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  1 / 36970 MEDLINE  
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PMID:29351567
Autor:Ghandhi SA; Turner HC; Shuryak I; Dugan GO; Bourland JD; Olson JD; Tooze JA; Morton SR; Batinic-Haberle I; Cline JM; Amundson SA
Endereço:Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
Título:Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells.
Fonte:PLoS One; 13(1):e0191402, 2018.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta) that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI) allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT) and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN) assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected up to 8 months after irradiation. Regression analysis showed significant induction of micronuclei in NHP blood cells that persisted with a gradual decline over the 8-month study period, suggesting long-term DNA damage in blood lymphocytes after WTLI. We also report transcriptomic changes in blood up to 30 days after WTLI. We isolated total RNA from peripheral blood at 3 days before and then at 2, 5 and 30 days after irradiation. We identified 1187 transcripts that were significantly changed across the 30-day time course. From changes in gene expression, we identified biological processes related to immune responses, which persisted across the 30-day study. Response to oxygen-containing compounds and bacteria were implicated by gene-expression changes at the earliest day 2 and latest, day 30 time-points. Gene expression changes suggest a persistent altered state of the immune system, specifically response to infection, for at least a month after WTLI.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T


  2 / 36970 MEDLINE  
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PMID:29289882
Autor:Lara LS; Moreira CS; Calvet CM; Lechuga GC; Souza RS; Bourguignon SC; Ferreira VF; Rocha D; Pereira MCS
Endereço:Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil.
Título:Efficacy of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinone derivatives against different Trypanosoma cruzi discrete type units: Identification of a promising hit compound.
Fonte:Eur J Med Chem; 144:572-581, 2018 Jan 20.
ISSN:1768-3254
País de publicação:France
Idioma:eng
Resumo:The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T. cruzi Dm28c-luciferase) and/or counting with a light microscope. Reactive oxygen species (ROS) production and intracellular targets of promising compounds were assessed with 2',7'-dichlorodihydrofluorescein diacetate (H DCFDA) probe and ultrastructural analysis, respectively. ADMET properties were analyzed by in silico modeling. Most of the compounds showed low cytotoxic effect. Only two compounds (Compounds 2 and 11) had IC values lower than Bz, showing higher susceptibility of bloodstream trypomastigotes. Compound 2 exhibited greater efficacy against trypomastigotes from different T. cruzi DTUs, even better than Bz against Brazil and CL strains. Ultrastructural analysis revealed changes in intracellular compartments, suggesting autophagy as one possible mechanism of action. Oxidative stress, induced by Compound 2, resulted in elevated level of ROS, leading to parasite death. Compound 2 was also effective against intracellular amastigotes, showing high selectivity index. ADMET analysis predicted good oral bioavailability, reduced drug metabolism and no carcinogenic potential for Compound 2. The data highlight Compound 2 as a hit compound and stimulate further structural and pharmacological optimization to potentiate its trypanocidal activity and selectivity.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Naphthoquinones); 0 (Reactive Oxygen Species); 0 (Trypanocidal Agents)


  3 / 36970 MEDLINE  
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PMID:28466676
Autor:Backlund PS; Urbanski HF; Doll MA; Hein DW; Bozinoski M; Mason CE; Coon SL; Klein DC
Endereço:Biomedical Mass Spectrometry Facility, Intramural Research Program.
Título:Daily Rhythm in Plasma N-acetyltryptamine.
Fonte:J Biol Rhythms; 32(3):195-211, 2017 Jun.
ISSN:1552-4531
País de publicação:United States
Idioma:eng
Resumo:Normal physiology undergoes 24-h changes in function that include daily rhythms in circulating hormones, most notably melatonin and cortical steroids. This study focused on N-acetyltryptamine, a little-studied melatonin receptor mixed agonist-antagonist and the likely evolutionary precursor of melatonin. The central issue addressed was whether N-acetyltryptamine is physiologically present in the circulation. N-acetyltryptamine was detected by LC-MS/MS in daytime plasma of 3 different mammals in subnanomolar levels (mean ± SEM: rat, 0.29 ± 0.05 nM, n = 5; rhesus macaque, 0.54 ± 0.24 nM, n = 4; human, 0.03 ± 0.01 nM, n = 32). Analysis of 24-h blood collections from rhesus macaques revealed a nocturnal increase in plasma N-acetyltryptamine (p < 0.001), which varied from 2- to 15-fold over daytime levels among the 4 animals studied. Related RNA sequencing studies indicated that the transcript encoding the tryptamine acetylating enzyme arylalkylamine N-acetyltransferase (AANAT) is expressed at similar levels in the rhesus pineal gland and retina, thereby indicating that either tissue could contribute to circulating N-acetyltryptamine. The evidence that N-acetyltryptamine is a physiological component of mammalian blood and exhibits a daily rhythm, together with known effects as a melatonin receptor mixed agonist-antagonist, shifts the status of N-acetyltryptamine from pharmacological tool to candidate for a physiological role. This provides a new opportunity to extend our understanding of 24-h biology.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Tryptamines); 1016-47-3 (N-acetyltryptamine); EC 2.3.1.87 (Arylalkylamine N-Acetyltransferase); JL5DK93RCL (Melatonin)


