Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
1.
Am J Pathol ; 193(11): 1627-1637, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37156326

RESUMO

Age-related macular degeneration (AMD) is a progressive, degenerative retinal disease that is a leading cause of blindness globally. Although multiple risk factors have been identified regarding disease incidence and progression, including smoking, genetics, and diet, the understanding of AMD pathogenesis remains unclear. As such, primary prevention is lacking, and current treatments have limited efficacy. More recently, the gut microbiome has emerged as an influential player in various ocular pathologies. As mediators of metabolism and immune regulation, perturbations in gut microbiota may impart significant effects distally on the neuroretina and its adjacent tissues, termed the gut-retina axis. In this review, key studies over the past several decades are summarized, both in humans and in animal models, which shed insight on the relationships between the gut microbiome and retinal biology and their implications for AMD. The literature linking gut dysbiosis with AMD is examined, along with preclinical animal models and techniques apt for studying the role of gut microbiota in AMD pathogenesis, which include interactions with systemic inflammation, immune regulation, chorioretinal gene expression, and diet. As understanding of the gut-retina axis continues to advance, so too will the possibility for more accessible and effective prevention and therapy of this vision-threatening condition.

2.
Blood ; 139(16): 2534-2546, 2022 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-35030251

RESUMO

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.


Assuntos
Anemia , Fator de Transcrição GATA1 , Diferenciação Celular/genética , Cromatina/genética , Imunoprecipitação da Cromatina , Eritropoese/genética , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Humanos
3.
Retina ; 44(3): 392-399, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37948745

RESUMO

PURPOSE: To examine the efficacy and clinical characteristics of successful full-thickness macular hole closure with topical therapy. METHODS: Retrospective case series of full-thickness macular holes managed by a single retinal physician (DS) diagnosed and treated from 2017 to 22. RESULTS: Of 168 patients with full-thickness macular holes, 71 patients were started on steroid, carbonic anhydrase inhibitor, and nonsteroidal antiinflammatory (NSAID) drops. 49 patients (mean 67 years, 59% women) were included in the analysis, and 22 patients were excluded for poor follow-up. In total, 7/49 were secondary post-PPV holes and 42/49 were idiopathic. In addition, 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10 µm decrease in size and odds of closure increased by 1.2× ( P = 0.001, CI 1.1-1.4). Average time to closure was 107.2 days (range 20-512 days) and was not correlated with hole size ( P = 0.217, CI -0.478 to +1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, P = 0.029, CI 1.2-31.3). There was no significant difference in final best-corrected visual acuity for eyes undergoing primary pars plana vitrectomy versus those trialing drops before undergoing pars plana vitrectomy ( P = 0.318, CI -0.094 to +0.112). CONCLUSION: In the first study to date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in central foveal thickness acted as predictors of effectiveness of drop therapy.


Assuntos
Perfurações Retinianas , Humanos , Feminino , Masculino , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/tratamento farmacológico , Perfurações Retinianas/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Tomografia de Coerência Óptica , Retina , Vitrectomia
4.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077073

RESUMO

Studies have begun to reveal significant connections between the gut microbiome and various retinal diseases, including age-related macular degeneration (AMD). As critical supporting tissues of the retina, the retinal pigment epithelium (RPE) and underlying choroid play a critical role in retinal homeostasis and degeneration. However, the relationship between the microbiome and RPE/choroid remains poorly understood, particularly in animal models of AMD. In order to better elucidate this role, we performed high-throughput RNA sequencing of RPE/choroid tissue in germ-free (GF) and specific pathogen-free (SPF) mice. Furthermore, utilizing a specialized laser-induced choroidal neovascularization (CNV) model that we developed, we compared CNV size and inflammatory response between GF and SPF mice. After correction of raw data, 660 differentially expressed genes (DEGs) were identified, including those involved in angiogenesis regulation, scavenger and cytokine receptor activity, and inflammatory response-all of which have been implicated in AMD pathogenesis. Among lasered mice, the GF group showed significantly decreased CNV lesion size and microglial infiltration around CNV compared to the SPF group. Together, these findings provide evidence for a potential gut-RPE/choroidal axis as well as a correlation with neovascular features of AMD.


