RESUMEN
Pronounced antihypoxic and antioxidant effects of preventive injection of succinic acid, aminothiol antihypoxants gutimine and amtizol, and succinate-containing aminothiol antihypoxants gutimine succinate and amtizol succinate to Wistar rats with acute hypoxic hypoxia have been demonstrated. Exogenous succinic acid was inferior to aminothiol compounds by antihypoxic effect, but superior to them by its effect on the level of LPO products. Succinate in the aminothiol molecule modulated the intensity of their antihypoxic and antioxidant effects. It did not modulate the antihypoxic activity of amtizol, but reduced the antihypoxic effect of gutimine, presumably because of the physicochemical characteristics of aminothiols. Comparison of the intensities of antihypoxic and antioxidant effects of the studied drugs showed no direct relationship between these effects.
Asunto(s)
Antioxidantes/uso terapéutico , Hipoxia/tratamiento farmacológico , Ácido Succínico/uso terapéutico , Animales , Antioxidantes/química , Guaniltiourea/química , Guaniltiourea/uso terapéutico , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Ácido Succínico/química , Tiadiazoles/química , Tiadiazoles/uso terapéuticoRESUMEN
The effect of 2-amino-4-acetylthiazolo[5, 4-b]indole hydrobromide (compound VM-605), a new antihypoxic drug and an analog of antihypoxant amtizole, on physical capability was studied in mice under swimming test conditions. The action of VM-605 depended both on the terms of testing upon administration of the drug and on the psychoemotional type of test animals. Maximum increase of the physical capacity in test mice was observed in delayed (up to 72 h) period after drug injection rather than in early (within 1-3 h) period. This increase was more typical of emotionally active and high-stress-resistant mice that were preliminarily selected in open field and forced swimming tests. It is suggested that delayed effects of VM-605 on physical capacity are related to the formation of active metabolites of the drug.
Asunto(s)
Indoles/farmacología , Resistencia Física/efectos de los fármacos , Tiazoles/farmacología , Animales , Emociones , Masculino , Ratones , Condicionamiento Físico Animal , Especificidad de la Especie , Estrés Psicológico/psicología , Factores de TiempoRESUMEN
The antihypoxic activity of six aminothiol and triazinoindole derivatives was studied on a model of hypobaric (hypoxic) hypoxia in rats. With respect to the antihypoxic activity, the compounds can be arranged in the following order: amtizole succinate = amtizole approximately equal to gutimine > T-475 > gutimine > succinate succinate. One of the possible mechanisms of action for all antyhypoxants is the inhibition of lipid peroxidation and recovery of hypoxia-induced antioxidant defense system in the brain, kidneys, liver, myocardium, and muscles, which results in reduction of the contents of malonic dialdehyde and lipid hydroperoxides and an increase in the activity of superoxide dismutase and the content of recovered glutathione. Amtizole showed the most pronounced antihypoxic activity and eliminated all negative shifts caused by moderate and heavy hypoxia in the organs studied. Succinic acid did not potentiate the antihypoxic and antioxidant properties of amtizole. Gutimine inhibited the activation of lipid peroxidation and prevented the accumulation of malonic dialdehyde and lipid hydroperoxides and the decrease of recovered glutathione caused by hypoxia in all organs studied. In addition, gutimine inhibited the activity of both superoxide dismutase and catalase. Gutimine succinate exhibited enhanced inhibitory action (as compared to that of gutimine) on lipid peroxidation and removed the inhibition of superoxide dismutase activity in all organs studied. Thus, the present study revealed a parallelism in the antihypoxic and antioxidant effects of aminothiol and triazinoindole derivatives.