  4 / 36970 MEDLINE  
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PMID:29374153
Autor:Lundqvist M; Herman P; Warden MR; Brincat SL; Miller EK
Endereço:The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA, 02139, USA. lundqvis@mit.edu.
Título:Gamma and beta bursts during working memory readout suggest roles in its volitional control.
Fonte:Nat Commun; 9(1):394, 2018 01 26.
ISSN:2041-1723
País de publicação:England
Idioma:eng
Resumo:Working memory (WM) activity is not as stationary or sustained as previously thought. There are brief bursts of gamma (~50-120 Hz) and beta (~20-35 Hz) oscillations, the former linked to stimulus information in spiking. We examined these dynamics in relation to readout and control mechanisms of WM. Monkeys held sequences of two objects in WM to match to subsequent sequences. Changes in beta and gamma bursting suggested their distinct roles. In anticipation of having to use an object for the match decision, there was an increase in gamma and spiking information about that object and reduced beta bursting. This readout signal was only seen before relevant test objects, and was related to premotor activity. When the objects were no longer needed, beta increased and gamma decreased together with object spiking information. Deviations from these dynamics predicted behavioral errors. Thus, beta could regulate gamma and the information in WM.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T


  5 / 36970 MEDLINE  
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PMID:27770624
Autor:Rocchi F; Dylla ME; Bohlen PA; Ramachandran R
Endereço:Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
Título:Spatial and temporal disparity in signals and maskers affects signal detection in non-human primates.
Fonte:Hear Res; 344:1-12, 2017 Feb.
ISSN:1878-5891
País de publicação:Netherlands
Idioma:eng
Resumo:Detection thresholds for auditory stimuli (signals) increase in the presence of maskers. Natural environments contain maskers/distractors that can have a wide range of spatiotemporal properties relative to the signal. While these parameters have been well explored psychophysically in humans, they have not been well explored in animal models, and their neuronal underpinnings are not well understood. As a precursor to the neuronal measurements, we report the effects of systematically varying the spatial and temporal relationship between signals and noise in macaque monkeys (Macaca mulatta and Macaca radiata). Macaques detected tones masked by noise in a Go/No-Go task in which the spatiotemporal relationships between the tone and noise were systematically varied. Masked thresholds were higher when the masker was continuous or gated on and off simultaneously with the signal, and lower when the continuous masker was turned off during the signal. A burst of noise caused higher masked thresholds if it completely temporally overlapped with the signal, whereas partial overlap resulted in lower thresholds. Noise durations needed to be at least 100 ms before significant masking could be observed. Thresholds for short duration tones were significantly higher when the onsets of signal and masker coincided compared to when the signal was presented during the steady state portion of the noise (overshoot). When signal and masker were separated in space, masked signal detection thresholds decreased relative to when the masker and signal were co-located (spatial release from masking). Masking release was larger for azimuthal separations than for elevation separations. These results in macaques are similar to those observed in humans, suggesting that the specific spatiotemporal relationship between signal and masker determine threshold in natural environments for macaques in a manner similar to humans. These results form the basis for future investigations of neuronal correlates and mechanisms of masking.
Tipo de publicação: JOURNAL ARTICLE