Assuntos
Neovascularização de Coroide , Microbioma Gastrointestinal , Degeneração Macular , Animais , Corioide/irrigação sanguínea , Neovascularização de Coroide/genética , Neovascularização de Coroide/patologia , Degeneração Macular/genética , Degeneração Macular/patologia , Camundongos , Camundongos Endogâmicos C57BL , Epitélio Pigmentado da Retina/patologia , Transcriptoma
5.
Am J Pathol ; 193(11): 1622-1626, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37683929
6.
Regul Toxicol Pharmacol ; 79 Suppl 1: S3-S10, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27230736

RESUMO

Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations.


Assuntos
Contaminação de Medicamentos/prevenção & controle , Indústria Farmacêutica , Nível de Efeito Adverso não Observado , Exposição Ocupacional/prevenção & controle , Saúde Ocupacional , Preparações Farmacêuticas/análise , Animais , Difusão de Inovações , Contaminação de Medicamentos/legislação & jurisprudência , Indústria Farmacêutica/história , Indústria Farmacêutica/legislação & jurisprudência , Indústria Farmacêutica/normas , Indústria Farmacêutica/tendências , Previsões , Guias como Assunto , Política de Saúde , História do Século XX , História do Século XXI , Humanos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/legislação & jurisprudência , Exposição Ocupacional/normas , Saúde Ocupacional/história , Saúde Ocupacional/legislação & jurisprudência , Saúde Ocupacional/normas , Saúde Ocupacional/tendências , Preparações Farmacêuticas/classificação , Preparações Farmacêuticas/normas , Formulação de Políticas , Controle de Qualidade , Medição de Risco , Testes de Toxicidade
7.
bioRxiv ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38826324

RESUMO

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome- based identification to be successful and explored various features of these data.

8.
Nat Genet ; 55(7): 1198-1209, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37386249

RESUMO

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.


Assuntos
DNA Mitocondrial , Doenças Mitocondriais , Humanos , DNA Mitocondrial/genética , Multiômica , Doenças Mitocondriais/genética , Mitocôndrias/genética , Mutação
9.
Nat Biotechnol ; 2023 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-37537502

RESUMO

Single-cell assay for transposase-accessible chromatin by sequencing (scATAC-seq) has emerged as a powerful tool for dissecting regulatory landscapes and cellular heterogeneity. However, an exploration of systemic biases among scATAC-seq technologies has remained absent. In this study, we benchmark the performance of eight scATAC-seq methods across 47 experiments using human peripheral blood mononuclear cells (PBMCs) as a reference sample and develop PUMATAC, a universal preprocessing pipeline, to handle the various sequencing data formats. Our analyses reveal significant differences in sequencing library complexity and tagmentation specificity, which impact cell-type annotation, genotype demultiplexing, peak calling, differential region accessibility and transcription factor motif enrichment. Our findings underscore the importance of sample extraction, method selection, data processing and total cost of experiments, offering valuable guidance for future research. Finally, our data and analysis pipeline encompasses 169,000 PBMC scATAC-seq profiles and a best practices code repository for scATAC-seq data analysis, which are freely available to extend this benchmarking effort to future protocols.

10.
Appetite ; 59(3): 927-32, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22967817

RESUMO

Developing interventions to prevent and treat obesity are medical and public health imperatives. Taste is a major determinant of food intake and reliable methods to measure taste preferences need to be established. This study aimed to establish the short-term reproducibility of sweet taste preference measurements using 5-level sucrose concentrations in healthy adult volunteers. We defined sweet taste preference as the geometric mean of the preferred sucrose concentration determined from two series of two-alternative, forced-choice staircase procedures administered 10min apart on a single day. We repeated the same procedures at a second visit 3-7days later. Twenty-six adults (13 men and 13 women, age 33.2±12.2years) completed the measurements. The median number of pairs presented for each series was three (25th and 75th percentiles: 3, 4). The intraclass correlation coefficients between the measurements was 0.82 (95% confidence interval [CI]: 0.63-0.92) within a few days. This study showed high short-term reproducibility of a simple, 5-level procedure for measuring sweet taste preferences. This method may be useful for assessing sweet taste preferences and the risks resulting from those preferences.


