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Pesquisa : D08.811.277.656.262.500.126.550.800 [Categoria DeCS]
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Texto completo SciELO Chile
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Id: biblio-950869
Autor: Visagie, Michelle Helen; Jaiswal, Seema Rummurat; Joubert, Anna Margaretha.
Título: In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
Fonte: Biol. Res;49:1-13, 2016. ilus, graf, tab.
Idioma: en.
Resumo: BACKGROUND: Computer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17ß-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2's poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 µM), were assessed on morphology and apoptosis induction in cervical cancer cells. RESULTS: Transmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 µM physiological concentration). CONCLUSION: Computer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.
Descritores: Sulfonamidas/farmacologia
Inibidores da Anidrase Carbônica/farmacologia
Neoplasias do Colo do Útero/tratamento farmacológico
Desenho Assistido por Computador
Estradiol/análogos & derivados
Antineoplásicos/farmacologia
-Fatores de Tempo
Células HeLa
Microscopia Eletrônica de Varredura
Ciclo Celular/efeitos dos fármacos
Ciclo Celular/fisiologia
Células Cultivadas
Neoplasias do Colo do Útero/patologia
Reprodutibilidade dos Testes
Apoptose/efeitos dos fármacos
Meios de Cultura
Microscopia Eletrônica de Transmissão
Estradiol/farmacologia
Caspase 8/metabolismo
Citometria de Fluxo/métodos
2-Metoxiestradiol
Microscopia de Polarização
Limites: Humanos
Feminino
Tipo de Publ: Estudo de Avaliação
Responsável: CL1.1 - Biblioteca Central


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Id: biblio-1019415
Autor: Ozkan, Ufuk; Akal, Ali; Ozkan, Kudret; Yilmaz, Omer Faruk; Adıbelli, Fatih Mehmet.
Título: Investigating the effect of intracameral cefuroxime on oxidative stress and apoptosis in the rat cornea / Investigando o efeito de cefuroxima intracameral sobre o estresse oxidativo e a apoptose na córnea de ratos
Fonte: Arq. bras. oftalmol;82(4):322-328, July-Aug. 2019. tab, graf.
Idioma: en.
Resumo: ABSTRACT PURPOSE: We examined the effect of intracameral administration of cefuroxime on oxidative stress and endothelial apoptosis in rat corneal tissue. METHODS: In total, 30 rats were divided into 3 groups of 10 rats each (intracameral administration of cefuroxime 0.1 mg/0.01 mL (cefuroxime group); intracameral administration of balanced salt solution 0.01 mL (control group); or absence of intracameral injection (sham group). Corneal endothelial apoptosis was assessed by immunohistochemical analysis using caspase-3 and caspase-8. Total oxidant status, total antioxidant status, oxidative stress index, and paraoxonase and arylesterase levels were examined in corneal endothelial tissue and serum. RESULTS: Paraoxonase levels in the serum were significantly different between the sham and cefuroxime groups (p=0.027). A significant difference was also observed in total oxidant status levels between the cefuroxime and balanced salt solution groups (p=0.023). In addition, there were significant differences in total antioxidant status levels in corneal tissue between the cefuroxime and sham groups (p<0.001) and between the cefuroxime and balanced salt solution groups (p<0.001). Furthermore, significant differences were also observed in oxidative stress index levels between the cefuroxime and balanced salt solution groups (p=0.001) and between the cefuroxime and sham groups (p=0.026). According to the immunohistochemical staining results, a significant association with caspase-3 activity existed between the cefuroxime and balanced salt solution groups (p=0.007), while no significant difference was found with caspase-8 activity (p=0.541). Caspase-3 activity exhibited a significant relationship between the sham and balanced salt solution groups (p=0.018), but no relationship was found with caspase-8 activity (p=0.623). CONCLUSION: Immunohistochemical examination revealed that intracameral cefuroxime increased apoptosis when compared to the sham and balanced salt solution groups. Moreover, intracameral cefuroxime increased oxidative stress in the cornea and simultaneously induced apoptosis.

