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1.
Regen Ther ; 22: 192-202, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36891355

RESUMEN

Microphysiological system (MPS), a new technology for in vitro testing platforms, have been acknowledged as a strong tool for drug development. In the central nervous system (CNS), the blood‒brain barrier (BBB) limits the permeation of circulating substances from the blood vessels to the brain, thereby protecting the CNS from circulating xenobiotic compounds. At the same time, the BBB hinders drug development by introducing challenges at various stages, such as pharmacokinetics/pharmacodynamics (PK/PD), safety assessment, and efficacy assessment. To solve these problems, efforts are being made to develop a BBB MPS, particularly of a humanized type. In this study, we suggested minimal essential benchmark items to establish the BBB-likeness of a BBB MPS; these criteria support end users in determining the appropriate range of applications for a candidate BBB MPS. Furthermore, we examined these benchmark items in a two-dimensional (2D) humanized tricellular static transwell BBB MPS, the most conventional design of BBB MPS with human cell lines. Among the benchmark items, the efflux ratios of P-gp and BCRP showed high reproducibility in two independent facilities, while the directional transports meditated through Glut1 or TfR were not confirmed. We have organized the protocols of the experiments described above as standard operating procedures (SOPs). We here provide the SOPs with the flow chart including entire procedure and how to apply each SOP. Our study is important developmental step of BBB MPS towards the social acceptance, which enable end users to check and compare the performance the BBB MPSs.

2.
Lab Chip ; 20(3): 537-547, 2020 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-31930237

RESUMEN

The microphysiological system (MPS) is a promising tool for predicting drug disposition in humans, although limited information is available on the quantitative assessment of sequential drug metabolism in MPS and its extrapolation to humans. In the present study, we first constructed a mechanism-based pharmacokinetic model for triazolam (TRZ) and its metabolites in the entero-hepatic two-organ MPS, composed of intestinal Caco-2 and hepatic HepaRG cells, and attempted to extrapolate the kinetic information obtained with the MPS to the plasma concentration profiles in humans. In the two-organ MPS and HepaRG single culture systems, TRZ was found to be metabolized into α- and 4-hydroxytriazolam and their respective glucuronides. All these metabolites were almost completely reduced in the presence of a CYP3A inhibitor, itraconazole, confirming sequential phase I and II metabolism. Both pharmacokinetic model-dependent and -independent analyses were performed, providing consistent results regarding the metabolic activity of TRZ: clearance of glucuronidation metabolites in the two-organ MPS was higher than that in the single culture system. The plasma concentration profile of TRZ and its two hydroxy metabolites in humans was quantitatively simulated based on the pharmacokinetic model, by incorporating several scaling factors representing quantitative gaps between the MPS and humans. Thus, the present study provided the first quantitative extrapolation of sequential drug metabolism in humans by combining MPS and pharmacokinetic modeling.


Asunto(s)
Dispositivos Laboratorio en un Chip , Hígado/metabolismo , Técnicas Analíticas Microfluídicas , Triazolam/metabolismo , Células CACO-2 , Humanos , Cinética , Hígado/patología , Técnicas Analíticas Microfluídicas/instrumentación , Modelos Biológicos , Triazolam/sangre , Triazolam/farmacocinética , Células Tumorales Cultivadas
3.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-31013780

RESUMEN

Hepatocyte growth factor (HGF) is an endogenously expressed bioactive substance that has a strong anti-apoptotic effect. In this study, we biochemically and histologically characterized the effects of rh-HGF on in vitro human hepatocyte injury and mouse acute liver failure (ALF) models, both of which were induced by antibody-mediated Fas signaling. rh-HGF inhibited intracellular caspase-3/7 activation and cytokeratin 18 (CK-18) fragment release in both models. Histologically, rh-HGF dramatically suppressed parenchymal damage and intrahepatic hemorrhage. Among the laboratory parameters, prothrombin time (PT) was strongly preserved by rh-HGF, and PT was well correlated with the degree of intrahepatic hemorrhage. These results showed that the anti-apoptotic effect of rh-HGF on hepatocytes coincided strikingly with the suppression of intrahepatic hemorrhage. PT was considered to be the best parameter that correlated with the intrahepatic hemorrhages associated with hepatocellular damage. The action of rh-HGF might derive not only from its anti-apoptosis effects on liver parenchymal cells but also from its stabilization of structural and vasculature integrity.


