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1.
Psychol Rep ; 113(2): 353-61, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24597434

RESUMEN

The cancellation task is a paper-and-pencil test commonly used to assess attention or planning. This study investigated whether the decision time performance on the task was influenced by the number of targets and distractors. This study reduced the demand of planning and used an index of the decision time, an estimate of the time taken to decide whether to mark a stimulus. Forty healthy adults (M age = 21.3 yr., SD = 1.5) performed five cancellation tasks. Four tasks were conducted with instructions to mark a detected target. The target-to-distractor ratio varied from 35/15, 40/10, 45/5, and 50/0, and one task with instructions to mark all stimuli (50/0), to measure the motor time to mark targets. One-way analysis of variance indicated statistically significant differences between conditions. There was a linear relationship between decision time and target-to-distractor ratio; the decision time increased as the proportion of distractors increased. The results suggested the decision time reflects the frequency of switches between responses to targets and distractors or attention modulation of processing to targets and distractors.


Asunto(s)
Atención/fisiología , Toma de Decisiones/fisiología , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Percepción Espacial/fisiología , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto Joven
2.
J Pharmacol Exp Ther ; 332(2): 380-7, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19910537

RESUMEN

We examined whether ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), a new orally available calpain inhibitor, might reduce retinal cell death in vivo and/or in vitro. Retinal cell damage was induced in vivo in mice by intravitreal injection of N-methyl-d-aspartate (NMDA), and SNJ-1945 was intraperitoneally or orally administered twice. NMDA-induced calpain activity (measured as the cleaved products of alpha-spectrin) and its substrate, p35 (a neuron-specific activator for cyclin-dependent kinase 5), in the retina were examined by immunoblotting. In RGC-5 (a rat retinal ganglion cell line) cell culture, cell damage was induced by a 4-h oxygen-glucose deprivation (OGD) treatment followed by an 18-h reoxygenation period. In mouse retinas, SNJ-1945 (30 or 100 mg/kg i.p., 100 or 200 mg/kg p.o.) significantly inhibited the cell loss in the ganglion cell layer (GCL) and the thinning of the inner plexiform layer induced by NMDA. Furthermore, the number of positive cells for terminal deoxynucleotidyl transferase dUTP nick-end labeling was significantly reduced in the GCL and the inner nuclear layer of retinas treated with SNJ-1945 compared with vehicle-treated retinas 24 h after NMDA injection. Levels of cleaved alpha-spectrin products increased and p35 decreased 6 h after NMDA injection or later, and their effects were attenuated by SNJ-1945. In vitro, SNJ-1945 (10 and 100 muM) inhibited the OGD stress-induced reduction in cell viability. In conclusion, SNJ-1945 may afford valuable neuroprotection against retinal diseases, because it was effective against retinal damage both in vitro and in vivo. Our results also indicate that calpain activation and subsequent p35 degradation may be involved in the mechanisms underlying retinal cell death.


Asunto(s)
Carbamatos/farmacología , Glicoproteínas/farmacología , Retina/efectos de los fármacos , Degeneración Retiniana/tratamiento farmacológico , Células Ganglionares de la Retina/efectos de los fármacos , Administración Oral , Animales , Calpaína/metabolismo , Carbamatos/administración & dosificación , Línea Celular , Supervivencia Celular/efectos de los fármacos , Glicoproteínas/administración & dosificación , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos , N-Metilaspartato , Retina/metabolismo , Retina/patología , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/patología , Células Ganglionares de la Retina/metabolismo
3.
J Pharmacol Exp Ther ; 329(2): 687-98, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19201991

RESUMEN

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. In this study, we investigated whether edaravone is neuroprotective against retinal damage. In vitro, we used a radical-scavenging capacity assay using reactive oxygen species-sensitive probes to investigate the effects of edaravone on H(2)O(2), superoxide anion (O(2)*), and hydroxyl radical (*OH) production in a rat retinal ganglion cell line (RGC-5). The effect of edaravone on oxygen-glucose deprivation (OGD)-induced RGC-5 damage was evaluated using a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt assay of cell viability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) significantly decreased radical generation and reduced the cell death induced by OGD stress. In vivo, retinal damage was induced by intravitreous injection of N-methyl-D-aspartate (NMDA; 5 nmol) and was evaluated by examining ganglion cell layer cell loss, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and the expressions of two oxidant-stress markers [4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG)]. In addition, activations of mitogen-activated protein kinases (MAPKs) [extracellular signal-regulated protein kinases (ERK), c-Jun NH(2)-terminal kinases (JNK), and p38 MAPK], as downstream signal pathways after NMDA receptor activation, were measured using immunoblotting and immunostaining. Edaravone at 5 and 50 nmol intravitreous injection or at 1 and 3 mg/kg i.v. significantly protected against NMDA-induced retinal cell death. At 50 nmol intravitreous injection, it 1) decreased the retinal expressions of TUNEL-positive cells, 4-HNE, and 8-OHdG and 2) reduced the retinal expressions of NMDA-induced phosphorylated JNK and phosphorylated p38 but not that of phosphorylated ERK. These findings suggest that oxidative stress plays a pivotal role in retinal damage and that edaravone may be a candidate for the effective treatment of retinal diseases.