RESUMO OBJETIVO: Examinamos o efeito da administração intracameral da cefuroxima sobre o estresse oxidativo e a apoptose endotelial no tecido corneano de ratos. MÉTODOS: No total, 30 ratos foram divididos em 3 grupos de 10 ratos cada (administração intracameral de cefuroxima 0,1 mg/0,01 mL (grupo cefuroxima), administração intracameral de solução salina balanceada 0,01 mL (grupo controle) ou ausência de injeção intracameral (grupo sham)). A apoptose endotelial da córnea foi avaliada por análise imuno-histoquimica usando caspase-3 e -8. O status oxidante total, o status antioxidante total, o índice de estresse oxidativo e os níveis de a paraoxonase e arilesterase foram investigados no tecido endotelial da córnea e no soro. RESULTADOS: Os níveis de paraoxonase no soro foram significativamente diferentes entre os grupos sham e cefuroxima (p=0,027). Foi também observada uma diferença significativa nos níveis de estado oxidante total entre os grupos cefuroxima e solução salina balanceada (p=0,023). Além disso, houve diferenças significativas nos níveis de status antioxidante total no tecido da córnea entre os grupos cefuroxima e sham (p<0,001) e entre os grupos cefuroxima e solução salina balanceada (p<0,001). Diferenças significativas também foram observadas nos níveis do índice de estresse oxidativo entre os grupos cefuroxima e solução salina balanceada (p=0,001) e entre os grupos cefuroxima e sham (p=0,026). De acordo com os resultados de coloração imuno-histoquimica, houve associação significativa com a atividade da caspase-3 entre os grupos cefuroxima e solução salina balanceada (p=0,007), enquanto não houve diferença significativa com a atividade da caspase-8 (p=0,541). A atividade da caspase-3 exibiu uma relação significativa entre os grupos sham e solução salina balanceada (p=0,018), mas nenhuma relação foi encontrada com a atividade da caspase-8 (p=0,623). CONCLUSÃO: O exame imuno-histoquímico revelou que a cefuroxima intracameral aumentou a apoptose quando comparada com os grupos sham e solução salina balanceada. Além disso, a cefuroxima intracameral aumentou o estresse oxidativo na córnea e induziu simultaneamente a apoptose.
Descritores: Cefuroxima/farmacologia
Apoptose/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Córnea/efeitos dos fármacos
Córnea/metabolismo
Antibacterianos/farmacologia
-Epitélio Posterior/efeitos dos fármacos
Epitélio Posterior/metabolismo
Epitélio Posterior/patologia
Imuno-Histoquímica
Hidrolases de Éster Carboxílico/análise
Reprodutibilidade dos Testes
Oxidantes/sangue
Ratos Wistar
Córnea/patologia
Arildialquilfosfatase/análise
Caspase 3/análise
Caspase 8/análise
Injeções Intraoculares
Limites: Animais
Masculino
Tipo de Publ: Estudo de Avaliação
Responsável: BR1.1 - BIREME


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Colli, Benedicto Oscar
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Id: biblio-1098282
Autor: Tirapelli, Daniela P. C; Cirino, Mucio Luiz de Assis; Carvalho, Camila A. Melo de; Novais, Paulo Cezar; Figueredo, Rafael Zimak; Porsani, Lucas Barbosa; Gula, Isabella Stracieri; Rodrigues, Andressa Romualdo; Silva, Jairo Pinheiro da; Pereira, Adriana Lis; Lizarte Neto, Fermino Sanches; Schimming, Bruno Cesar; Tazima, Maria de Fátima Galli Sorita; Fazan, Valéria de Paula Sassoli; Carlotti-Jr, Carlos Gilberto; Tirapelli, Luis Fernando; Colli, Benedicto Oscar.
Título: Morphometric analysis and pattern of protein and gene expression of apoptosis in focal cerebral ischemia in rats and the neuroprotetive action of hypothermia and ketoprofen / Análisis morfométrico y modelo de expresión de proteína y genes de apoptosis en isquemia cerebral focal en ratas y la acción neuroprotectora de hipotermia y ketoprofeno
Fonte: Int. j. morphol;38(3):523-529, June 2020. graf.
Idioma: en.
Projeto: Fundação de Amparo à Pesquisa do Estado de São Paulo.
Resumo: This study aimed to investigate the morphometric and the pattern of protein and gene expression related to the extrinsic apoptotic pathway in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. For this analysis, 120 rats were randomly divided into 3 groups (20 animals each): control - no surgery (20 animals); sham - simulation of surgery (20 animals); ischemic - focal ischemia for 1 hour, without reperfusion (80 animals) and divided into four subgroups with 20 animals each: ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the apoptosis genes (Fas, c-Flip, caspase-8 and caspase-3) and the apoptosis protein caspase-3 were evaluated by quantitative real-time PCR and immunohistochemistry, respectively. Hypo expression of genes of extrinsic pathway of apoptosis was observed: Fas receptor, c-Flip and caspase-8 in the ischemics areas. Increases in the gene and protein caspase-3 in the ischemic areas were also observed, and these increases were reduced by hypothermia and ketoprofen, also noted in the morphometric study. The caspases-3 increase suggests that this gene plays an important role in apoptosis, probably culminating in cell death and that the neuroprotective effect of hypothermia and ketoprofen is involved.