Assuntos
Dieta , Ingestão de Energia , Preferências Alimentares , Sacarose , Edulcorantes , Percepção Gustatória , Paladar , Adolescente , Adulto , Sacarose Alimentar , Feminino , Humanos , Masculino , Obesidade/prevenção & controle , Reprodutibilidade dos Testes , Fatores de Risco , Adulto Jovem
11.
J Alzheimers Dis ; 89(1): 309-321, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35871353

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer's disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference. OBJECTIVE: To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD. METHODS: Expression of target genes are determined by qPCR in postmortem hippocampus (Hip) and anterior cingulate cortex (ACC) of individuals with dementia and autopsy confirmed AD and those of AD+MDD. RESULTS: Transcript levels of the antioxidant enzymes catalase (CAT) and superoxide dismutase 1 (SOD1), as well as IGF2 and its receptor (IGF2R) were significantly lower in the Hip and ACC of individuals with both AD and MDD compared to those with AD and no MDD. Expressions of Progestin and AdipoQ Receptor Family Member 7 (PAQR7, alias progesterone receptor alpha, mPRa) and PAQR8 (mPRß), receptors that bind neurosteroids, were also lower in the Hip and ACC of AD+MDD samples compared to those of AD without MDD. Correlations among these transcripts revealed that estrogen receptor 2 (ESR2) and mPR ß are direct or indirect regulators of the expression of the antioxidant enzymes and IGF2R. CONCLUSION: Reduced levels of antioxidant enzymes, decreased IGF2 expression, and diminished estrogen or membrane progesterone receptor-dependent processes might be more pronounced in the subpopulation of individuals with AD and MDD than without MDD.


Assuntos
Doença de Alzheimer , Transtorno Depressivo Maior , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Antioxidantes/metabolismo , Depressão , Transtorno Depressivo Maior/genética , Estrogênios , Feminino , Giro do Cíngulo/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo
12.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857290

RESUMO

Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Polimorfismo de Nucleotídeo Único/genética , Trombocitopenia/genética , Adolescente , Adulto , Idoso , Linhagem Celular , Linhagem Celular Tumoral , Criança , Quebra Cromossômica , Transtornos Cromossômicos/genética , Exoma/genética , Feminino , Células HEK293 , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Trombocitopenia/congênito
13.
Nat Biotechnol ; 39(4): 451-461, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32788668

RESUMO

Natural mitochondrial DNA (mtDNA) mutations enable the inference of clonal relationships among cells. mtDNA can be profiled along with measures of cell state, but has not yet been combined with the massively parallel approaches needed to tackle the complexity of human tissue. Here, we introduce a high-throughput, droplet-based mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), a method that combines high-confidence mtDNA mutation calling in thousands of single cells with their concomitant high-quality accessible chromatin profile. This enables the inference of mtDNA heteroplasmy, clonal relationships, cell state and accessible chromatin variation in individual cells. We reveal single-cell variation in heteroplasmy of a pathologic mtDNA variant, which we associate with intra-individual chromatin variability and clonal evolution. We clonally trace thousands of cells from cancers, linking epigenomic variability to subclonal evolution, and infer cellular dynamics of differentiating hematopoietic cells in vitro and in vivo. Taken together, our approach enables the study of cellular population dynamics and clonal properties in vivo.