Asunto(s)
Antipirina/análogos & derivados , Depuradores de Radicales Libres/farmacología , Radicales Libres/metabolismo , Enfermedades de la Retina/prevención & control , Células Ganglionares de la Retina/efectos de los fármacos , Animales , Antipirina/administración & dosificación , Antipirina/farmacología , Antipirina/uso terapéutico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Medios de Cultivo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edaravona , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/uso terapéutico , Proteínas Fluorescentes Verdes/genética , Masculino , Ratones , Ratones Transgénicos , N-Metilaspartato , Estrés Oxidativo/efectos de los fármacos , Ratas , Enfermedades de la Retina/genética , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Antígenos Thy-1/genética
4.
BMC Complement Altern Med ; 9: 4, 2009 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-19243635

RESUMEN

BACKGROUND: Bee products (including propolis, royal jelly, and bee pollen) are popular, traditional health foods. We compared antioxidant effects among water and ethanol extracts of Brazilian green propolis (WEP or EEP), its main constituents, water-soluble royal jelly (RJ), and an ethanol extract of bee pollen. METHODS: The hydrogen peroxide (H2O2)-, superoxide anion (O2.-)-, and hydroxyl radical (HO.)- scavenging capacities of bee products were measured using antioxidant capacity assays that employed the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA) or aminophenyl fluorescein (APF). RESULTS: The rank order of antioxidant potencies was as follows: WEP > EEP > pollen, but neither RJ nor 10-hydroxy-2-decenoic acid (10-HDA) had any effects. Concerning the main constituents of WEP, the rank order of antioxidant effects was: caffeic acid > artepillin C > drupanin, but neither baccharin nor coumaric acid had any effects. The scavenging effects of caffeic acid were as powerful as those of trolox, but stronger than those of N-acetyl cysteine (NAC) or vitamin C. CONCLUSION: On the basis of the present assays, propolis is the most powerful antioxidant of all the bee product examined, and its effect may be partly due to the various caffeic acids it contains. Pollen, too, exhibited strong antioxidant effects.


Asunto(s)
Ácidos Grasos/farmacología , Depuradores de Radicales Libres/farmacología , Polen , Própolis/farmacología , Acetilcisteína/farmacología , Animales , Ácido Ascórbico/farmacología , Abejas , Ácidos Cafeicos/farmacología , Cromanos/farmacología , Cinamatos/farmacología , Ácidos Cumáricos/farmacología , Ácidos Grasos Monoinsaturados/farmacología , Fenilpropionatos/farmacología , Extractos Vegetales/farmacología , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacología , Tricotecenos/farmacología
5.
Phytother Res ; 23(10): 1431-8, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19277960

RESUMEN

Our purpose was to investigate the neuroprotective effects (and the underlying mechanism) exerted by water extract of Brazilian green propolis (WEP) and its main constituents against the neuronal damage induced by oxygen-glucose deprivation (OGD)/reoxygenation in retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus). Cell damage was induced by OGD 4 h plus reoxygenation 18 h exposure. In RGC-5, and also in PC12 (rat pheochromocytoma, neuronal cells), WEP and some of its main constituents attenuated the cell damage. At the end of the period of OGD/reoxygenation, RNA was extracted and DNA microarray analysis was performed to examine the gene-expression profile in RGC-5. Expression of casein kinase 2 (CK2) was down-regulated and that of Bcl-2-related ovarian killer protein (Bok) was up-regulated following OGD stress, results that were confirmed by quantitative reverse transcriptase-PCR (qRT-PCR). These effects were normalized by WEP. Our findings indicate that WEP has neuroprotective effects against OGD/reoxygenation-induced cell damage and that certain constituents of WEP (caffeoylquinic acid derivatives, artepillin C, and p-coumaric acid) may be partly responsible for its neuroprotective effects. Furthermore, the protective mechanism may involve normalization of the expressions of antioxidant- and apoptosis-related genes (such as CK2 and Bok, respectively).


