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1.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

2.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

3.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
4.
J Leukoc Biol ; 104(5): 925-930, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30134501

RESUMO

Atherosclerosis is a chronic inflammatory disease involving the infiltration of immune cells, such as monocytes/macrophages, neutrophils, T cells, and B cells, into the inner layer of vessel walls. T and B cell functions in the process of atherogenesis, as well as their mutual regulation, have been investigated but several aspects remain to be clarified. In the present review, we give a brief overview of the functions of follicular regulatory T cell (Tfr) on follicular T (Tfh) and B cell regulation related to atherosclerosis pathogenesis, including their influence on lymphangiogenesis and lipoprotein metabolism. We will also discuss their potential therapeutics properties in the resolution of established atherosclerotic lesions.

5.
Pesqui. vet. bras ; 38(7): 1278-1285, July 2018. tab
Artigo em Português | LILACS, VETINDEX | ID: biblio-976449

RESUMO

A presença de Salmonella spp. em produtos de origem avícola e seus subprodutos se mostra um grande desafio para a produção comercial. Dados de prevalência, dos sorotipos circulantes e do perfil de susceptibilidade antimicrobiana de cepas de Salmonella spp. no Estado do Rio de Janeiro são escassos. Portanto, objetivou-se detectar a presença Salmonella spp. em frangos vivos e carcaças em matadouros do Estados do Rio de Janeiro, identificar os sorotipos e avaliar a susceptibilidade antimicrobiana dessas cepas para fluoroquinolonas e betalactâmicos. Foram coletadas 60 amostras cloacais de frangos vivos e 60 amostras de carcaça de seis matadouros sob Inspeção Estadual (SIE). Os isolados foram sorotipificados e testados frente a oito antimicrobianos: enrofloxacina, ciprofloxacina, norfloxacina, cefalotina, ceftiofur, cefotaxima, amoxicilina/ácido clavulânico e ampicilina pelo método de difusão em disco. Os resultados mostraram uma prevalência de Salmonella spp. de 1,66% (1/60) em amostras de suabe de cloaca e de 26,66% (16/60) em carcaças. Em amostras de suabe de cloaca, somente o sorotipo Senftenberg (1,66%) foi isolado. No total, foram isolados sete sorotipos diferentes nas carcaças: Senftenberg (15%) o mais frequente, seguido por Mbandaka (8,3%), Schwarzengrund (3,3%), Cerro (3,3%), Ohio (3,3%), Minnesota (1,66%) e Tennessee (1,66%). Em relação à susceptibilidade antimicrobiana, 29 (87,87%) isolados foram sensíveis a todos os antimicrobianos testados e 4 (12,12%) isolados foram resistentes a pelo menos três antimicrobianos betalactâmicos ou mais. Não foi observada resistência às fluoroquinolonas. Os resultados encontrados demonstram uma prevalência de Salmonella spp. acima da esperada em matadouros do Estado do Rio de Janeiro, além da presença de vários sorotipos de Salmonella spp. A resistência encontrada para betalactâmicos alerta para a disseminação dessas cepas pela cadeia alimentar.(AU)


The presence of Salmonella spp. in poultry products and their by-products is a major challenge for commercial production. Data about the prevalence, the circulating serotypes and the antimicrobial susceptibility profile of Salmonella spp. strains in the State of Rio de Janeiro are scarce. Therefore, the aim of this study was to detect the presence of Salmonella spp. in live chickens and carcasses in slaughterhouses of the State of Rio de Janeiro, to identify the serotypes and to evaluate the antimicrobial susceptibility of these strains for fluoroquinolones and beta-lactams. Sixty cloacal swabs samples from broiler chickens and sixty samples of carcasses from six slaughterhouses under State Inspection were collected. The isolates were serotyped and resistance was tested to eight antimicrobials: enrofloxacin, ciprofloxacin, norfloxacin, cephalothin, ceftiofur, cefotaxime, amoxicillin/clavulanic acid and ampicillin by disc diffusion method. The results showed a prevalence of Salmonella spp. of 1.66% (1/60) in cloacal swabs samples and 26.66% (16/60) in carcasses. In cloacal swabs sample only Senftenberg (1.66%) serotype was isolated. In total, seven different serotypes were obtained from carcasses: Senftenberg (15%), followed by Mbandaka (8.3%), Schwarzengrund (3.3%), Cerro (3.3%), Ohio (3.3%), Minnesota (1.66%) and Tennessee (1.66%). Regarding antimicrobial susceptibility, 29 (87.87%) isolates were sensitive to all antimicrobials tested and 4 (12.12%) isolates were resistant to three or more beta-lactams antimicrobials. No susceptibility to fluoroquinolones was observed. These results showed a prevalence of Salmonella spp. higher than expected in slaughterhouses in the State of Rio de Janeiro, besides the presence of several serotypes of Salmonella spp. The resistance found for beta-lactams alerts to the spread of these strains through the food chain.(AU)


