The purified LCA-positive glycoform megalin had higher binding activity for RBP and vitamin D-binding protein than did WGA-positive glycoform megalin. Both glycoforms had nearly the same BSA- and kanamycin-binding activities. RBP-binding analysis of megalin lacking core fucose, in Fut8 mouse kidneys, had significantly decreased binding activity. CONCLUSIONS: N-Glycosylation of megalin can modulate its ligand-binding activity. Core fucosylation, in particular, is a modification crucial for megalin-RBP interactions. GENERAL SIGNIFICANCE: Cell type-specific glycoforms of megalin exist in the proximal tubular cells and modulate ligand absorption capacity.
[Mh] Termos MeSH primário: Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Polissacarídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Carbocianinas/metabolismo
Cromatografia de Afinidade
Feminino
Fucosiltransferases/deficiência
Fucosiltransferases/metabolismo
Glicosilação
Rim/metabolismo
Túbulos Renais Proximais/citologia
Túbulos Renais Proximais/metabolismo
Ligantes
Camundongos Endogâmicos C57BL
Camundongos Knockout
Especificidade de Órgãos
Lectinas de Plantas/metabolismo
Ligação Proteica
Proteínas de Ligação ao Retinol/metabolismo
Aglutininas do Germe de Trigo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbocyanines); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Plant Lectins); 0 (Polysaccharides); 0 (Retinol-Binding Proteins); 0 (Wheat Germ Agglutinins); 0 (cyanine dye 5); 0 (lentil lectin); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.68 (Glycoprotein 6-alpha-L-fucosyltransferase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171224
[Lr] Data última revisão:
171224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:28739605
[Au] Autor:Zhou Y; Graves JS; Simpson S; Charlesworth JC; Mei IV; Waubant E; Barcellos LF; Belman A; Krupp L; Lucas R; Ponsonby AL; Taylor BV; Ausimmmune/AusLong investigators group
[Ad] Endereço:Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
[Ti] Título:Genetic variation in the gene increases relapse risk in multiple sclerosis.
[So] Source:J Neurol Neurosurg Psychiatry;88(10):864-868, 2017 Oct.
[Is] ISSN:1468-330X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Due to the lack of prospective studies with longitudinal data on relapse, past genetic studies have not attempted to identify genetic factors that predict relapse risk (the primary endpoint of many pivotal clinical trials testing the efficacy of multiple sclerosis (MS) disease-modifying drugs) at a genome-wide scale. METHODS: We conducted a genome-wide association analysis (GWAS) to identify genetic variants that predict MS relapse risk, using a three-stage approach. First, GWAS was conducted using the southern Tasmania MS Longitudinal Study with 141 cases followed prospectively for a mean of 2.3 years. Second, GWAS was conducted using the Ausimmune Longitudinal Study with 127 cases having a classic first demyelinating event followed for 5 years from onset. Third, the top hits with p<5.0×10 from the first two stages were combined with a longitudinal US paediatric MS cohort with 181 cases followed for 5 years after onset. Predictors of time to relapse were evaluated by a mixed effects Cox model. An inverse variance fixed effects model was then used to undertake a meta-analysis. RESULTS: In the pooled results, using these three unique longitudinal MS cohorts, we discovered one novel locus ( ; most significant single nucleotide polymorphism rs12988804) that reached genome-wide significance in predicting relapse risk (HR=2.18, p=3.30×10 ). LRP2 is expressed on the surface of many central nervous system cells including neurons and oligodendrocytes and is a critical receptor in axonal guidance. CONCLUSIONS: The finding of a genetic locus that has extensive effects on neuronal development and repair is of interest as a potential modulator of MS disease course.
[Mh] Termos MeSH primário: Variação Genética
Estudo de Associação Genômica Ampla
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Esclerose Múltipla/genética
[Mh] Termos MeSH secundário: Adulto
Austrália
Criança
Progressão da Doença
Feminino
Seres Humanos
Estudos Longitudinais
Masculino
Meia-Idade
Polimorfismo de Nucleotídeo Único
Estudos Prospectivos
Recidiva
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LRP2 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1136/jnnp-2017-315971


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[PMID]:28575050
[Au] Autor:Jensen D; Kierulf-Lassen C; Kristensen MLV; Nørregaard R; Weyer K; Nielsen R; Christensen EI; Birn H
[Ad] Endereço:Department of Biomedicine, Institute of Health, Aarhus University, Aarhus, Denmark.