Asunto(s)
Antioxidantes/farmacología , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Indoles/farmacología , Peroxidación de Lípido/efectos de los fármacos , Compuestos de Sulfhidrilo/farmacología , Animales , Encéfalo/metabolismo , Riñón/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Malondialdehído/metabolismo , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Ratas , Ratas WistarRESUMEN
Melanoma is notorious for its high tendency to metastasize and its refractoriness to treatment thereafter. Metastasis is believed to occur mostly through the lymphatic system, and the status of sentinel lymph nodes is currently recognized as the best prognostic indicator. Unfortunately, the lymphatic metastatic process is still poorly understood and the occurrence of sentinel node metastases (micrometastases) may be underestimated. We performed genome-wide gene expression analyses of melanoma lymph node micrometastases and macrometastases, and of primary melanomas and benign naevi, to characterize the early metastatic cells molecularly and to disclose the best diagnostic markers and rational targets for therapy. Significance analysis of microarrays identified 22 over- and five under-expressed genes with > or = four-fold changes in the micrometastases. Of these genes, MLANA, TYR, MIA, ERBB3, PRAME, and SPP1 were tested as potential markers by RT-PCR and immunohistochemistry. In a prospective study of 160 patients, our graded MLANA and TYR RT-PCR analyses disclosed clinically significant metastases, as assessed by disease recurrence, better than histological and immunohistochemical examinations. These results strongly suggest the clinical implementation of quantifiable RT-PCR assays to confirm and complement the pathological examination of sentinel node metastases. Furthermore, SPP1 and PRAME proved valuable as melanoma-specific markers capable of differentiating melanoma cells from benign naevi in the sentinel lymph nodes. Importantly, these two genes may also prove to be ideal targets for drug development and therapy. Most molecular traits of the micrometastases were already present in the primary tumours, suggesting that micrometastasis to sentinel lymph nodes is a fairly non-selective process.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Melanoma/diagnóstico , Melanoma/secundario , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/genética , Diagnóstico Diferencial , Humanos , Metástasis Linfática , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Nevo/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Osteopontina/genética , Osteopontina/metabolismo , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/metabolismoRESUMEN
UNLABELLED: ArrayExpress is a public database for high throughput functional genomics data. ArrayExpress consists of two parts--the ArrayExpress Repository, which is a MIAME supportive public archive of microarray data, and the ArrayExpress Data Warehouse, which is a database of gene expression profiles selected from the repository and consistently re-annotated. Archived experiments can be queried by experiment attributes, such as keywords, species, array platform, authors, journals or accession numbers. Gene expression profiles can be queried by gene names and properties, such as Gene Ontology terms and gene expression profiles can be visualized. ArrayExpress is a rapidly growing database, currently it contains data from >50,000 hybridizations and >1,500,000 individual expression profiles. ArrayExpress supports community standards, including MIAME, MAGE-ML and more recently the proposal for a spreadsheet based data exchange format: MAGE-TAB. AVAILABILITY: www.ebi.ac.uk/arrayexpress.
Asunto(s)
Bases de Datos Genéticas , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Animales , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Internet , Ratones , Ratas , Interfaz Usuario-ComputadorRESUMEN
Malignant melanomas are characterized by their high propensity to invade and metastasize, but the molecular mechanisms of these traits have remained elusive. Our DNA microarray analyses of benign nevi and melanoma tissue specimens revealed that the genes encoding extracellular matrix proteins tenascin-C (TN-C), fibronectin (FN), and procollagen-I (PCOL-I) are highly upregulated in invasive and metastatic melanomas. The expression and distribution of these proteins were further studied by immunohistochemistry in benign nevi, radially and vertically growing melanomas, sentinel node micrometastases, and macrometastases. TN-C was increased in all invasive tumours and metastases, especially at invasion fronts, but not in benign nevi or non-invasive melanomas. Significantly, the intensity of TN-C staining correlated with metastasis to sentinel lymph nodes, better than tumour thickness (Breslow). Moreover, TN-C, FN, and PCOL-I appeared to co-localize in the tumours and form tubular meshworks and channels ensheathing the melanoma cells. Our data suggest that melanoma invasion is associated with the formation of special channel-like structures, providing a new concept, structured tumour cell spreading. Altogether, these data provide potential new prognostic markers and therapeutic targets/strategies for preventing melanoma dissemination.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Cutáneas/metabolismo , Biomarcadores de Tumor/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Metástasis Linfática , Melanoma/patología , Melanoma/secundario , Invasividad Neoplásica , Nevo/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Neoplásico/genética , Neoplasias Cutáneas/patología , Tenascina/genética , Tenascina/metabolismo , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
We describe a new probabilistic method for finding haplotype blocks that is based on the use of the minimum description length (MDL) principle. We give a rigorous definition of the quality of a segmentation of a genomic region into blocks and describe a dynamic programming algorithm for finding the optimal segmentation with respect to this measure. We also describe a method for finding the probability of a block boundary for each pair of adjacent markers: this gives a tool for evaluating the significance of each block boundary. We have applied the method to the published data of Daly and colleagues. The results expose some problems that exist in the current methods for the evaluation of the significance of predicted block boundaries. Our method, MDL block finder, can be used to compare block borders in different sample sets, and we demonstrate this by applying the MDL-based method to define the block structure in chromosomes from population isolates.
Asunto(s)
Haplotipos , Humanos , Modelos GenéticosRESUMEN
We describe a new method for finding haplotype blocks based on the use of the minimum description length principle. We give a rigorous definition of the quality of a segmentation of a genomic region into blocks, and describe a dynamic programming algorithm for finding the optimal segmentation with respect to this measure. We also describe a method for finding the probability of a block boundary for each pair of adjacent markers: this gives a tool for evaluating the significance of each block boundary. We have applied the method to the published data of Daly et al. The results are in relatively good agreement with the published results, but also show clear differences in the predicted block boundaries and their strengths. We also give results on the block structure in population isolates.