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FASEB J ; 14(11): 1485-9, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10928982


Glial activation contiguous to deposits of amyloid peptide (Abeta) is a characteristic feature in Alzheimer's disease. We performed complementary in vitro and in vivo experiments to study the extent, kinetics, and mechanisms of microglial generation of nitric oxide (NO) induced by challenge with Abeta. We showed that Abeta fibrils dose-dependently induced a marked release of stable metabolites of NO in vivo that was strikingly similar regarding extent and temporal profile to the one in the parallel designed microglial cell culture experiments. However, costimulation with interferon gamma, which was a prerequisite for Abeta-induced NO generation in vitro, was not required in vivo, demonstrating that factors are present in the living brain that activate glial cells synergistically with Abeta. Therefore, in Alzheimer's disease, deposits of Abeta fibrils alone may be sufficient to induce a chronic release of neurotoxic microglial products, explaining the progressive neurodegeneration associated with this disease. Our observation that systemic administration of selective iNOS inhibitors abolishes Abeta-induced NO generation in vivo may have implications for therapy of Alzheimer's disease.

Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Lisina/análogos & derivados , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Péptidos beta-Amiloides/administración & dosificación , Animales , Encéfalo/enzimología , Encéfalo/patología , Células Cultivadas , Indometacina/farmacología , Interferón gamma/farmacología , Cinética , Lisina/farmacología , Ratones , Ratones Endogámicos BALB C , Microglía/efectos de los fármacos , Microglía/enzimología , Microglía/metabolismo , Microglía/patología , Nitratos/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Nitritos/metabolismo , Fragmentos de Péptidos/administración & dosificación , Placa Amiloide/efectos de los fármacos , Placa Amiloide/metabolismo , Placa Amiloide/patología
Electrophoresis ; 21(17): 3634-8, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11271481


Cancer chemotherapy is a new and important medical science and much interest has been focused on catechins, not only for their antioxidant activity, but also because of their known antimutagenic and antitumorigenic properties. Green tea and black tea, which are among the most popular beverages consumed worldwide, contain many different catechins. We developed an analytical method capable of separating six different catechins and caffeine in tea by micellar electrokinetic chromatography in only 20 min without extensive sample preparation. Furthermore, we compared the amount of catechins and caffeine in several teas and different preparation modes.

Cafeína/análisis , Catequina/análisis , Té/química , Cromatografía Capilar Electrocinética Micelar/métodos , Estructura Molecular , Extractos Vegetales/química , Reproducibilidad de los Resultados
Carcinogenesis ; 18(5): 1063-7, 1997 May.
Artículo en Inglés | MEDLINE | ID: mdl-9163697


Recently, we reported that aristolochic acid (AA) a naturally occurring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified the principal aristolochic acid-DNA adduct in the kidney of five such patients. We now extend these observations and demonstrate the presence of additional AA-DNA adducts by the 32P-post-labelling method not only in the kidneys, but also in a ureter obtained after renal transplantation. Using the nuclease P1 version of the assay not only the major DNA adduct of aristolochic acid, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), but also the minor adducts, 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and identified by cochromatographic analyses with TLC and HPLC. Quantitative analyses of six kidneys revealed relative adduct levels from 0.7 to 5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/ 10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is consistent with the occurrence of aristolochic acid II (AAII) in the herb powder imported under the name of Stephania tetrandra and confirms that the patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-labelling analyses of further biopsy samples of one patient showed the known adduct pattern of AA exposure not only in the kidney, but also in the ureter, whereas in skin and muscle tissue no adduct spots were detectable. In an attempt to explain the higher level of the dA-AAI adduct compared to the dG-AAI adduct level in renal tissue even 44 months after the end of regimen, the persistence of these two purine adducts was investigated in the kidney of rats given a single oral dose of pure AAI. In contrast to the dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the kidney of rats. Our data demonstrate that AA forms DNA adducts in human tissue by the same activation mechanism(s) reported from animal studies. Thus, the carcinogenic/mutagenic activity of AA observed in animals could also be responsible for the urothelial cancers observed in two of the CHN patients.

Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/genética , Fenantrenos/química , Adulto , Animales , Aductos de ADN/metabolismo , Femenino , Humanos , Enfermedades Renales/inducido químicamente , Masculino , Persona de Mediana Edad , Ratas , Ratas Wistar , Factores de Tiempo
Cancer Res ; 56(9): 2025-8, 1996 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-8616845


A unique type of rapidly progressive renal fibrosis, designated Chinese herbs nephropathy (CHN), has been described in young Belgian women who had followed a slimming regimen including recently introduced Chinese herbs (Stephania tetrandra and Magnolia officinalis). Aristolochic acid (AA), a known nephrotoxin and carcinogen, was suspected as its causal factor. To substantiate this hypothesis, renal tissue from five patients with CHN and six patients with other renal diseases was analyzed for the presence of AA-derived DNA adducts, a described biomarker of AA exposure associated with its carcinogenic and mutagenic activity. Using the 32P-postlabeling method, a major distinct DNA adduct spot was found in all five cases of CHN and identified by cochromatographic analyses with authentic markers as the deoxyadenosine adduct of AA-I [7-(deoxyadenosin-N6-yl)-aristolactam I], the major component of the plant extract AA. This DNA adduct was absent in the six control cases. The 7-(deoxyadenosin-N6-yl)-aristolactam I adduct levels in CHN ranged from 0.7 to 5.3/10(7) nucleotides. Our data demonstrate that AA is implicated in CHN. They suggest a mechanism for the urothelial atypia and cancers observed in this disease and raise the possibility that a DNA mutation is responsible for the kidney-destructive fibrotic process.

Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/inducido químicamente , Riñón/efectos de los fármacos , Fenantrenos/efectos adversos , Adulto , Femenino , Humanos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Fenantrenos/metabolismo
Int J Cancer ; 38(5): 689-95, 1986 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-3770997


In 50% of BALB/c mice pretreated with atropine, tongue tumours were induced by fortnightly application of DMN-OAc (2 mg/kg) on the tongue. When DMN-OAc + TPA was used for the initiation-promotion protocol, tumours were observed on the tongue, the site of application, in only 10% of animals. In the same group, stomach tumours were obtained in 63% of mice, denoting that initiation-promotion could be successfully used to induce stomach tumours. Using a protocol of DMN-OAc + chilli as a promoter, we observed induction of stomach tumours. The promoter effect of chilli extract was also seen in the BHC-induced hepato-carcinogenesis system. It thus appears that, in BALB/c mice, chilli acts as a promoter in stomach and liver carcinogenesis.

Capsaicina/toxicidad , Cocarcinogénesis , Condimentos/toxicidad , Ratones Endogámicos BALB C , Extractos Vegetales/toxicidad , Administración Tópica , Animales , Atropina/farmacología , Carcinoma de Células Escamosas/inducido químicamente , Femenino , Masculino , Ratones , Neoplasias Gástricas/inducido químicamente , Neoplasias de la Lengua/inducido químicamente