Assuntos
DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mitocôndrias/genética , Neoplasias/genética , Análise de Célula Única/métodos , Idoso de 80 Anos ou mais , Diferenciação Celular , Células Cultivadas , Evolução Clonal , Células Clonais , Epigênese Genética , Feminino , Técnicas de Genotipagem , Hematopoese , Humanos , Mutação , Análise de Sequência de DNA
14.
Nat Biotechnol ; 39(10): 1246-1258, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34083792

RESUMO

Recent technological advances have enabled massively parallel chromatin profiling with scATAC-seq (single-cell assay for transposase accessible chromatin by sequencing). Here we present ATAC with select antigen profiling by sequencing (ASAP-seq), a tool to simultaneously profile accessible chromatin and protein levels. Our approach pairs sparse scATAC-seq data with robust detection of hundreds of cell surface and intracellular protein markers and optional capture of mitochondrial DNA for clonal tracking, capturing three distinct modalities in single cells. ASAP-seq uses a bridging approach that repurposes antibody:oligonucleotide conjugates designed for existing technologies that pair protein measurements with single-cell RNA sequencing. Together with DOGMA-seq, an adaptation of CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) for measuring gene activity across the central dogma of gene regulation, we demonstrate the utility of systematic multi-omic profiling by revealing coordinated and distinct changes in chromatin, RNA and surface proteins during native hematopoietic differentiation and peripheral blood mononuclear cell stimulation and as a combinatorial decoder and reporter of multiplexed perturbations in primary T cells.


Assuntos
RNA-Seq/métodos , Análise de Célula Única/métodos , Diferenciação Celular , Linhagem da Célula , Cromatina/genética , Cromatina/metabolismo , DNA Mitocondrial/genética , Epigenômica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Proteínas/genética , Proteínas/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
15.
Am J Gastroenterol ; 105(6): 1266-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20040914

RESUMO

OBJECTIVES: Arbaclofen placarbil (AP), previously designated as XP19986, is an investigational prodrug of the active R-isomer of baclofen, a gamma-aminobutyric acid agonist reflux inhibitor. The aim of this study was to assess the efficacy and safety of AP for decreasing meal-induced reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: We conducted a multicenter, randomized, double-blind, crossover study comparing single doses of AP with placebo. Different patients were enrolled at each of four escalating AP doses: 10, 20, 40, and 60 mg. Enrolled patients had GERD symptoms at least three times a week and 20 reflux episodes on impedance/pH monitoring over a period of 2 h. During study visits separated by periods of 3-7 days, patients received single doses of AP or placebo, followed by high-fat meals 2 and 6 h after treatment. The primary end point was the number of reflux episodes over 12 h after treatment. RESULTS: A total of 50 patients were treated; efficacy analysis included 44 patients who received both AP and placebo and had technically satisfactory impedance/pH data. For the combined data from all dose cohorts, there was a statistically significant (P=0.01) decrease in reflux episodes over 12 h after treatment with AP compared with placebo. The mean (s.d.) number of reflux episodes over 12 h after AP treatment was 50.5 (27.2), with a mean reduction of 10.4 (23.9) episodes (17%) compared with placebo, for which a mean (s.d.) number of 60.9 (35.3) episodes was observed. Heartburn events associated with reflux were reduced during treatment with AP compared with placebo. AP seemed to be the most efficacious in the 60-mg dose group, and was well tolerated at all dose levels. CONCLUSIONS: AP decreased reflux and associated symptoms with good tolerability in patients with GERD.


Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Pró-Fármacos/uso terapêutico , Adulto , Baclofeno/análogos & derivados , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento do pH Esofágico , Feminino , Azia/tratamento farmacológico , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Adulto Jovem
16.
Br J Clin Pharmacol ; 69(5): 498-507, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20573085

RESUMO

AIM: Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug-drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate). METHODS: Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination. RESULTS: When gabapentin enacarbil was co-administered with naproxen, gabapentin C(ss,max) increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUC(ss) increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated. CONCLUSIONS: No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine.