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Quinasa de la Caseína II/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Própolis/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Animales , Apiterapia , Baccharis , Isquemia Encefálica/metabolismo , Brasil , Quinasa de la Caseína II/genética , Línea Celular , Perfilación de la Expresión Génica , Glucosa/metabolismo , Peróxido de Hidrógeno , Fármacos Neuroprotectores/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxígeno/metabolismo , Própolis/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas , Daño por Reperfusión/metabolismo , Células Ganglionares de la Retina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
6.
J Cereb Blood Flow Metab ; 28(2): 354-66, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17653128

RESUMEN

The main objective of this study, on mice, was to compare the neuroprotective effects of propofol with those of propofol plus disodium edetate (propofol EDTA). We also administered propofol EDTA (0.005% (w/v) EDTA) to mice intravenously, and measured the changes in zinc concentrations occurring after permanent middle cerebral artery occlusion. In the in vivo study, propofol EDTA displayed stronger neuroprotective effects than propofol alone. Furthermore, we examined the neuroprotective effects of EDTA administered alone, and found that EDTA Na significantly reduced the infarct volume. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells in the ischemic penumbra was reduced more by propofol EDTA than by propofol alone. We performed in the in vitro study in five groups (aerobic, vehicle (control), propofol, EDTA, and propofol plus EDTA). Propofol and EDTA each protected PC12 cells against oxygen-glucose deprivation-induced cell damage, and the effect of propofol was increased by adding EDTA. Because the chelating action of EDTA was a potential causal mechanism, we examined the effect of propofol EDTA on intracerebral zinc homeostasis. When propofol EDTA was given intravenously 10 mins before cerebral ischemia, the zinc concentration decreased significantly in the cortical area, but not in the subcortex. In conclusion, (a) propofol provides neuroprotection against both in vivo and in vitro ischemic damage, and its effects are enhanced when EDTA is added; and (b) EDTA itself protects against ischemic neuronal damage, possibly, owing to its zinc-chelating action.


Asunto(s)
Anestésicos Intravenosos/farmacología , Quelantes/farmacología , Ácido Edético/farmacología , Fármacos Neuroprotectores , Síndromes de Neurotoxicidad/prevención & control , Propofol/farmacología , Animales , Apoptosis/efectos de los fármacos , Bencimidazoles , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Colorantes Fluorescentes , Glucosa/deficiencia , Hipoxia/patología , Hipoxia/fisiopatología , Etiquetado Corte-Fin in Situ , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/prevención & control , Masculino , Ratones , Síndromes de Neurotoxicidad/patología , Células PC12 , Ratas , Zinc/metabolismo , Zinc/toxicidad
7.
Brain Res ; 1226: 226-33, 2008 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-18598676

RESUMEN

PURPOSE: To investigate the neuroprotective effects of coenzyme Q10 and/or a vitamin E analogue on retinal damage both in vitro and in vivo. METHODS: We employed cultured retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus) in vitro. Cell damage was induced by 24-h hydrogen peroxide (H2O2) exposure, and cell viability was measured using tetrazolium salt (WST-8). To examine the retinal damage induced by intravitreal N-methyl-d-aspartate (NMDA) injection in mice in vivo, coenzyme Q10 at 10 mg/kg with or without alpha-tocopherol at 10 mg/kg was administered orally (p.o.) each day for 14 days, with NMDA being intravitreally injected on day 7 of this course. RESULTS: In RGC-5, a combination of coenzyme Q10 and trolox, a water-soluble vitamin E analogue (a derivative of alpha-tocopherol), prevented cell damage more effectively than either agent alone. Coenzyme Q10 and alpha-tocopherol (separately or together) reduced the retinal damage, number of TUNEL-positive cells in the ganglion cell layer (GCL), and 4-hydroxyl-2-nonenal (4-HNE) expression induced by NMDA in mice in vivo. CONCLUSIONS: Coenzyme Q10 and/or these vitamin E analogues exert neuroprotective effects against retinal damage both in vitro and in vivo.


