Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 97
Filtrar
1.
J Toxicol Sci ; 46(9): 425-435, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34470994

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 enters host cells by binding with the receptor angiotensin-converting enzyme 2 (ACE2). While ACE2 is expressed in multiple cell types, it has been implicated in the clinical progression of COVID-19 as an entry point for SARS-CoV-2 into respiratory cells. Human respiratory cells, such as airway and alveolar epithelial type II (ATII) cells, are considered essential for COVID-19 research; however, primary human respiratory cells are difficult to obtain. In the present study, we generated ATII and club cells from human induced pluripotent stem cells (hiPSCs) for SARS-CoV-2 infection and drug testing. The differentiated cells expressed ATII markers (SFTPB, SFTPC, ABCA3, SLC34A2) or club cell markers (SCGB1A1 and SCGB3A2). Differentiated cells, which express ACE2 and TMPRSS2, were infected with SARS-CoV-2. Remdesivir treatment decreased intracellular SARS-CoV-2 viral replication and, furthermore, treatment with bleomycin showed cytotoxicity in a concentration-dependent manner. These data suggest that hiPSC-derived AT2 and club cells provide a useful in vitro model for drug development.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Células Epiteliais Alveolares/efeitos dos fármacos , Antivirais/farmacologia , Bleomicina/toxicidade , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Testes de Toxicidade , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , COVID-19/tratamento farmacológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/virologia , Fenótipo , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Replicação Viral/efeitos dos fármacos
2.
Oxid Med Cell Longev ; 2021: 6685204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336113

RESUMO

The developing brain is extremely sensitive to many chemicals. Perinatal exposure to neurotoxicants has been implicated in several neurodevelopmental disorders, including autism spectrum disorder, attention-deficit hyperactive disorder, and schizophrenia. Studies of the molecular and cellular events related to developmental neurotoxicity have identified a number of "adverse outcome pathways," many of which share oxidative stress as a key event. Oxidative stress occurs when the balance between the production of free oxygen radicals and the activity of the cellular antioxidant system is dysregulated. In this review, we describe some of the developmental neurotoxins that target the antioxidant system and the mechanisms by which they elicit stress, including oxidative phosphorylation in mitochondria and plasma membrane redox system in rodent models. We also discuss future directions for identifying adverse outcome pathways related to oxidative stress and developmental neurotoxicity, with the goal of improving our ability to quickly and accurately screen chemicals for their potential developmental neurotoxicity.

3.
J Toxicol Sci ; 46(8): 359-369, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334557

RESUMO

Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the anti-hepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was withdrawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addition, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.

4.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298877

RESUMO

Growing evidence suggests that breast cancer originates from a minor population of cancer cells termed cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry analysis. However, novel therapeutic drugs for the eradication of CSCs have not been discovered yet. Recently, drug repositioning, which finds new medical uses from existing drugs, has been expected to facilitate drug discovery. We have previously reported that sphingosine kinase 1 (SphK1) induced proliferation of breast CSCs. In the present study, we focused on the immunosuppressive agent FTY720 (also known as fingolimod or Gilenya), since FTY720 is known to be an inhibitor of SphK1. We found that FTY720 blocked both proliferation of ALDH-positive cells and formation of mammospheres. In addition, we showed that FTY720 reduced the expression of stem cell markers such as Oct3/4, Sox2 and Nanog via upregulation of protein phosphatase 2A (PP2A). These results suggest that FTY720 is an effective drug for breast CSCs in vitro.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cloridrato de Fingolimode/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Proteína Fosfatase 2/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Células MCF-7 , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
Elife ; 102021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34212860

RESUMO

The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology, and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability, and immature phenotype of the iPSC-CM platform. The rationale for combining translation and classification tasks is because the most likely application of the deep learning technology we describe here is to translate iPSC-CMs following application of a perturbation. The deep learning network was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.

6.
Nihon Yakurigaku Zasshi ; 156(4): 208-213, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34193697

RESUMO

The mission of regulatory science is to promote human longevity by providing safer and more effective drugs and ensuring human health. At present, various in vitro and in vivo evaluation methods are used for drug development, and no major problems have been observed. However, there is still room for improvement in terms of risk prediction in humans. Thus, new approaches and methodologies (NAMs) have recently been developed to predict adverse events in humans more accurately. Based on the animal alternative methods and the current COVID-19 pandemic, in vitro methods, such as human iPS cells, and computational approach are accelerated to improve the efficiency of drug development, ensure the patients' safety and speed up the review process. In this review, we would like to summarize the current status and future perspectives of pharmacological assay system using NAM in drug development.