  6 / 36970 MEDLINE  
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PMID:29251972
Autor:Hutsell BA; Banks ML
Endereço:Department of Pharmacology and Toxicology, Virginia Commonwealth University.
Título:Remifentanil maintains lower initial delayed nonmatching-to-sample accuracy compared to food pellets in male rhesus monkeys.
Fonte:Exp Clin Psychopharmacol; 25(6):441-447, 2017 12.
ISSN:1936-2293
País de publicação:United States
Idioma:eng
Resumo:Emerging human laboratory and preclinical drug self-administration data suggest that a history of contingent abused drug exposure impairs performance in operant discrimination procedures, such as delayed nonmatching-to-sample (DNMTS), that are hypothesized to assess components of executive function. However, these preclinical discrimination studies have exclusively used food as the reinforcer and the effects of drugs as reinforcers in these operant procedures are unknown. The present study determined effects of contingent intravenous remifentanil injections on DNMTS performance hypothesized to assess 1 aspect of executive function, working memory. Daily behavioral sessions consisted of 2 components with sequential intravenous remifentanil (0, 0.01-1.0 µg/kg/injection) or food (0, 1-10 pellets) availability in nonopioid dependent male rhesus monkeys (n = 3). Remifentanil functioned as a reinforcer in the DNMTS procedure. Similar delay-dependent DNMTS accuracy was observed under both remifentanil- and food-maintained components, such that higher accuracies were maintained at shorter (0.1-1.0 s) delays and lower accuracies approaching chance performance were maintained at longer (10-32 s) delays. Remifentanil maintained significantly lower initial DNMTS accuracy compared to food. Reinforcer magnitude was not an important determinant of DNMTS accuracy for either remifentanil or food. These results extend the range of experimental procedures under which drugs function as reinforcers. Furthermore, the selective remifentanil-induced decrease in initial DNMTS accuracy is consistent with a selective impairment of attentional, but not memorial, processes. (PsycINFO Database Record
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
Nome de substância:0 (Anesthetics, Intravenous); 0 (Piperidines); P10582JYYK (remifentanil)


  7 / 36970 MEDLINE  
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PMID:29381706
Autor:Mohr EL; Block LN; Newman CM; Stewart LM; Koenig M; Semler M; Breitbach ME; Teixeira LBC; Zeng X; Weiler AM; Barry GL; Thoong TH; Wiepz GJ; Dudley DM; Simmons HA; Mejia A; Morgan TK; Salamat MS; Kohn S; Antony KM; Aliota MT; Mohns MS; Hayes JM; Schultz-Darken N; Schotzko ML; Peterson E; Capuano S; Osorio JE; O'Connor SL; Friedrich TC; O'Connor DH; Golos TG
Endereço:Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Título:Ocular and uteroplacental pathology in a macaque pregnancy with congenital Zika virus infection.
Fonte:PLoS One; 13(1):e0190617, 2018.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM), intraamniotic bacterial infection and fetal demise 49 days post infection (gestational day 95). Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout fetal tissues and maternal immune system tissues at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal uterus, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in a rhesus macaque. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital ZIKV infection previously. While this case of ZIKV infection during pregnancy was complicated by bacterial infection with PPROM, the role of ZIKV on this outcome cannot be precisely defined, and further nonhuman primate studies will determine if increased risk for PPROM or other adverse pregnancy outcomes are associated with congenital ZIKV infection.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (RNA, Viral)


  8 / 36970 MEDLINE  
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PMID:28467930
Autor:Park SJ; Gavrilova O; Brown AL; Soto JE; Bremner S; Kim J; Xu X; Yang S; Um JH; Koch LG; Britton SL; Lieber RL; Philp A; Baar K; Kohama SG; Abel ED; Kim MK; Chung JH
Endereço:Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Título:DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging.
Fonte:Cell Metab; 25(5):1135-1146.e7, 2017 May 02.
ISSN:1932-7420
País de publicação:United States
Idioma:eng
Resumo:Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 ((3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide); 0 (Benzofurans); 0 (Quinolines); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.31 (AMP-Activated Protein Kinases)