Asunto(s)
Apoptosis/efectos de los fármacos , Coagulación Sanguínea/efectos de los fármacos , Hemorragia/metabolismo , Factor de Crecimiento de Hepatocito/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatopatías/metabolismo , Proteínas Recombinantes/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Humanos , Concentración 50 Inhibidora , Hepatopatías/tratamiento farmacológico , Hepatopatías/etiología , Hepatopatías/patología , Fallo Hepático Agudo/sangre , Fallo Hepático Agudo/tratamiento farmacológico , Fallo Hepático Agudo/etiología , Fallo Hepático Agudo/patología , Masculino , Ratones , Tiempo de Protrombina , Receptor fas/metabolismo
4.
BMC Psychiatry ; 11: 56, 2011 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-21477384

RESUMEN

BACKGROUND: Depressive disorder is often chronic and recurrent, and results in a heavy psychosocial burden on the families of patients with this disorder. This study aims to examine the effectiveness of brief multifamily psychoeducation designed to alleviate their psychosocial burden. METHODS: Thirty-two relatives of patients with major depressive disorder participated in an open study testing the effectiveness of brief multifamily psychoeducation. The intervention consisted of four sessions over the course of 6 weeks. Outcome measures focused on emotional distress, care burden and Expressed Emotion (EE). RESULTS: The emotional distress, care burden and EE of the family all showed statistically significant improvements from baseline to after the family intervention. The proportion of relatives scoring 9 or more on K6, which indicates possible depressive or anxiety disorder, decreased from sixteen relatives (50.0%) at baseline, to only 3 relatives (9.3%) after the intervention. CONCLUSIONS: This study suggests that brief multifamily psychoeducation is a useful intervention to reduce the psychosocial burden of the relatives of patients with depressive disorder. Further evaluation of family psychoeducation for relatives of patients with depressive disorder is warranted.


Asunto(s)
Trastorno Depresivo Mayor/terapia , Salud de la Familia , Terapia Familiar/métodos , Familia/psicología , Educación del Paciente como Asunto/métodos , Adaptación Psicológica , Cuidadores/psicología , Costo de Enfermedad , Trastorno Depresivo Mayor/psicología , Emoción Expresada , Femenino , Humanos , Relaciones Interpersonales , Masculino , Persona de Mediana Edad , Proyectos Piloto , Psicoterapia Breve/métodos , Ajuste Social , Resultado del Tratamiento
5.
Assay Drug Dev Technol ; 5(4): 523-33, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17767420

RESUMEN

The kinase signaling cascades related to mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2, respectively) are attractive targets for pharmaceutical intervention, especially for neural injury. Therefore, we have developed a high throughput and cost-effective detection platform for measuring selective activity of MSK1/MSK2 in cells. Through the serial monitoring of both the p38 mitogen-activated protein kinase (stress-activated protein kinase 2B)-MSK1/MSK2- cyclic AMP response element binding protein (CREB)/activating transcription factor 1 (ATF1) pathway and the p38-mammalian heat shock protein 27 (Hsp27) pathway in HeLa cells treated with anisomycin, two selective MSK1 inhibitors showed inhibition of CREB (Ser-133) and ATF1 (Ser-63) phosphorylation and no interference with Hsp-27 phosphorylation (Ser-82). On the other hand, the p38 inhibitor SB-220025 showed equipotent inhibition of CREB/ATF1 and Hsp27 phosphorylation. This study demonstrated that the specific inhibition of a target kinase could be subsequently monitored by a secondary assay that measures the intervention arising from the modulation of off-target kinases. Our established system is applicable to inhibitor screening and drug discovery related to MSK1/MSK2.


Asunto(s)
Ensayo de Inmunoadsorción Enzimática/métodos , Proteína Quinasa 11 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Anisomicina/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Células HeLa , Proteínas de Choque Térmico/metabolismo , Humanos , Immunoblotting , Inmunoprecipitación , Fosforilación , Plásmidos/genética , Inhibidores de la Síntesis de la Proteína/farmacología , Transfección , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
6.
J Med Chem ; 50(18): 4453-70, 2007 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-17676829

RESUMEN

We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the N1 nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the N1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.


Asunto(s)
Bencimidazoles/síntesis química , Modelos Moleculares , Receptor TIE-2/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , Ratones , Estructura Molecular , Células 3T3 NIH , Fosforilación , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química
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