RESUMO
Medulloblastoma (MB) is the most common solid tumor among pediatric patients and corresponds to 20 % of all pediatric intracranial tumors in this age group. Its treatment currently involves significant side effects. Epigenetic changes such as DNA methylation may contribute to its development and progression. DNA methyltransferase (DNMT) inhibitors have shown promising anticancer effects. The agent Zebularine acts as an inhibitor of DNA methylation and shows low toxicity and high efficacy, being a promising adjuvant agent for anti-cancer chemotherapy. Several studies have reported its effects on different types of tumors; however, there are no studies reporting its effects on MB. We analyzed its potential anticancer effects in four pediatric MB cell lines. The treatment inhibited proliferation and clonogenicity, increased the apoptosis rate and the number of cells in the S phase (p < 0.05), as well as the expression of p53, p21, and Bax, and decreased cyclin A, Survivin and Bcl-2 proteins. In addition, the combination of zebularine with the chemotherapeutic agents vincristine and cisplatin resulted in synergism and antagonism, respectively. Zebularine also modulated the activation of the SHH pathway, reducing SMO and GLI1 levels and one of its targets, PTCH1, without changing SUFU levels. A microarray analysis revealed different pathways modulated by the drug, including the Toll-Like Receptor pathway and high levels of the BATF2 gene. The low expression of this gene was associated with a worse prognosis in MB. Taken together, these data suggest that Zebularine may be a potential drug for further in vivo studies of MB treatment.
Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Neoplasias Cerebelares/tratamento farmacológico , Citidina/análogos & derivados , Metilases de Modificação do DNA/antagonistas & inibidores , Meduloblastoma/tratamento farmacológico , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Apoptose/efeitos dos fármacos , Biomarcadores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Criança , Pré-Escolar , Cisplatino/farmacologia , Citidina/farmacologia , Metilases de Modificação do DNA/metabolismo , Interações Medicamentosas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Vincristina/farmacologia , Adulto JovemRESUMO
The whole set of human imprinted genes, termed imprintome, is here analysed by means of a reasonable, valid application of the Semantic Web and Linked Data approaches to a few structured datasets in order to provide a comprehensive collection of imprinted genes in the human genome. Thus, we have stored, organised, filtered, and analysed massive amounts of existing data on human imprinted genes towards compiling, structuring and linking data to comprise a sharing resource for genome and epigenome interrogated studies. Our datasets of linked data are the actual research outcome of this human imprintome analysis because as genomics become more and more data intensive, due to huge amounts of biological data, so does our needs for more structured data to be easier mined and shared. We present the resulting first version of the Linked Human Imprintome as a project within Linked Open Data (LOD) initiative (http://lod-cloud.net/) through Data Hub (http:// thedatahub.org/en/dataset/a-draft-version-of-the-linked-human-imprintome).
Assuntos
Biologia Computacional/métodos , Impressão Genômica , Genômica/métodos , Acesso à Informação , Algoritmos , Ilhas de CpG , Bases de Dados Factuais , Epigenômica , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Pseudogenes , Semântica , SoftwareRESUMO
Visceral leishmaniasis (VL) is a widely spread zoonotic disease. In Brazil the disease is caused by Leishmania (Leishmania)infantum chagasi. Peridomestic sandflies acquire the etiological agent by feeding on blood of infected reservoir animals, such as dogs or wildlife. The disease is endemic in Brazil and epidemic foci have been reported in densely populated cities all over the country. Many clinical features of Leishmania infection are related to the host-parasite relationship, and many candidate virulence factors in parasites that cause VL have been studied such as A2 genes. The A2 gene was first isolated in 1994 and then in 2005 three new alleles were described in Leishmania (Leishmania) infantum. In the present study we amplified by polymerase chain reaction (PCR) and sequenced the A2 gene from the genome of a clonal population of L. (L.) infantum chagasi VL parasites. The L. (L.) infantum chagasi A2 gene was amplified, cloned, and sequenced in. The amplified fragment showed approximately 90% similarity with another A2 allele amplified in Leishmania (Leishmania) donovani and in L. (L.) infantum described in literature. However, nucleotide translation shows differences in protein amino acid sequence, which may be essential to determine the variability of A2 genes in the species of the L. (L.) donovani complex and represents an additional tool to help understanding the role this gene family may have in establishing virulence and immunity in visceral leishmaniasis. This knowledge is important for the development of more accurate diagnostic tests and effective tools for disease control.