Este estudio tuvo como objetivo investigar la morfometría y el patrón de expresión de proteínas y genes relacionados con la vía apoptótica extrínseca en la isquemia cerebral focal experimental y el agujero de neuroprotección con hipotermia y ketoprofeno. Se dividieron aleatoriamente 120 ratas en 3 grupos (20 animales cada uno): control - sin cirugía (20 animales); simulación - simulación de cirugía (20 animales); isquemia isquemia focal durante 1 hora, sin reperfusión (80 animales) y dividida en cuatro subgrupos con 20 animales cada uno: isquemia + hipotermia intraisquémica; isquemia + ketoprofeno intravenoso previo, e isquemia + hipotermia y ketoprofeno. El volumen del infarto se midió utilizando un análisis morfométrico de áreas de infarto definidas por cloruro de trifenil tetrazolio y los patrones de expresión de los genes de apoptosis (Fas, c-Flip, caspase-8 y caspase-3) y la proteína de apoptosis caspase-3 fueron evaluados por PCR cuantitativa en tiempo real e inmunohistoquímica, respectivamente. Se observó hipoexpresión de genes de la vía extrínseca de la apoptosis: receptor Fas, c-Flip y caspasa-8 en las áreas isquémicas. También se observaron aumentos en el gen y la proteína caspasa-3 en las áreas isquémicas y estos aumentos se redujeron por hipotermia y ketoprofeno, también observado por estudio morfométrico. El aumento de caspasas-3 sugiere que este gen tiene un papel importante en la apoptosis, y probable causa de muerte celular, involucrando el efecto neuroprotector de la hipotermia y el ketoprofeno.
Descritores: Isquemia Encefálica/genética
Isquemia Encefálica/metabolismo
-Imuno-Histoquímica
Isquemia Encefálica/patologia
Isquemia Encefálica/terapia
Cetoprofeno/farmacologia
Apoptose/genética
Fármacos Neuroprotetores/farmacologia
Modelos Animais de Doenças
Caspase 3/genética
Caspase 8/genética
Reação em Cadeia da Polimerase em Tempo Real
Hipotermia Induzida
Limites: Animais
Ratos
Responsável: CL1.1 - Biblioteca Central


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Id: biblio-839255
Autor: Zhang, ZW; Li, H; Chen, SS; Li, Y; Cui, ZY; Ma, J.
Título: MicroRNA-122 regulates caspase-8 and promotes the apoptosis of mouse cardiomyocytes
Fonte: Braz. j. med. biol. res = Rev. bras. pesqui. méd. biol;50(2):e5760, 2017. graf.
Idioma: en.
Resumo: Cardiomyocyte apoptosis plays key roles in the pathogenesis of heart diseases such as myocardial infarction. MicroRNAs are important regulators of gene expression, which are also involved in the regulation of cardiomyocyte apoptosis. However, cardiomyocyte apoptosis regulated by microRNA (miR)-122 is largely unexplored. The aim of this study focused on the role of miR-122 in cardiomyocyte apoptosis. Cardiomyocytes were isolated from neonatal mice and primarily cultured. MiR-122 mimic and inhibitor were transfected to cardiomyocytes and verified by qRT-PCR. Cell viability and apoptosis post-transfection were assessed by MTT assay and flow cytometry, respectively. Changes in expression of caspase-8 were quantified by qRT-PCR and western blot. Results showed that miR-122 mimic and inhibitor successfully induced changes in miR-122 levels in cultured cardiomyocytes (P<0.01). MiR-122 overexpression suppressed viability and promoted apoptosis of cardiomyocytes (P<0.05), and miR-122 knockdown promoted cell viability and inhibited apoptosis (P<0.05). The mRNA and protein levels of caspase-8 were elevated by miR-122 overexpression (P<0.01) and reduced by miR-122 knockdown (P<0.001). These results suggest an inductive role of miR-122 in cardiomyocyte apoptosis, which may be related to its regulation on caspase-8.
Descritores: Apoptose/genética
Caspase 8/genética
Expressão Gênica/genética
MicroRNAs/genética
MicroRNAs/fisiologia
Miócitos Cardíacos/patologia
-Animais Recém-Nascidos
Expressão Gênica/fisiologia
Camundongos Endogâmicos BALB C
Limites: Animais
Camundongos
Responsável: BR1.1 - BIREME



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