Assuntos
COVID-19 , Pandemias , Alternativas aos Testes com Animais , Animais , Desenvolvimento de Medicamentos , Humanos , SARS-CoV-2
7.
Methods Mol Biol ; 2320: 151-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302656

RESUMO

Human-induced pluripotent stem cell (iPSC) technology paves the way for next-generation drug-safety assessment. In particular, human iPSC-derived cardiomyocytes, which exhibit electrical activity, are useful as a human cell model for assessing QT-interval prolongation and the risk of the lethal arrhythmia Torsade de Pointes (TdP). In addition to proarrhythmia assay, contractile behavior has received increased attention in drug development. In this study, we developed a novel high-throughput in vitro assay system using motion vectors to evaluate the contractile activity of iPSC-derived cardiomyocytes as a physiologically relevant human platform. The methods presented here highlight the use of commercially available iPSC-derived cardiomyocytes, iCell cardiomyocytes, for contractility evaluation recorded by the motion vector system.


Assuntos
Bioensaio/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Arritmias Cardíacas/terapia , Células Cultivadas , Humanos , Síndrome do QT Longo/terapia , Torsades de Pointes/terapia
8.
Nihon Yakurigaku Zasshi ; 156(4): 207, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34193696
9.
Toxicol Sci ; 183(1): 227-239, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34142159

RESUMO

Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In this study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat, and ivermectin had little effect on field potentials. We then analyzed electromechanical window, which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased electromechanical window of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs had little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in nonclinical settings.


Assuntos
COVID-19 , Células-Tronco Pluripotentes Induzidas , COVID-19/tratamento farmacológico , Cardiotoxicidade , Células Cultivadas , Humanos , Miócitos Cardíacos , SARS-CoV-2
10.
Methods Mol Biol ; 2367: 27-35, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661485

RESUMO

The small intestine plays roles in the absorption and metabolism of orally administered drugs and chemicals. Tight junctions between intestinal epithelial cells, which form a tight barrier preventing the invasion of pathogens and toxins, are essential components of the intestinal defense system. These intestinal functions have generally been evaluated using established cell lines or primary cells in two-dimensional culture. However, these culture systems have not shown the complexity of the three-dimensional structure and diversity of cell types comprising the intestinal epithelial tissue. Here, we report the generation of intestinal organoids using human induced pluripotent stem cells subjected to sequential treatment with different cytokines and compounds. We further describe the tool for evaluating intestinal barrier functions using organoids as a physiologically relevant human platform.

11.
Nihon Yakurigaku Zasshi ; 156(2): 107-113, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33642528

RESUMO

Predicting drug-induced side effects in central nervous system is important because they can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although many efforts are made, evaluation system using animals have not been highly predictive in humans. In addition, animal experiments are time-consuming and costly. To address these issues, in vitro evaluation methods, such as the use of New Approach Methodologies (NAM) have been explored. Human iPS cell technology has already been applied to assess drug-induced cardiotoxicity. In addition, the use of human iPS cell technology and in silico has been promoted for neurotoxicity assessment during the developmental neurotoxicity in terms of chemical safety issues. Organization for Economic Cooperation and Development (OECD) guidance regarding developmental neurotoxicity is under preparation. In this review, we will review the current trends in safety assessment methods for the central nervous system in light of these international trends.


Assuntos
Células-Tronco Pluripotentes Induzidas , Síndromes Neurotóxicas , Animais , Simulação por Computador , Humanos , Síndromes Neurotóxicas/etiologia
12.
Toxicol Sci ; 181(1): 125-133, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33544870

RESUMO

In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n = 5 for each dose), dl-sotalol (0, 1, 3, and 10 mg/kg, n = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl-sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl-sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol >bepridil ≥cisapride >verapamil in our study. Since the order was bepridil ≥dl-sotalol >cisapride >verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.


Assuntos
Bloqueio Atrioventricular , Torsades de Pointes , Animais , Bepridil , Cisaprida/toxicidade , Simulação por Computador , Macaca fascicularis , Sotalol/toxicidade , Torsades de Pointes/induzido quimicamente , Verapamil/toxicidade
13.
J Med Chem ; 64(1): 516-526, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33369416

RESUMO

Lithocholic acid (2) was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to 2. Among the synthesized compounds, 6 bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of 2 showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid (2) and 3 times more potent than 1α,25-dihydroxyvitamin D3 (1). Although the binding affinities of 6 and its epimer 7 were less than that of 1, their transactivation activities were greater than that of 1. X-ray structure analyses of VDR LBD bound to 6 or 7 showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of 1.