Assuntos
Animais , Aves Domésticas/microbiologia , Salmonella/isolamento & purificação , Anti-Infecciosos/isolamento & purificação , Prevalência , Suscetibilidade a Doenças
6.
J Am Soc Nephrol ; 29(1): 335-348, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29093028

RESUMO

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

7.
Nature ; 515(7525): 116-9, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25174710

RESUMO

Long-term synaptic potentiation (LTP) is thought to be a key process in cortical synaptic network plasticity and memory formation. Hebbian forms of LTP depend on strong postsynaptic depolarization, which in many models is generated by action potentials that propagate back from the soma into dendrites. However, local dendritic depolarization has been shown to mediate these forms of LTP as well. As pyramidal cells in supragranular layers of the somatosensory cortex spike infrequently, it is unclear which of the two mechanisms prevails for those cells in vivo. Using whole-cell recordings in the mouse somatosensory cortex in vivo, we demonstrate that rhythmic sensory whisker stimulation efficiently induces synaptic LTP in layer 2/3 (L2/3) pyramidal cells in the absence of somatic spikes. The induction of LTP depended on the occurrence of NMDAR (N-methyl-d-aspartate receptor)-mediated long-lasting depolarizations, which bear similarities to dendritic plateau potentials. In addition, we show that whisker stimuli recruit synaptic networks that originate from the posteromedial complex of the thalamus (POm). Photostimulation of channelrhodopsin-2 expressing POm neurons generated NMDAR-mediated plateau potentials, whereas the inhibition of POm activity during rhythmic whisker stimulation suppressed the generation of those potentials and prevented whisker-evoked LTP. Taken together, our data provide evidence for sensory-driven synaptic LTP in vivo, in the absence of somatic spiking. Instead, LTP is mediated by plateau potentials that are generated through the cooperative activity of lemniscal and paralemniscal synaptic circuitry.


Assuntos
Dendritos/fisiologia , Potenciação de Longa Duração , Córtex Somatossensorial/citologia , Córtex Somatossensorial/fisiologia , Potenciais de Ação , Animais , Channelrhodopsins , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Física , Receptores de N-Metil-D-Aspartato/metabolismo , Tálamo/citologia , Tálamo/fisiologia , Vibrissas/fisiologia
8.
Behav Brain Res ; 235(1): 42-7, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22800924

RESUMO

Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1 µl intra-dPAG injections of vehicle, 5.6 and 10 nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1 nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1 ml/10 g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5 min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01 nmol) enhanced it. Combined injections of ketanserin (10 nmol/0.1 µl), a 5-HT(2A/2C) receptor antagonist, and 0.01 nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01 nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice.


Assuntos
Analgésicos/farmacologia , Aprendizagem em Labirinto/fisiologia , Nociceptividade/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Ácido Acético/antagonistas & inibidores , Ácido Acético/farmacologia , Analgésicos/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Ketanserina/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Microinjeções , Nociceptividade/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/antagonistas & inibidores , Piperazinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacologia
9.
Brain Res ; 1294: 29-37, 2009 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-19635465