Asunto(s)
Estrés Oxidativo/efectos de los fármacos , Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Ubiquinona/análogos & derivados , Vitaminas/administración & dosificación , Aldehídos/metabolismo , Animales , Antioxidantes/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Transformada , Cromanos/administración & dosificación , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Agonistas de Aminoácidos Excitadores/toxicidad , Peróxido de Hidrógeno/toxicidad , Etiquetado Corte-Fin in Situ/métodos , Ratones , N-Metilaspartato/toxicidad , Oxidantes/toxicidad , Ratas , Retina/efectos de los fármacos , Retina/lesiones , Ubiquinona/administración & dosificación , Vitamina E/farmacología
8.
J Pharm Pharmacol ; 60(10): 1365-74, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18812030

RESUMEN

We have investigated whether astaxanthin exerted neuroprotective effects in retinal ganglion cells in-vitro and in-vivo. In-vitro, retinal damage was induced by 24-h hydrogen peroxide (H2O2) exposure or serum deprivation, and cell viability was measured using a WST assay. In cultured retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus), astaxanthin inhibited the neurotoxicity induced by H2O2 or serum deprivation, and reduced the intracellular oxidation induced by various reactive oxygen species (ROS). Furthermore, astaxanthin decreased the radical generation induced by serum deprivation in RGC-5. In mice in-vivo, astaxanthin (100 mg kg(-1), p.o., four times) reduced the retinal damage (a decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitreal N-methyl-D-aspartate (NMDA) injection. Furthermore, astaxanthin reduced the expressions of 4-hydroxy-2-nonenal (4-HNE)-modified protein (indicator of lipid peroxidation) and 8-hydroxy-deoxyguanosine (8-OHdG; indicator of oxidative DNA damage). These findings indicated that astaxanthin had neuroprotective effects against retinal damage in-vitro and in-vivo, and that its protective effects may have been partly mediated via its antioxidant effects.


Asunto(s)
Estrés Oxidativo/efectos de los fármacos , Retina/efectos de los fármacos , Enfermedades de la Retina/prevención & control , Animales , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cromanos/farmacología , Relación Dosis-Respuesta a Droga , Compuestos Férricos/química , Compuestos Férricos/farmacología , Fluoresceínas/química , Fluoresceínas/metabolismo , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/toxicidad , Radical Hidroxilo/metabolismo , Etiquetado Corte-Fin in Situ/métodos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , N-Metilaspartato/administración & dosificación , N-Metilaspartato/toxicidad , Proteínas de Unión a Fosfato , Ratas , Especies Reactivas de Oxígeno/metabolismo , Retina/citología , Retina/metabolismo , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Xantófilas/química , Xantófilas/farmacología
9.
Brain Res ; 1154: 215-24, 2007 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-17482584

RESUMEN

BACKGROUND AND PURPOSE: Recently, fasudil, a Rho kinase (ROCK) inhibitor, was reported to prevent cerebral ischemia in vivo by increasing cerebral blood flow and inhibiting inflammatory responses. However, it is uncertain whether a ROCK inhibitor can directly protect neurons against ischemic damage. Our purpose was to evaluate both the involvement of ROCK activity in ischemic neuronal damage and any direct neuroprotective effect of fasudil against cerebral infarction. METHODS: In vivo, focal cerebral ischemia was induced by permanent middle cerebral artery occlusion in mice, and the resulting infarction was evaluated 24 h later. ROCK expression and activity were assessed using Western blotting and immunohistochemistry. In vitro, the effects of fasudil and hydroxyfasudil (a main metabolite of fasudil) were examined on oxygen-glucose deprivation (OGD)-induced PC12 cell death and on glutamate-induced neurotoxicity in primary cerebral neuronal culture. RESULTS: ROCK expression and activity increased in the striatum, especially in axons, in the early phase of ischemia. Fasudil reduced this ROCK activity and protected against cerebral infarction in vivo. Hydroxyfasudil inhibited OGD-induced PC12 cell death, and fasudil and hydroxyfasudil each attenuated glutamate-induced neurotoxicity in vitro. CONCLUSIONS: These findings indicate that ROCK plays a pivotal role in the mechanism underlying ischemic neuronal damage and that a direct effect of fasudil on neurons may be partly responsible for its protective effects against such damage.


Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Glucosa/deficiencia , Ácido Glutámico/farmacología , Hipoxia , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones , Proteínas de Neurofilamentos/metabolismo , Células PC12 , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Factores de Tiempo , Quinasas Asociadas a rho
10.
Life Sci ; 80(4): 370-7, 2007 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-17046025

RESUMEN

We investigated whether water extract of Brazilian green propolis (WEP) and its main constituents [caffeoylquinic acid derivatives (3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, chlorogenic acid) and cinnamic acid derivatives (p-coumaric acid, artepillin C, drupanin, baccharin)] exert neuroprotective effects against the retinal damage induced by oxidative stress. Additionally, their neuroprotective effects were compared with their antioxidant effects. WEP, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, chlorogenic acid, and p-coumaric acid (but not artepillin C, baccharin, or drupanin) concentration-dependently inhibited oxidative stress-induced neurotoxicity [achieved using L-buthionine-(S,R)-sulfoximine (BSO) to deplete glutathione in combination with glutamate to inhibit cystine uptake] in cultured retinal ganglion cells (RGC-5, a rat ganglion cell line transformed using E1A virus). At their effective concentrations against oxidative stress-induced retinal damage, WEP, 3,4-di-caffeoylquinic acid, 3,5-di-caffeoylquinic acid, and chlorogenic acid (but not cinnamic acid derivatives) inhibited lipid peroxidation (LPO) in mouse forebrain homogenates. Thus, the neuroprotective effects of WEP and caffeoylquinic acid derivatives paralleled those against LPO. These findings indicate that WEP and caffeoylquinic acid derivatives have neuroprotective effects against retinal damage in vitro, and that these effects may be partly mediated via antioxidant effects.


Asunto(s)
Antiinfecciosos/farmacología , Antioxidantes/farmacología , Fármacos Neuroprotectores/farmacología , Própolis/farmacología , Ácido Quínico/análogos & derivados , Células Ganglionares de la Retina/efectos de los fármacos , Animales , Antiinfecciosos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cinamatos/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Ácido Glutámico/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Própolis/análogos & derivados , Própolis/química , Prosencéfalo/efectos de los fármacos , Prosencéfalo/metabolismo , Ácido Quínico/farmacología , Ratas , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Agua/química
11.
World J Gastroenterol ; 12(11): 1805-9, 2006 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-16586560

RESUMEN

A 42-year-old woman was admitted to our hospital because of multiple liver tumors detected by ultrasonography. Colonoscopy revealed submucosal tumor in the rectum, which was considered the primary lesion. Endoscopic mucosal resection followed by histopathological examination revealed that the tumor was carcinoid. The resected margin of the tumor was positive for malignant cells. Two courses to transcatheter arterial chemotherapy for liver metastasis were ineffective. Accordingly, the rectal tumor and metastatic lymph nodes were surgically resected. One month after the operation, she received liver transplantation (left lateral segment and caudate lobe) from her son. No recurrent lesion has been observed at two years after the liver transplantation. Liver transplantation should be considered as a treatment option even in advanced case of carcinoid metastasis to the liver. We also discuss the literature on liver transplantation for metastatic carcinoid tumor.


Asunto(s)
Tumor Carcinoide/patología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Neoplasias del Recto/patología , Adulto , Tumor Carcinoide/diagnóstico , Colonoscopía , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Relaciones Madre-Hijo , Neoplasias del Recto/diagnóstico , Ultrasonografía
12.
Anticancer Res ; 23(6a): 4427-34, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14666730

RESUMEN

BACKGROUND: Hypoxia represents an important tumor-specific target for cancer therapy. We have reported that hypoxic cytotoxins, such as TX-1102, tirapazamine (TPZ) and TX-402, selectively induced tumor cells to p53-independent apoptosis under hypoxic conditions and inhibited angiogenesis. MATERIALS AND METHODS: We investigated the effects of the antiangiogenic hypoxic cytotoxins on hypoxia-induced gene expression and their hypoxia-selective cytotoxicity in human squamous cell carcinoma of the head and neck (SAS cells) and p53-deficient human non-small cell lung carcinoma H1299 cells transfected with either wild-type or mutant p53 gene. RESULTS: TX-402 had more potent hypoxia-selective cytotoxicity than TPZ in either cell regardless of p53 status. All the compounds inhibited angiogenesis potently at doses of more than 5 micrograms/CAM in chick embryo chorioallantoic membrane (CAM) assay. RT-PCR analyses indicated that TX-402 reduced the inducible expression of vascular endothelial cell growth factors (VEGF) and glucose transporter type 3 (GLUT-3) under hypoxic conditions selectively. The mRNA and protein expression of HIF-1 alpha were also suppressed by TX-402 at the same time. CONCLUSION: The potent antiangiogenic effects of hypoxic cytotoxins can be attributed to the suppression of VEGF and HIF-1 induction through the hypoxia-inducible pathway. We show an other aspect of the hypoxic cytotoxin as an HIF-1 inhibitor for hypoxia-targeted therapy to improve cancer treatment and prognosis.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Unión al ADN/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción , Triazinas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Carcinoma de Pulmón de Células no Pequeñas/genética , Hipoxia de la Célula/genética , Línea Celular Tumoral , Embrión de Pollo , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes p53 , Humanos , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/genética , Transducción de Señal/efectos de los fármacos , Tirapazamina , Transfección
13.
Anticancer Res ; 32(12): 5251-62, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23225424