Assuntos
Ácido Litocólico/farmacologia , Receptores de Calcitriol/agonistas , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Ligantes , Ácido Litocólico/administração & dosagem , Ácido Litocólico/química , Estrutura Molecular , Ligação Proteica , Receptores de Calcitriol/metabolismo
14.
PLoS One ; 15(11): e0241287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137106

RESUMO

Currently, cardiomyocyte (CM) differentiation methods require a purification step after CM induction to ensure the high purity of the cell population. Here we show an improved human CM differentiation protocol with which high-purity ventricular-type CMs can be obtained and maintained without any CM purification process. We induced and collected a mesodermal cell population (platelet-derived growth factor receptor-α (PDGFRα)-positive cells) that can respond to CM differentiation cues, and then stimulated CM differentiation by means of Wnt inhibition. This method reproducibly generated CMs with purities above 95% in several human pluripotent stem cell lines. Furthermore, these CM populations were maintained in culture at such high purity without any further CM purification step for over 200 days. The majority of these CMs (>95%) exhibited a ventricular-like phenotype with a tendency to structural and electrophysiological maturation, including T-tubule-like structure formation and the ability to respond to QT prolongation drugs. This is a simple and valuable method to stably generate CM populations suitable for cardiac toxicology testing, disease modeling and regenerative medicine.


Assuntos
Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Mesoderma/crescimento & desenvolvimento , Miócitos Cardíacos/citologia , Técnicas de Cultura de Células/métodos , Linhagem da Célula/genética , Fenômenos Eletrofisiológicos , Ventrículos do Coração/citologia , Humanos , Mesoderma/citologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Wnt/antagonistas & inibidores
15.
Front Cell Dev Biol ; 8: 542562, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33015053

RESUMO

Contractility of the human heart increases as its beating rate is elevated, so-called positive force-frequency relationship; however, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been reported to exert a negative force-frequency relationship. We tested the hypothesis that the regulation of motion directions by electrical pacing and/or oxygen supply may improve the electro-mechanical properties of hiPSC-CMs monolayers. To better evaluate the spatial and temporal relationship between electrical excitation and contractile motion, we simultaneously observed the field potential and motion vector of hiPSC-CMs sheets. Under spontaneous contraction, although an electrical excitation originating from a region propagated unidirectionally over the cell sheet, contraction wave started from multiple sites, and relaxation wave was initiated from a geometric center of hiPSC-CMs sheet. During electrical pacing, contraction and relaxation waves were propagated from the stimulated site. Interestingly, the maximum contraction speed was more increased when the hiPSC-CMs sheet was stimulated at an area relaxation initiated under spontaneous condition. Furthermore, motion vector analysis demonstrated that "positive contraction velocity-frequency relationship" in contraction and "frequency-dependent enhancement of relaxation" were produced in the cell sheet by optimizing the direction and order of the contractile motion with pacing at the relaxation-initiating area. A close analysis of motion vectors along with field potential recording demonstrated that relaxation process consists of fast and slow phases, and suggest that intracellular Ca2+ dynamics may be closely related to functions of Ca2+-ATPase pump and Na+-Ca2+ exchangers. Namely, the slow relaxation phase occurred after the second peak of field potential, suggesting that the slow phase may be associated with extrusion of Ca2+ by Na+-Ca2+ exchangers during repolarization. Increase of oxygen concentration from 20 to 95% as well as ß-adrenergic stimulation with isoproterenol accelerated the fast relaxation, suggesting that it could depend on Ca2+ uptake via Ca2+-ATPase during the depolarization phase. The ratio of maximum contraction speed to field potential duration was increased by the ß-adrenergic stimulation, indicating the elevated contraction efficiency per Ca2+-influx. Thus, these findings revealed potential ability of conventional monolayers of hiPSC-CMs, which will help apply them to translational study filling the gap between physiological as well as pharmacological studies and clinical practice.

16.
Toxicol In Vitro ; 69: 104999, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32949729

RESUMO

The Organization for Economic Co-operation and Development (OECD) test guideline 426 for developmental neurotoxicity (DNT) of industrial/environmental chemicals depends primarily on animal experimentation. This requirement raises various critical issues, such as high cost, long duration, the sacrifice of large numbers of animals, and interspecies differences. This study demonstrates an alternative protocol that is simple, quick, less expensive, and standardized to evaluate DNT of many chemicals using human induced pluripotent stem cells (iPSC) and their differentiation to neural progenitor cells (NPC). Initially, concentration-dependent cytotoxicity of 35 DNT chemicals, including industrial materials, insecticides, and clinical drugs, were compared among iPSC, NPC, and two transformed cells, Cos-7 and HepG2, using tetrazolium dye (MTS)-reducing colorimetric and ATP luciferase assays, and IC50 values were calculated. Next, inhibitory effects of the 14 representative chemicals (mainly insecticides) on iPSC differentiation to NPC were evaluated by measuring altered expression of neural differentiation and undifferentiation marker genes. Results show that both iPSC and NPC were much more sensitive to most DNT chemicals than the transformed cells, and 14 chemicals induced differential patterns of marker gene expression, highlighting the validity and utility of the protocol for evaluation and classification of DNT chemicals and preclinical DNT tests for safety assessment.