[Ti] Título:Megalin dependent urinary cystatin C excretion in ischemic kidney injury in rats.
[So] Source:PLoS One;12(6):e0178796, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cystatin C, a marker of kidney injury, is freely filtered in the glomeruli and reabsorbed by the proximal tubules. Megalin and cubilin are endocytic receptors essential for reabsorption of most filtered proteins. This study examines the role of these receptors for the uptake and excretion of cystatin C and explores the effect of renal ischemia/reperfusion injury on renal cystatin C uptake and excretion in a rat model. METHODS: Binding of cystatin C to megalin and cubilin was analyzed by surface plasmon resonance analysis. ELISA and/or immunoblotting and immunohistochemistry were used to study the urinary excretion and tubular uptake of endogenous cystatin C in mice. Furthermore, renal uptake and urinary excretion of cystatin C was investigated in rats exposed to ischemia/reperfusion injury. RESULTS: A high affinity binding of cystatin C to megalin and cubilin was identified. Megalin deficient mice revealed an increased urinary excretion of cystatin C associated with defective uptake by endocytosis. In rats exposed to ischemia/reperfusion injury urinary cystatin C excretion was increased and associated with a focal decrease in proximal tubule endocytosis with no apparent change in megalin expression. CONCLUSIONS: Megalin is essential for the normal tubular recovery of endogenous cystatin C. The increase in urinary cystatin C excretion after ischemia/reperfusion injury is associated with decreased tubular uptake but not with reduced megalin expression.
[Mh] Termos MeSH primário: Cistatina C/urina
Isquemia/urina
Rim/irrigação sanguínea
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
[Mh] Termos MeSH secundário: Animais
Masculino
Camundongos
Camundongos Transgênicos
Ligação Proteica
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cystatin C); 0 (Low Density Lipoprotein Receptor-Related Protein-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178796


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[PMID]:28446629
[Au] Autor:Beydoun MA; Tajuddin SM; Dore GA; Canas JA; Beydoun HA; Evans MK; Zonderman AB
[Ad] Endereço:National Institute on Aging, Intramural Research Program, NIH, Baltimore, MD; baydounm@mail.nih.gov.
[Ti] Título:Vitamin D Receptor and Megalin Gene Polymorphisms Are Associated with Longitudinal Cognitive Change among African-American Urban Adults.
[So] Source:J Nutr;147(6):1048-1062, 2017 Jun.
[Is] ISSN:1541-6100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The link between longitudinal cognitive change and polymorphisms in the vitamin D receptor ( ) and [or LDL receptor-related protein 2 ( )] genes remains unclear, particularly among African-American (AA) adults. We aimed to evaluate associations of single nucleotide polymorphisms (SNPs) for [rs11568820 (Cdx-2:T/C), rs1544410 (BsmI:G/A), rs7975232 (ApaI:A/C), rs731236 (TaqI:G/A)] and [rs3755166:G/A,rs2075252:C/T, rs2228171:C/T] genes with longitudinal cognitive performance change in various domains of cognition. Data from 1024 AA urban adult participants in the Healthy Aging in Neighborhoods of Diversity Across the Life Span (Baltimore, Maryland) with complete genetic data were used, of whom 660-797 had complete data on 9 cognitive test scores at baseline and/or the first follow-up examination and complete covariate data (∼52% female; mean age: ∼52 y; mean years of education: 12.6 y). Time between examination visits 1 (2004-2009) and 2 (2009-2013) ranged from <1 y to ∼8 y, with a mean ± SD of 4.64 ± 0.93 y. Latent class and haplotype analyses were conducted by creating gene polymorphism groups that were related to longitudinal annual rate of cognitive change predicted from mixed-effects regression models. Among key findings, the rs3755166:G/A SNP was associated with faster decline on the Mini-Mental State Examination overall (ß = -0.002, = 0.018) and among women. (BsmI/ApaI/TaqI: G-/A-/A-) SNP latent class [SNPLC; compared with (ApaI: "AA")] was linked to faster decline on the Verbal Fluency Test, Categorical, in women, among whom the (rs2228171: "TT") SNPLC (compared with :rs2228171: "CC") was also associated with a faster decline on the Trailmaking Test, Part B (Trails B), but with a slower decline on the Digit Span Backward (DS-B). Moreover, among men, the SNP haplotype (SNPHAP; GCA:baT) was associated with a slower decline on the Trails B, whereas the SNPHAP (GCC) was associated with a faster decline on the DS-B, reflected as a faster decline on cognitive domain 2 ("visual/working memory"). and gene variations can alter age-related cognitive trajectories differentially between men and women among AA urban adults, specifically in global mental status and domains of verbal fluency, visual/working memory, and executive function.