RESUMEN

BACKGROUND: Cholangiocarcinoma (CCC) is the second most common type of primary liver cancer, and is associated with a high rate of mortality due to the difficulty of early detection and resistance to chemotherapeutic agents. To evaluate the possibility for new therapeutic strategies, we examined the combined effect of gefitinib and gemcitabine on CCC. MATERIALS AND METHODS: The effect of gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) signaling, gemcitabine, which is a pyrimidine analog, and the combined effect of gefitinib and gemcitabine on CCC cells were evaluated both in vitro and in vivo. RESULTS: EGFR mRNA expression and phosphorylation of EGFR were elevated in both human CCC cell lines studied, HuCCT1 and RBE, suggesting EGFR signaling is up-regulated in CCC cell lines. Gefitinib treatment at high concentration inhibited the proliferation of the CCC cell lines. Furthermore, gefitinib reduced the transforming growth factor alpha (TGFα)-induced proliferation of these cells. Gemcitabine also suppressed the growth of the CCC cell lines in a concentration-dependent manner. The combination of gefitinib and gemcitabine synergistically suppressed the growth of the CCC cell lines and induced greater apoptosis compared to the use of either agent alone. As a mechanism for this effect, we found less phosphorylation of the extracellular signal-regulated kinase (ERK) protein, which means the suppression of EGFR signaling, when these compounds were administered together. Cell transplantation assay dramatically demonstrated the synergistic effect of this combination on HuCCT1 xenografts in vivo. CONCLUSION: The combination of gefitinib and gemcitabine inhibited the proliferation of CCC cells via induction of apoptosis. The combination of EGFR inhibitor and additional chemicals could be a new therapeutic approach for CCC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Quinazolinas/farmacología , Animales , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Receptores ErbB/metabolismo , Gefitinib , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Quinazolinas/administración & dosificación , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
14.
Brain Res ; 1251: 269-75, 2009 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-19056360

RESUMEN

We examined the radical-scavenging activity of docosahexaenoic acid (DHA) and its effects on the neuronal cell death induced by oxidative or hypoxic stress in cultured retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus). The radical-scavenging activity [hydrogen peroxide (H(2)O(2)), superoxide anion (O(2)*(-)), and hydroxyl radical (*OH)] of DHA in RGC-5 cells was measured using the ROS-sensitive probes CM-H(2)DCFDA and APF. DHA concentration-dependently scavenged the intracellular radical productions induced by H(2)O(2) radical, O(2)*(-), and *OH (minimum effective DHA concentrations 0.1, 10 and 100 microM, respectively). Cell damage was induced by H(2)O(2), oxygen-glucose deprivation (OGD), or tunicamycin (an endoplasmic reticulum-stress inducer), and cell viability was assessed by Hoechst 33342 nuclear staining or by the tetrazolium salt (WST-8) cell-viability assay. H(2)O(2) (0.3 mM for 24 h), 4-h OGD exposure followed by 18-h reoxygenation, or tunicamycin at 2 microg/ml for 24 h induced apoptotic cell death accompanied by nuclear condensation and/or fragmentation, and each maneuver decreased cell viability. Treatment with DHA at 0.1 and 1 microM significantly inhibited the decrease in cell viability induced by H(2)O(2). Treatment with DHA at 0.1, 1, or 10 microM significantly inhibited the decrease in cell viability induced by OGD/reoxygenation exposure. However, DHA (0.1 to 10 microM) had no effect on the decrease in cell viability induced by tunicamycin. These results indicate that DHA may be protective against oxidative or hypoxic stress-induced cell damage in retinal ganglion cells.


