Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
AAPS J ; 20(5): 90, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30109442

RESUMO

Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.


Assuntos
Técnicas de Cultura de Células , Células Epiteliais/efeitos dos fármacos , Nefropatias/induzido quimicamente , Túbulos Renais Proximais/efeitos dos fármacos , Moduladores de Transporte de Membrana/toxicidade , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Perfusão , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico , Linhagem Celular , Polaridade Celular , Cisplatino/toxicidade , Ciclosporina/toxicidade , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Dispositivos Lab-On-A-Chip , Proteínas de Membrana Transportadoras/metabolismo , Técnicas Analíticas Microfluídicas , Florizina/toxicidade , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/toxicidade , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
2.
Mol Hum Reprod ; 21(10): 803-15, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26194608

RESUMO

In this study, we aimed to investigate modulation of glucose uptake by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line by a series of compounds and to study its consequences upon cell proliferation, viability and migration. We observed that uptake of (3)H-deoxy-d-glucose ((3)H-DG; 10 nM) was time-dependent, saturable, inhibited by cytochalasin B (50 and 100 µM), phloretin (0.5 mM) and phloridzin (1 mM), insulin-insensitive and sodium-independent. In the short term (30 min), neither 5-HT (100-1000 µM), melatonin (10 nM) nor the drugs of abuse ethanol (100 mM), nicotine (100 µM), cocaine (25 µM), amphetamine (10-25 µM) and 3,4-methylenedioxy-N-methamphetamine (10 µM) affected (3)H-DG uptake, while dexamethasone (100-1000 µM), fluoxetine (100-300 µM), quercetin, epigallocatechin-3-gallate (30-1000 µM), xanthohumol (XH) and resveratrol (1-500 µM) decreased it. XH was the most potent inhibitor [IC50 = 3.55 (1.37-9.20) µM] of (3)H-DG uptake, behaving as a non-competitive inhibitor of (3)H-DG uptake, both after short- and long-term (24 h) treatment. The effect of XH (5 µM; 24 h) upon (3)H-DG uptake involved mammalian target of rapamycin, tyrosine kinases and c-Jun N-terminal kinases intracellular pathways. Moreover, XH appeared to decrease cellular uptake of lactate due to inhibition of the monocarboxylate transporter 1. Additionally, XH (24 h; 5 µM) decreased cell viability, proliferation, culture growth and migration. The effects of XH upon cell viability and culture growth, but not the antimigratory effect, were mimicked by low extracellular glucose conditions and reversed by high extracellular glucose conditions. We thus suggest that XH, by inhibiting glucose cellular uptake and impairing HTR-8/SVneo cell viability and proliferation, may have a deleterious impact in the process of placentation.


Assuntos
Desoxiglucose/metabolismo , Flavonoides/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Placentação/efeitos dos fármacos , Propiofenonas/farmacologia , Trofoblastos/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Transformada , Movimento Celular/efeitos dos fármacos , Citocalasina B/farmacologia , Citocalasina B/toxicidade , Dexametasona/farmacologia , Dexametasona/toxicidade , Feminino , Flavonoides/toxicidade , Glucose/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/fisiologia , Humanos , Drogas Ilícitas/farmacologia , Drogas Ilícitas/toxicidade , Melatonina/farmacologia , Melatonina/toxicidade , Floretina/farmacologia , Floretina/toxicidade , Florizina/farmacologia , Florizina/toxicidade , Polifenóis/farmacologia , Polifenóis/toxicidade , Gravidez , Primeiro Trimestre da Gravidez , Propiofenonas/toxicidade , Proteínas Tirosina Quinases/fisiologia , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Estilbenos/toxicidade , Serina-Treonina Quinases TOR/fisiologia , Trofoblastos/citologia
3.
Diabetes Metab Res Rev ; 21(1): 31-8, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15624123

RESUMO

The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia.


Assuntos
Diabetes Mellitus/fisiopatologia , Florizina/fisiologia , Animais , Transporte Biológico , Glucose/metabolismo , Glicosúria , Humanos , Florizina/farmacologia , Florizina/toxicidade
4.
J Anim Sci ; 76(11): 2938-46, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9856405

RESUMO

Four Dorset wethers were studied in a Latin square design with 72-h periods to determine the metabolic adaptations that occur in support of increased glucose demand in ruminants. Wethers injected at 8-h intervals with excipient or a total of .5, 1.0, or 2.0 g/d of phlorizin excreted an average of 0, 72.7, 97.9, and 98.5 g/d of glucose into the urine, respectively. Both acute (2 to 24 h after the first injection) and chronic (8-h intervals from 8 to 72 h after the first injection) adaptations of plasma variables to phlorizin treatment were assessed. Concentrations of plasma glucose decreased linearly with increasing phlorizin dose during the 1st 24 h of treatment and tended to decrease linearly with phlorizin dose during 8 to 72 h of treatment. Urea N tended to increase linearly during 2 to 24 h and increased linearly during 8 to 72 h. Nonesterified fatty acids increased linearly with phlorizin injection during the entire treatment period. beta-Hydroxybutyrate increased quadratically with phlorizin injection during 2 to 24 h and tended to increase quadratically during 8 to 72 h. The ratio of insulin to glucagon tended to decrease linearly with phlorizin injection during the 1st 24 h but was unaffected from 8 to 72 h. Triiodothyronine, but not thyroxine, tended to decrease linearly with phlorizin injection during 8 to 72 h. Cortisol was not affected by treatment. Digestibilities of energy and N were not affected by treatment. Urinary energy excretion increased with phlorizin injection in proportion to the amounts of glucose excreted into the urine. These data indicate that phlorizin-treated wethers largely adapted to phlorizin treatment by 24 h after the first injection and are a suitable model for further investigations of hepatic adaptation to increased glucose demand in ruminants.


Assuntos
Glucose/metabolismo , Glicosúria/veterinária , Florizina/toxicidade , Ovinos/metabolismo , Ácido 3-Hidroxibutírico/sangue , Animais , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/sangue , Glucagon/sangue , Gluconeogênese/efeitos dos fármacos , Glicosúria/induzido quimicamente , Glicosúria/metabolismo , Hidrocortisona/sangue , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Florizina/administração & dosagem , Ovinos/urina , Doenças dos Ovinos/induzido quimicamente , Doenças dos Ovinos/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue
5.
Anticancer Res ; 13(6A): 2287-92, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8297148

RESUMO

This study utilized phloridzin (P1) and its aglucone phloretin (P2), two known inhibitors of glucose transmembrane transport, to inhibit tumor cell growth in vivo. The efficacy of hydrazine sulfate as an anticachexic agent was also evaluated. Utilizing the rat mammary adenocarcinoma and Fischer bladder cell carcinoma cell lines, it has been shown that the i.p. administration of P1 and P2 can produce significant differences in mean tumor diameters as compared to the untreated controls.


Assuntos
Adenocarcinoma/patologia , Antineoplásicos/toxicidade , Carcinoma de Células de Transição/patologia , Neoplasias Mamárias Experimentais/patologia , Floretina/toxicidade , Florizina/toxicidade , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Animais , Antineoplásicos/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/metabolismo , Divisão Celular/efeitos dos fármacos , Feminino , Glicosúria , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Floretina/uso terapêutico , Florizina/uso terapêutico , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...