  9 / 36970 MEDLINE  
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PMID:29220358
Autor:Dorta-Estremera S; Nehete PN; Yang G; He H; Nehete BP; Shelton KA; Barry MA; Sastry KJ
Endereço:The University of Texas MD Anderson Cancer Center, Department of Immunology, Houston, TX, United States of America.
Título:Minimally invasive monitoring of CD4 T cells at multiple mucosal tissues after intranasal vaccination in rhesus macaques.
Fonte:PLoS One; 12(12):e0188807, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Studies in nonhuman primates (NHP) for prospective immune cell monitoring subsequent to infection and/or vaccination usually rely on periodic sampling of the blood samples with only occasional collections of biopsies from mucosal tissues because of safety concerns and practical constraints. Here we present evidence in support of cytobrush sampling of oral, rectal, and genital mucosal tissues as a minimally invasive approach for the phenotypic analyses of different T cells subsets de novo as well as prospectively after intranasal immunization in rhesus macaques. Significant percentages of viable lymphocytes were obtained consistently from both naïve and chronically SIV-infected rhesus macaques. The percentages of CD3+ T cells in the blood were significantly higher compared to those in the mucosal tissues analyzed in the naïve animals, while in the SIV+ animals the CD3+ T cells were significantly elevated in the rectal tissues, relative to all other sites analyzed. In the naïve, but not SIV+ macaques, the rectal and vaginal mucosal tissues, compared to oral mucosa and blood, showed higher diversity and percentages of CD4+ T cells expressing the HIV entry co-receptor CCR5 and mucosal specific adhesion (CD103) as well as activation (HLA-DR) and proliferation (Ki67) markers. Sequential daily cytobrush sampling from the oral, rectal, and genital mucosal tissues was performed in SIV+ animals from an ongoing study where they were administered intranasal immunization with adenoviral vectored vaccines incorporating the green fluorescent protein (GFP) reporter gene. We detected a transient increase in GFP+ CD4 T cells in only oral mucosa suggesting limited mucosal trafficking. In general, CD4+ and CD8+ T cells expressing Ki67 transiently increased in all mucosal tissues, but those expressing the CCR5, HLA-DR, and CD103 markers exhibited minor changes. We propose the minimally invasive cytobrush sampling as a practical approach for effective and prospective immune monitoring of the oral-genital mucosal tissues in NHP.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Viral Vaccines)


  10 / 36970 MEDLINE  
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PMID:28452143
Autor:Jain MR; Joharapurkar AA; Kshirsagar SG; Patel VJ; Bahekar RH; Patel HV; Jadav PA; Patel PR; Desai RC
Endereço:Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Título:ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.
Fonte:Br J Pharmacol; 174(14):2346-2357, 2017 Jul.
ISSN:1476-5381
País de publicação:England
Idioma:eng
Resumo:BACKGROUND AND PURPOSE: Dipeptidyl peptidase (DPP)-4 inhibitors increase levels of glucagon-like peptide-1 (GLP-1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP-4 inhibitor, ZY15557, that has a sustained action and long half-life. EXPERIMENTAL APPROACH: We studied the potency, selectivity, efficacy and duration of action of ZY15557, in vitro, with assays of DPP-4 activity. In vivo, the pharmacodymamics and pharmacokinetics of ZY15557 were studied, using db/db mice and Zucker fatty rats, along with normal mice, rats, dogs and non-human primates. KEY RESULTS: ZY15557 is a potent, competitive and long acting inhibitor of DPP-4 (K 5.53 nM; K 3.2 × 10 ·s , half-life 35.8 min). ZY15557 treatment inhibited DPP-4 activity, and enhanced active GLP-1 and insulin in mice and rats, providing dose-dependent anti-hyperglycaemic effects. Anti-hyperglycaemic effects were also observed in db/db mice and Zucker fatty rats. Following oral dosing, ZY15557 significantly inhibited plasma DPP-4 activity, determined ex vivo, in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicts a half-life for ZY15557 in humans of up to 60 h. CONCLUSIONS AND IMPLICATIONS: ZY15557 is a potent, competitive and long acting DPP-4 inhibitor. ZY15557 showed similar DPP-4 inhibition across different species. ZY15557 showed excellent oral bioavailability in preclinical species. It showed a low plasma clearance (CL) and large volume of distribution (V ) across species, resulting in an extended half-life.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Dipeptidyl-Peptidase IV Inhibitors); 0 (Pyrans); 0 (ZY15557); EC 3.4.14.5 (Dipeptidyl Peptidase 4)



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