Asunto(s)
Citoprotección/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Hipoxia/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Células Ganglionares de la Retina/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citoprotección/fisiología , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/metabolismo , Depuradores de Radicales Libres/farmacología , Radicales Libres/antagonistas & inhibidores , Radicales Libres/metabolismo , Peróxido de Hidrógeno/antagonistas & inhibidores , Hipoxia/metabolismo , Hipoxia/fisiopatología , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Isquemia/fisiopatología , Estrés Oxidativo/fisiología , Ratas , Células Ganglionares de la Retina/metabolismo , Superóxidos/antagonistas & inhibidores , Tunicamicina/farmacología
15.
Curr Eye Res ; 34(4): 311-8, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19373580

RESUMEN

PURPOSE: To investigate whether zeaxanthin, the predominant carotenoid pigment of the macular pigments in human retina, provides neuroprotection against retinal cell damage. METHODS: We used in vitro cultured retinal ganglion cells (RGCs), specifically RGC-5, an E1A virus-transformed rat cell line. Cell damage was induced either by a 24-hr exposure to hydrogen peroxide (H2O2) or by serum deprivation. Cell viability was measured using the tetrazolium salt, WST-8. The scavenging capacity of zeaxanthin for H2O2, superoxide anion radical (O2.-), and hydroxyl radical (HO.) was measured using a radical scavenging capacity assay with CM-H2DCFDA, a reactive oxygen species (ROS)-sensitive probe. RESULTS: When added to RGC-5 cell cultures, 0.1, 10, and 1 microM zeaxanthin scavenged the free radicals induced by H2O2, O2.-, and HO., respectively. In addition, pretreatment with 1 microM zeaxanthin permitted scavenging of staurosporine-induced intracellular radicals. Zeaxanthin also inhibited the neurotoxicity induced by H2O2 or serum deprivation and scavenged the intracellular radicals induced by H2O2 or serum deprivation. CONCLUSIONS: Our results suggest that zeaxanthin provides effective protection against oxidative stress-induced retinal cell damage.


Asunto(s)
Depuradores de Radicales Libres/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Xantófilas/farmacología , Animales , Línea Celular Transformada , Medio de Cultivo Libre de Suero/farmacología , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/administración & dosificación , Radicales Libres/metabolismo , Peróxido de Hidrógeno/farmacología , Fármacos Neuroprotectores/administración & dosificación , Ratas , Células Ganglionares de la Retina/efectos de los fármacos , Estaurosporina/farmacología , Factores de Tiempo , Xantófilas/administración & dosificación , Zeaxantinas
16.
Invest Ophthalmol Vis Sci ; 50(1): 334-44, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18757512

RESUMEN

PURPOSE: The effect of a preferential inducer of 78 kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein (BiP; BiP inducer X, BIX) against tunicamycin-induced cell death in RGC-5 (a rat ganglion cell line), and also against tunicamycin- or N-methyl-D-aspartate (NMDA)-induced retinal damage in mice was evaluated. METHODS: In vitro, BiP mRNA was measured after BIX treatment using semi-quantitative RT-PCR or real-time PCR. The effect of BIX on tunicamycin (at 2 microg/mL)-induced damage was evaluated by measuring the cell-death rate and CHOP protein expression. In vivo, BiP protein induction was examined by immunostaining. The retinal cell damage induced by tunicamycin (1 microg) or NMDA (40 nmol) was assessed by examining ganglion cell layer (GCL) cell loss, terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, and CHOP protein expression. RESULTS: In vitro, BIX preferentially induced BiP mRNA expression both time- and concentration-dependently in RGC-5 cells. BIX (1 and 5 microM) significantly reduced tunicamycin-induced cell death, and BIX (5 microM) significantly reduced tunicamycin-induced CHOP protein expression. In vivo, intravitreal injection of BIX (5 nmol) significantly induced BiP protein expression in the mouse retina. Co-administration of BIX (5 nmol) significantly reduced both the retinal cell death and the CHOP protein expression in GCL induced by intravitreal injection of tunicamycin or NMDA. CONCLUSIONS: These findings suggest that this BiP inducer may have the potential to be a therapeutic agent for endoplasmic reticulum (ER) stress-induced retinal diseases.