17.
Regul Toxicol Pharmacol ; 117: 104756, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32822771

RESUMO

Human stem cell-derived cardiomyocytes (hSC-CMs) hold great promise as in vitro models to study the electrophysiological effects of novel drug candidates on human ventricular repolarization. Two recent large validation studies have demonstrated the ability of hSC-CMs to detect drug-induced delayed repolarization and "cellrhythmias" (interrupted repolarization or irregular spontaneous beating of myocytes) linked to Torsade-de-Pointes proarrhythmic risk. These (and other) studies have also revealed variability of electrophysiological responses attributable to differences in experimental approaches and experimenter, protocols, technology platforms used, and pharmacologic sensitivity of different human-derived models. Thus, when evaluating drug-induced repolarization effects, there is a need to consider 1) the advantages and disadvantages of different approaches, 2) the need for robust functional characterization of hSC-CM preparations to define "fit for purpose" applications, and 3) adopting standardized best practices to guide future studies with evolving hSC-CM preparations. Examples provided and suggested best practices are instructional in defining consistent, reproducible, and interpretable "fit for purpose" hSC-CM-based applications. Implementation of best practices should enhance the clinical translation of hSC-CM-based cell and tissue preparations in drug safety evaluations and support their growing role in regulatory filings.

18.
J Occup Health ; 62(1): e12135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32715571

RESUMO

OBJECTIVES: Although 1-Bromopropane (1-BP) exposure has been reported to cause neurotoxicity in adult humans and animals, its effects on the development of the central nervous system remain unclear. Recently, we reported delayed developmental neurotoxicity (DNT) upon 1-BP exposure in rats. Here we aimed to study the effect of prenatal 1-BP exposure on the hippocampal excitability in the juvenile offspring. METHODS: Pregnant Wistar rats were exposed to vaporized 1-BP for 20 days (6 h/d) with concentrations of 0 (control), 400, or 700 ppm. Hippocampal slices were prepared from male offspring during postnatal days (PNDs) 13, 14, and 15. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded simultaneously from the CA1 region. RESULTS: In the exposed groups, the stimulation/response relationships of fEPSP slope and PS amplitude were enhanced more than in the control group at PND 14. Analysis of fEPSP-spike coupling demonstrated increased values of Top and Eslope50 in the exposed groups. Real-time PCR analysis showed a significant increase in the mRNA levels of the adult type Nav 1.1 Na+ channel subunit and the GluR1 glutamate receptor subunit in the hippocampus of the 700 ppm group at PND 14. CONCLUSIONS: Our results provide evidence that prenatal exposure to 1-BP accelerates developmental enhancement of hippocampal excitability in the pups before eye-opening. The current study suggests that our evaluation method of DNT is applicable to the industrial chemical 1-BP.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Excitabilidade Cortical/efeitos dos fármacos , Exposição por Inalação , Lactação , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Feminino , Hidrocarbonetos Bromados/efeitos adversos , Gravidez , Ratos , Ratos Wistar
19.
EMBO Mol Med ; 12(6): e12634, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32375201

RESUMO

Current demand for SARS-CoV-2 testing is straining material resource and labor capacity around the globe. As a result, the public health and clinical community are hindered in their ability to monitor and contain the spread of COVID-19. Despite broad consensus that more testing is needed, pragmatic guidance toward realizing this objective has been limited. This paper addresses this limitation by proposing a novel and geographically agnostic framework (the 4Ps framework) to guide multidisciplinary, scalable, resource-efficient, and achievable efforts toward enhanced testing capacity. The 4Ps (Prioritize, Propagate, Partition, and Provide) are described in terms of specific opportunities to enhance the volume, diversity, characterization, and implementation of SARS-CoV-2 testing to benefit public health. Coordinated deployment of the strategic and tactical recommendations described in this framework has the potential to rapidly expand available testing capacity, improve public health decision-making in response to the COVID-19 pandemic, and/or to be applied in future emergent disease outbreaks.


Assuntos
Infecções por Coronavirus/diagnóstico , Saúde Global , Pneumonia Viral/diagnóstico , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , RNA Viral/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Planejamento Estratégico
20.
Nihon Yakurigaku Zasshi ; 155(3): 164, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378636
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...