RESUMO

Intra-amygdala infusion of midazolam, a benzodiazepine receptor agonist, produces anxiolytic-like effects in mice when first exposed to the elevated plus-maze (EPM) and blocks antinociception induced in mice confined in the open arm of the EPM. However, benzodiazepines fail to alter anxiety in maze-experienced rodents, a phenomenon defined as "one-trial tolerance" (OTT). The main purpose of the present study was to investigate whether intra-amygdala midazolam attenuates the open arm-induced antinociception (OAA) in maze-experienced mice. Nociception was assessed by the writhing test (intra-peritoneal injection of 0.6% acetic acid). In Experiment 1, nociception was recorded in maze-experienced mice without prior drug treatment. Experiment 2 investigated the effects of systemic midazolam (0.5, 1.0 and 2.0 mg/kg, s.c.), injected before EPM trial 2, on OAA in maze-experienced mice. In Experiment 3, the effects on OAA of intra-amygdala midazolam (30 nmol/0.1 microl), injected before trial 1 (maze-naive) or before trial 2 (maze-experienced), were observed. The effects on OAA of intra-amygdala midazolam injected before trial 1 and trial 2 were also investigated (Experiment 4). The results showed that OAA remained unchanged in maze-experienced mice and was insensitive to systemic midazolam. However, intra-amygdala midazolam attenuated OAA in maze-naive mice, but not in maze-experienced mice. Even when given before both trial 1 and trial 2, intra-amygdala midazolam failed to alter OAA in maze-experienced mice. Taken together, these results confirm that the GABA(A)/benzodiazepine receptor complex located within the amygdala plays a role in OAA in maze-naive mice. The lack of effects following systemic or intra-amygdala midazolam on OAA in maze-experienced mice suggests that the OTT is also observed in the modulation of nociception and that the GABA(A)/benzodiazepine receptor located within this limbic forebrain structure participates in this process.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Ansiolíticos/farmacologia , Medo/efeitos dos fármacos , Midazolam/farmacologia , Dor/tratamento farmacológico , Ácido Acético , Tonsila do Cerebelo/fisiopatologia , Análise de Variância , Animais , Ansiolíticos/administração & dosagem , Cateterismo , Relação Dose-Resposta a Droga , Medo/fisiologia , Medo/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Microinjeções , Midazolam/administração & dosagem , Dor/fisiopatologia , Dor/psicologia , Medição da Dor , Fatores de Tempo
10.
Arch Insect Biochem Physiol ; 62(4): 164-75, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16933278

RESUMO

Lipophorin (Lp), either labeled in diacylglycerol moiety with [(3)H]-Palmitic acid or in phospholipid moiety with (32)Pi, was injected into Rhodnius prolixus females. Insects were induced to flight for different times. In just a few minutes of flight, the transfer of radioactivity to ovaries decreased, accompanied by its increase to flight muscles. After one hour of flight, Lp density was higher (1.132 g/mL) than before flight (1.116 g/mL). Lp purified from insects after flight was analyzed by gel filtration chromatography and a polyacrylamide gel pore limit electrophoresis. Both analyses demonstrated a decrease in Lp molecular mass after flight but no changes in apoLp-III amounts were observed. Time-course experiments showed that only 30 min of flight are required for the detection of changes in Lp density and molecular mass. About the same time of rest is necessary for Lp density and molecular mass to return to the baseline value. The lipid content from Lp particles, determined by high-performance thin-layer chromatography (HPTLC), showed a decrease in total lipids after flight. At the same time, an increase of many classes of lipids was observed in flight muscles except for triacylglycerol, which was reduced. The increase of flight muscle lipids was accompanied by a decrease of the ovaries lipid content. The insects subjected to daily exhaustive flight showed a significant decrease in total number of eggs produced. But insects subjected to a single exhaustive flight showed only a small reduction in total number of eggs. Lp density variation during the flight activity of Rhodnius prolixus females is discussed in association with physiological events such as oogenesis.


Assuntos
Voo Animal/fisiologia , Metabolismo dos Lipídeos/fisiologia , Lipoproteínas/metabolismo , Oogênese/fisiologia , Rhodnius/fisiologia , Animais , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel de Poliacrilamida , Feminino , Hemolinfa/metabolismo , Músculos/metabolismo , Radioisótopos de Fósforo/metabolismo , Trítio/metabolismo
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