Asunto(s)
Apoptosis/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Chaperonas Moleculares/farmacología , Células Ganglionares de la Retina/patología , Tiocianatos/farmacología , Animales , Western Blotting , Línea Celular , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/genética , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Transgénicos , Chaperonas Moleculares/genética , N-Metilaspartato/toxicidad , ARN Mensajero/metabolismo , Ratas , Enfermedades de la Retina/genética , Enfermedades de la Retina/prevención & control , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Factor de Transcripción CHOP/metabolismo , Tunicamicina/toxicidad
17.
Evid Based Complement Alternat Med ; 3(1): 71-7, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16550226

RESUMEN

Propolis, a honeybee product, has gained popularity as a food and alternative medicine. Its constituents have been shown to exert pharmacological (anticancer, antimicrobial and anti-inflammatory) effects. We investigated whether Brazilian green propolis exerts neuroprotective effects in the retina in vitro and/or in vivo. In vitro, retinal damage was induced by 24 h hydrogen peroxide (H2O2) exposure, and cell viability was measured by Hoechst 33342 and YO-PRO-1 staining or by a resazurin-reduction assay. Propolis inhibited the neurotoxicity and apoptosis induced in cultured retinal ganglion cells (RGC-5, a rat ganglion cell line transformed using E1A virus) by 24 h H2O2 exposure. Propolis also inhibited the neurotoxicity induced in RGC-5 cultures by staurosporine. Regarding the possible underlying mechanism, in pig retina homogenates propolis protected against oxidative stress (lipid peroxidation), as also did trolox (water-soluble vitamin E). In mice in vivo, propolis (100 mg kg(-1); intraperitoneally administered four times) reduced the retinal damage (decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitreal in vivo N-methyl-d-aspartate injection. These findings indicate that Brazilian green propolis has neuroprotective effects against retinal damage both in vitro and in vivo, and that a propolis-induced inhibition of oxidative stress may be partly responsible for these neuroprotective effects.

18.
J Pharmacol Sci ; 102(2): 196-204, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17031070

RESUMEN

Lig-8, a lignophenol derivative from bamboo lignin, potently suppresses oxidative stress-induced apoptosis. Here, we first examined in vitro whether lig-8 protects against neuronal damage induced by oxygen-glucose deprivation (OGD) followed by reoxygenation, tunicamycin [endoplasmic reticulum (ER)-stress inducer], or PSI (proteasome inhibitor). In pheochromocytoma (PC12) cell cultures, lig-8 (1 to 30 microM) concentration-dependently inhibited OGD- and tunicamycin (2 microg/ml)-induced cell deaths (significant at >/=3 microM and >/=1 microM, respectively). In human neuroblastoma (SH-SY5Y) cell culture, the PSI-induced apoptotic cell death and fusion protein accumulation (revealing reduced proteasome activity) was inhibited by lig-8 (30 microM). On the other hand, lig-8 at 30 microM alone did not affect any proteasome activity under resting conditions. In vivo, lig-8 (0.1 nmol/eye) reduced intravitreal N-methyl-D-aspartate (NMDA, 20 nmol)-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness). Hence, lig-8 protects, partly by inhibiting excessive ER-stress, against neuronal damage in vitro and in vivo.


Asunto(s)
Apoptosis/efectos de los fármacos , Bambusa/química , Lignina/análogos & derivados , Lignina/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedades de la Retina/prevención & control , Animales , Técnicas de Cultivo de Célula , Relación Dosis-Respuesta a Droga , Proteínas Fluorescentes Verdes/análisis , Humanos , Lignina/aislamiento & purificación , Masculino , Ratones , Ratones Endogámicos , Neuronas/patología , Fármacos Neuroprotectores/aislamiento & purificación , Células PC12 , Inhibidores de Proteasoma , Ratas , Enfermedades de la Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Tunicamicina/farmacología
19.
Int J Clin Oncol ; 10(5): 342-7, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16247662

RESUMEN

Pancreatic or gastric metastases from other primary malignancies are rare, especially from leiomyosarcoma. We report a case of leiomyosarcoma in the left lower leg with metastases to the pancreas and stomach. A 61-year-old man had liver cirrhosis caused by hepatitis C virus infection and was followed up by his primary physician. Two years before presentation at our hospital, he had undergone surgical resection of leiomyosarcoma in the left lower leg and systemic chemotherapy for multiple metastatic tumors in the lung. On admission, endoscopic examination and computed tomography were performed for a routine checkup to exclude esophageal varices and liver tumor. Although the patient had no specific symptoms, multiple gastric and pancreatic metastases were identified by endoscopy and computed tomography, respectively. In general, metastases to the pancreas and stomach are rare. We discuss the clinical and diagnostic findings of pancreatic and gastric metastases by reviewing previously reported cases.


Asunto(s)
Pierna , Leiomiosarcoma/secundario , Neoplasias de los Músculos/patología , Neoplasias Pancreáticas/secundario , Neoplasias Gástricas/secundario , Humanos , Leiomiosarcoma/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Gástricas/diagnóstico
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