[Mh] Termos MeSH primário: Afroamericanos/genética
Cognição
Função Executiva
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Memória
Polimorfismo de Nucleotídeo Único
Receptores de Calcitriol/genética
[Mh] Termos MeSH secundário: Afroamericanos/psicologia
Envelhecimento/genética
Envelhecimento/psicologia
Feminino
Haplótipos
Seres Humanos
Estudos Longitudinais
Masculino
Meia-Idade
População Urbana
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Receptors, Calcitriol); 0 (VDR protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170705
[Lr] Data última revisão:
170705
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.3945/jn.116.244962


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[PMID]:28356267
[Au] Autor:Eshbach ML; Kaur A; Rbaibi Y; Tejero J; Weisz OA
[Ad] Endereço:Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
[Ti] Título:Hemoglobin inhibits albumin uptake by proximal tubule cells: implications for sickle cell disease.
[So] Source:Am J Physiol Cell Physiol;312(6):C733-C740, 2017 Jun 01.
[Is] ISSN:1522-1563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proximal tubule (PT) dysfunction, including tubular proteinuria, is a significant complication in young sickle cell disease (SCD) that can eventually lead to chronic kidney disease. Hemoglobin (Hb) dimers released from red blood cells upon hemolysis are filtered into the kidney and internalized by megalin/cubilin receptors into PT cells. The PT is especially sensitive to heme toxicity, and tubular dysfunction in SCD is thought to result from prolonged exposure to filtered Hb. Here we show that concentrations of Hb predicted to enter the tubule lumen during hemolytic crisis competitively inhibit the uptake of another megalin/cubilin ligand (albumin) by PT cells. These effects were independent of heme reduction state. The Glu7Val mutant of Hb that causes SCD was equally effective at inhibiting albumin uptake compared with wild-type Hb. Addition of the Hb scavenger haptoglobin (Hpt) restored albumin uptake in the presence of Hb, suggesting that Hpt binding to the Hb αß dimer-dimer interface interferes with Hb binding to megalin/cubilin. BLAST searches and structural modeling analyses revealed regions of similarity between Hb and albumin that map to this region and may represent sites of Hb interaction with megalin/cubilin. Our studies suggest that impaired endocytosis of megalin/cubilin ligands, rather than heme toxicity, may be the cause of tubular proteinuria in SCD patients. Additionally, loss of these filtered proteins into the urine may contribute to the extra-renal pathogenesis of SCD.
[Mh] Termos MeSH primário: Anemia Falciforme/metabolismo
Haptoglobinas/química
Hemoglobinas/química
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Albumina Sérica/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Anemia Falciforme/genética
Anemia Falciforme/patologia
Animais
Sítios de Ligação
Ligação Competitiva
Linhagem Celular
Linhagem Celular Transformada
Feminino
Haptoglobinas/metabolismo
Heme/química
Hemoglobinas/metabolismo
Hemólise
Seres Humanos
Túbulos Renais Proximais/citologia
Túbulos Renais Proximais/metabolismo
Ligantes
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Gambás
Oxirredução
Ligação Proteica
Conformação Proteica em alfa-Hélice
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Albumina Sérica/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HP protein, human); 0 (Haptoglobins); 0 (Hemoglobins); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Serum Albumin); 42VZT0U6YR (Heme)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170331
[St] Status:MEDLINE
[do] DOI:10.1152/ajpcell.00021.2017


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[PMID]:28351841
[Au] Autor:Arora K; Sequeira JM; Quadros EV
[Ad] Endereço:Department of Cell Biology, School of Graduate Studies, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, USA.
[Ti] Título:Maternofetal transport of vitamin B : role of TCblR/ and megalin.
[So] Source:FASEB J;31(7):3098-3106, 2017 Jul.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vitamin B deficiency causes megaloblastic anemia and neurologic disorder in humans. Gene defects of transcobalamin (TC) and the transcobalamin receptor (TCblR), needed for cellular uptake of the TC-bound B , do not confer embryonic lethality. TC deficiency can produce the hematologic and neurologic complications after birth, whereas TCblR/ gene defects appear to produce mild metabolic changes. Alternate maternofetal transport mechanisms appear to provide adequate B to the fetus. To understand this mechanism, we evaluated the role of TC, TCblR/ , and megalin in maternofetal transport of B in a TCblR/ -knockout (KO) mouse. Our results showed high expression of TCblR/ in the labyrinth of the placenta, embryonic brain, and spinal column in wild-type (WT) mice. Megalin expression was about the same in both WT and KO mouse visceral yolk sac, brain, and spinal column. Megalin mRNA was down-regulated in the KO embryonic spinal cord (SC) and kidneys. Megalin expression remained unaltered in adult WT and KO mouse brain, SC, and kidneys. Injected dsRed-TC-B and TC- CoB accumulated in the visceral yolk sac of KO mice where megalin is expressed and provides an alternate mechanism for the maternofetal transport of Cbl during fetal development.-Arora, K., Sequeira, J. M., Quadros, E. V. Maternofetal transport of vitamin B : role of TCblR/ and megalin.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica/fisiologia
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Troca Materno-Fetal/fisiologia
Receptores de Superfície Celular/fisiologia
Vitamina B 12/metabolismo
[Mh] Termos MeSH secundário: Animais
Transporte Biológico
Sistema Nervoso Central/metabolismo
Feminino
Rim/metabolismo
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Camundongos
Placenta/metabolismo
Gravidez
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Distribuição Tecidual
Saco Vitelino/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Lrp2 protein, mouse); 0 (RNA, Messenger); 0 (Receptors, Cell Surface); 0 (transcobalamin receptor); P6YC3EG204 (Vitamin B 12)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700025R


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[PMID]:28331063
[Au] Autor:Wen L; Andersen PK; Husum DMU; Nørregaard R; Zhao Z; Liu Z; Birn H
[Ad] Endereço:Department of Biomedicine, Aarhus University, Aarhus, Denmark.
[Ti] Título:MicroRNA-148b regulates megalin expression and is associated with receptor downregulation in mice with unilateral ureteral obstruction.
[So] Source:Am J Physiol Renal Physiol;313(2):F210-F217, 2017 Aug 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Megalin is a multiligand, endocytic receptor that is important for the normal, proximal tubule reabsorption of filtered proteins, hormones, enzymes, essential nutrients, and nephrotoxins. Megalin dysfunction has been associated with acute, as well as chronic kidney diseases. Tubular proteinuria has been observed following unilateral ureteral obstruction (UUO), suggesting megalin dysfunction; however, the pathophysiological mechanism has not been determined. To identify potential regulators of megalin expression, we examined renal microRNAs (miRNAs) expression and observed an upregulation of microRNA-148b (miR-148b) in obstructed mouse kidneys 7 days after UUO, which was associated with a significant reduction in proximal tubule megalin expression and accumulation of megalin ligands. By in silico miRNA target prediction analysis, we identified megalin messenger RNA (mRNA) as a potential target of miR-148b and confirmed using a dual-luciferase reporter assay that miR-148b targeted the 3'-untranslated region of the megalin gene. Transfection of LLC-PK1 cells with miR-148b mimic reduced endogenous megalin mRNA and protein levels in a concentration-dependent manner, while transfection with miR-148b inhibitor resulted in an increase. Our findings suggest that miR-148b directly downregulates megalin expression and that miR-148b negatively regulates megalin expression in UUO-induced kidney injury. Furthermore, the identification of a miRNA regulating megalin expression may allow for targeted interventions to modulate megalin function and proximal tubule uptake of proteins, as well as other ligands.
[Mh] Termos MeSH primário: Nefropatias/metabolismo
Túbulos Renais Proximais/metabolismo
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
MicroRNAs/metabolismo
Obstrução Ureteral/complicações
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Animais
Sítios de Ligação
Modelos Animais de Doenças
Regulação para Baixo
Células HEK293
Seres Humanos
Nefropatias/etiologia
Nefropatias/genética
Nefropatias/patologia
Túbulos Renais Proximais/patologia
Células LLC-PK1
Ligantes
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Masculino
Camundongos Endogâmicos C57BL
MicroRNAs/genética
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Suínos
Fatores de Tempo
Transcrição Genética
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Lrp2 protein, mouse); 0 (MIRN148 microRNA, human); 0 (MicroRNAs); 0 (Mirn148 microRNA, mouse); 0 (RNA, Messenger)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00585.2016


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[PMID]:28323095
[Au] Autor:Oroojalian F; Rezayan AH; Shier WT; Abnous K; Ramezani M
[Ad] Endereço:Nanobiotechnology Group, Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, USA.
[Ti] Título:Megalin-targeted enhanced transfection efficiency in cultured human HK-2 renal tubular proximal cells using aminoglycoside-carboxyalkyl- polyethylenimine -containing nanoplexes.
[So] Source:Int J Pharm;523(1):102-120, 2017 May 15.
[Is] ISSN:1873-3476
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Non-viral vectors are of interest as therapeutic gene delivery agents in gene therapy, because they are simple to prepare, easy to modify and have definable safety profiles compared to viral vectors. The potential of gene therapy in the treatment of renal diseases is limited by a lack of effective kidney-targeted gene delivery systems. Aminoglycoside antibiotics gentamicin and neomycin were connected by amide linkages to carboxyl groups on carboxyalkylated-PEI (25kDa PEI) or carboxyalkylated-PEI (10kDa PEI). Aminoglycoside-carboxyalkylated-PEI conjugates were characterized with respect to size, surface charge density, DNA condensation ability, and buffering capacity. Polyplexes prepared by electrostatic interaction between aminoglycoside-carboxyalkylated-PEIs and enhanced green fluorescent protein-expressing (EGFP) plasmid DNA had appropriate nano-scale size (143-173nm). Their targeting potential was investigated in cultured HK-2 immortalized human cortex/proximal tubule kidney epithelial cells, which expresses megalin, a scavenger receptor that mediates endocytosis of a diverse group of ligands, including aminoglycoside antibiotics. Aminoglycoside-carboxyalkylated-PEIs significantly increased EGFP gene transfection efficiency in HK-2 cells by ∼13-fold for aminoglycoside-carboxyalkylated-PEI and ∼7-fold increase for aminoglycoside-carboxyalkylated-PEI relative to the corresponding PEIs without aminoglycosides. The transfection efficiency of polyplexes was dependent on the weight ratio of aminoglycoside-containing ligand in the carrier. In the presence of a range of concentrations of human serum albumin, which competes for megalin binding, aminoglycoside-carboxyalkylated-PEI-mediated transfection was reduced to background levels. These results suggest that aminoglycoside-carboxyalkylated-PEI polyplexes can target megalin-expressing kidney-derived cells in vitro resulting in improved transfection efficiency with low cytotoxicity.
[Mh] Termos MeSH primário: Aminoglicosídeos/administração & dosagem
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Nanoestruturas/administração & dosagem
Polietilenoimina/administração & dosagem
Transfecção/métodos
[Mh] Termos MeSH secundário: Aminoglicosídeos/química
Animais
Linhagem Celular
Sobrevivência Celular
DNA/administração & dosagem
DNA/química
Cães
Proteínas de Fluorescência Verde/genética
Células Hep G2
Seres Humanos
Túbulos Renais Proximais/citologia
Células Madin Darby de Rim Canino
Masculino
Camundongos Endogâmicos BALB C
Nanoestruturas/química
Plasmídeos
Polietilenoimina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (enhanced green fluorescent protein); 147336-22-9 (Green Fluorescent Proteins); 9002-98-6 (Polyethyleneimine); 9007-49-2 (DNA)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE


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[PMID]:28289043
[Au] Autor:De S; Kuwahara S; Hosojima M; Ishikawa T; Kaseda R; Sarkar P; Yoshioka Y; Kabasawa H; Iida T; Goto S; Toba K; Higuchi Y; Suzuki Y; Hara M; Kurosawa H; Narita I; Hirayama Y; Ochiya T; Saito A
[Ad] Endereço:Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Niigata, Japan.
[Ti] Título:Exocytosis-Mediated Urinary Full-Length Megalin Excretion Is Linked With the Pathogenesis of Diabetic Nephropathy.
[So] Source:Diabetes;66(5):1391-1404, 2017 May.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Efficient biomarkers for diabetic nephropathy (DN) have not been established. Using ELISA, we found previously that urinary levels of full-length megalin (C-megalin), a multiligand endocytic receptor in proximal tubules, was positively correlated with DN progression in patients with type 2 diabetes mellitus (T2DM). Here, we found that urinary extracellular vesicle (UEV) excretion and C-megalin content in UEVs or in their exosomal fraction increased along with the progression of the albuminuric stages in patients with T2DM. Cultured immortalized rat proximal tubule cells (IRPTCs) treated with fatty acid-free BSA or advanced glycation end product-modified BSA (AGE-BSA), endocytic ligands of megalin, increased EV excretion, and their C-megalin content. C-megalin excretion from IRPTCs via extracellular vesicles was significantly blocked by an exosome-specific inhibitor, GW4869, indicating that this excretion is mainly exocytosis-mediated. AGE-BSA treatment of IRPTCs caused apparent lysosomal dysfunction, which stimulated multivesicular body formation, resulting in increased exosomal C-megalin excretion. In a high-fat diet-induced, megalin-mediated kidney injury model in mice, urinary C-megalin excretion also increased via UEVs. Collectively, exocytosis-mediated urinary C-megalin excretion is associated with the development and progression of DN in patients with T2DM, particularly due to megalin-mediated lysosomal dysfunction in proximal tubules, and hence it could be a candidate biomarker linked with DN pathogenesis.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/metabolismo
Nefropatias Diabéticas/metabolismo
Exocitose
Vesículas Extracelulares/metabolismo
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
[Mh] Termos MeSH secundário: Lesão Renal Aguda/metabolismo
Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Estudos de Casos e Controles
Diabetes Mellitus Tipo 2/complicações
Diabetes Mellitus Tipo 2/urina
Nefropatias Diabéticas/etiologia
Nefropatias Diabéticas/urina
Dieta Hiperlipídica
Vesículas Extracelulares/ultraestrutura
Feminino
Produtos Finais de Glicação Avançada/farmacologia
Seres Humanos
Immunoblotting
Túbulos Renais Proximais/efeitos dos fármacos
Túbulos Renais Proximais/metabolismo
Túbulos Renais Proximais/ultraestrutura
Masculino
Camundongos
MicroRNAs
Microscopia Eletrônica de Transmissão
Microscopia Imunoeletrônica
Meia-Idade
RNA Mensageiro
Ratos
Soroalbumina Bovina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycation End Products, Advanced); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (MicroRNAs); 0 (RNA, Messenger); 0 (advanced glycation end products-bovine serum albumin); 27432CM55Q (Serum Albumin, Bovine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170315
[St] Status:MEDLINE
[do] DOI:10.2337/db16-1031


  10 / 462 MEDLINE  
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[PMID]:28241077
[Au] Autor:Mitchell CL; Latuszek CE; Vogel KR; Greenlund IM; Hobmeier RE; Ingram OK; Dufek SR; Pecore JL; Nip FR; Johnson ZJ; Ji X; Wei H; Gailing O; Werner T
[Ad] Endereço:Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
[Ti] Título:α-amanitin resistance in Drosophila melanogaster: A genome-wide association approach.
[So] Source:PLoS One;12(2):e0173162, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We investigated the mechanisms of mushroom toxin resistance in the Drosophila Genetic Reference Panel (DGRP) fly lines, using genome-wide association studies (GWAS). While Drosophila melanogaster avoids mushrooms in nature, some lines are surprisingly resistant to α-amanitin-a toxin found solely in mushrooms. This resistance may represent a pre-adaptation, which might enable this species to invade the mushroom niche in the future. Although our previous microarray study had strongly suggested that pesticide-metabolizing detoxification genes confer α-amanitin resistance in a Taiwanese D. melanogaster line Ama-KTT, none of the traditional detoxification genes were among the top candidate genes resulting from the GWAS in the current study. Instead, we identified Megalin, Tequila, and widerborst as candidate genes underlying the α-amanitin resistance phenotype in the North American DGRP lines, all three of which are connected to the Target of Rapamycin (TOR) pathway. Both widerborst and Tequila are upstream regulators of TOR, and TOR is a key regulator of autophagy and Megalin-mediated endocytosis. We suggest that endocytosis and autophagy of α-amanitin, followed by lysosomal degradation of the toxin, is one of the mechanisms that confer α-amanitin resistance in the DGRP lines.
[Mh] Termos MeSH primário: Alfa-Amanitina/farmacologia
Drosophila melanogaster/efeitos dos fármacos
Drosophila melanogaster/genética
Resistência a Medicamentos
[Mh] Termos MeSH secundário: Animais
Cruzamentos Genéticos
Proteínas de Drosophila/metabolismo
Endocitose
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Estudos de Associação Genética
Variação Genética
Larva/efeitos dos fármacos
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Análise de Sequência com Séries de Oligonucleotídeos
Praguicidas/química
Fenótipo
RNA/análise
Serina-Treonina Quinases TOR/metabolismo
Taiwan
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alpha-Amanitin); 0 (Drosophila Proteins); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Pesticides); 63231-63-0 (RNA); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173162



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