Assuntos
Carbamatos/farmacocinética , Cimetidina/farmacocinética , Naproxeno/farmacocinética , Ácido gama-Aminobutírico/análogos & derivados , Adolescente , Adulto , Transporte Biológico , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Cimetidina/administração & dosagem , Cimetidina/efeitos adversos , Constipação Intestinal/induzido quimicamente , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações Medicamentosas , Dispepsia/induzido quimicamente , Fadiga/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Naproxeno/administração & dosagem , Naproxeno/efeitos adversos , Pró-Fármacos , Adulto Jovem , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinética
17.
Front Behav Neurosci ; 14: 589967, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192370

RESUMO

Postpartum depression is a complex illness that often occurs in genetically predisposed individuals. Closely related inbred rat strains are a great resource to identify novel causative genes and mechanisms underlying complex traits such as postpartum behavior. We report differences in these behaviors between the inbred depression model, Wistar Kyoto (WKY) More Immobile (WMI), and the isogenic control Wistar Kyoto Less Immobile (WLI) dams. WMI dams showed significantly lower litter survival rate and frequency of arched back and blanket nursing, but increased pup-directed licking, grooming, and retrieval during postpartum days (PPD) 1-10, compared to control WLIs. This increased pup-directed behavior and the frequency of self-directed behaviors segregated during selective breeding of the progenitor strain of WKY, which is also a depression model. These behaviors are manifested in the WMIs in contrast to those of WLIs. Furthermore, habitual differences in the self-directed behavior between light and dark cycles present in WLIs were missing in WMI dams. Hypothalamic transcript levels of the circadian rhythm-related gene Lysine Demethylase 5A (Kdm5a), period 2 (Per2), and the maternal behavior-related oxytocin receptor (Oxtr), vasopressin (Avp), and vasopressin receptor 1a (Avpr1a) were significantly greater in the post-weaning WMI dams at PPD 24 compared to those of WLIs, and also to those of WMI dams whose litter died before PPD 5. Expression correlation amongst genes differed in WLI and WMI dams and between the two time-points postpartum, suggesting genetic and litter-survival differences between these strains affect transcript levels. These data demonstrate that the genetically close, but behaviorally disparate WMI and WLI strains would be suitable for investigating the underlying genetic basis of postpartum behavior.

18.
Neuroscience ; 444: 76-91, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768618

RESUMO

The role of stress in altering fear memory is not well understood. Since individual variations in stress reactivity exist, and stress alters fear memory, exposing individuals with differing stress-reactivity to repeated stress would affect their fear memory to various degrees. We explored this question using the average stress-reactive Fisher 344 (F344) rat strain and the Wistar-Kyoto (WKY) strain with its heightened stress-reactivity. Male F344 and WKY rats were exposed to the contextual fear conditioning (CFC) paradigm and then chronic restraint stress (CRS) or no stress (NS) was administered for two weeks before a second CFC. Both recent and reinstated fear memory were greater in F344s than WKYs, regardless of the stress status. In contrast, remote memory was attenuated only in F344s after CRS. In determining whether this strain-specific response to CRS was mirrored by transcriptomic changes in the blood, RNA sequencing was carried out. Overlapping differentially expressed genes (DEGs) between NS and CRS in the blood of F344 and WKY suggest a convergence of stress-related molecular mechanisms, independent of stress-reactivity. In contrast, DEGs unique to the F344 and the WKY stress responses are divergent in their functionality and networks, beyond that of strain differences in their non-stressed state. These results suggest that in some individuals chronic or repeated stress, different from the original fear memory-provoking stress, can attenuate prior fear memory. Furthermore, the novel blood DEGs can report on the general state of stress of the individual, or can be associated with individual variation in stress-responsiveness.


Assuntos
Medo , Transcriptoma , Animais , Masculino , Memória , Memória de Longo Prazo , Ratos , Ratos Endogâmicos WKY , Estresse Psicológico
19.
J Pharmacol Exp Ther ; 330(3): 911-21, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19502531

RESUMO

Baclofen is a racemic GABA(B) receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.


Assuntos
Baclofeno/farmacocinética , Agonistas GABAérgicos/farmacocinética , Pró-Fármacos/farmacocinética , Animais , Ligação Competitiva/efeitos dos fármacos , Butiratos/metabolismo , Carboxilesterase/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Células Cultivadas , Química Farmacêutica , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Hidrólise , Absorção Intestinal , Isobutiratos , Isoenzimas/efeitos dos fármacos , Células LLC-PK1 , Masculino , Membranas Artificiais , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Vinho
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA