No abstract

Usurpation of the host's signalling pathways is a common strategy employed by viruses to promote their successful replication. Here we show that infection with the orthopoxvirus vaccinia virus (VACV) leads to sustained stimulation of c-Jun activity during the entire infective cycle. This stimulation is temporally regulated through MEK/ERK or MKK/JNK pathways, i.e. during the early/mid phase (1 to 6 hpi) and in the late phase (9 to 24 hpi) of the infective cycle, respectively. As a transcriptional regulator, upon infection with VACV, c-Jun is translocated from the cytoplasm to the nucleus, where it binds to the AP-1 DNA sequence found at the promoter region of its target genes. To investigate the role played by c-Jun during VACV replication cycle, we generated cell lines that stably express a c-Jun-dominant negative (DNc-Jun) mutation. Our data revealed that c-Jun is required during early infection to assist with viral DNA replication, as demonstrated by the decreased amount of viral DNA found in the DNc-Jun cells. We also demonstrated that c-Jun regulates the expression of the early growth response gene (egr-1), a gene previously shown to affect VACV replication mediated by MEK/ERK signalling. VACV-induced stimulation of the MKK/JNK/JUN pathway impacts viral dissemination, as we observed a significant reduction in both viral yield, during late stages of infection, and virus plaque size. Collectively, our data suggest that, by modulating the host's signalling pathways through a common target such as c-Jun, VACV temporally regulates its infective cycle in order to successfully replicate and subsequently spread.

The pharmacological inhibitor SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone] has been largely employed as a c-JUN N-terminal kinase (JNK1/2) inhibitor. In this study, we evaluated whether pretreatment with SP600125 was able to prevent Orthopoxviruses Vaccinia virus (VACV), Cowpox virus (CPXV) and modified Vaccinia virus Ankara (MVA) replication. We found that incubation with SP600125 not only blocked virus-stimulated JNK phosphorylation, but also, significantly reduced virus production. We observed 1-3 log decline in viral yield depending on the cell line infected (A31, BSC-40 or BHK-21). The reduction in viral yield correlated with a dramatic impact on virus morphogenesis progress, intracellular mature viruses (IMV) were barely detected. Despite the fact that SP600125 can act as an efficient anti-orthopoxviral compound, we also provide evidence that this antiviral effect is not specifically exerted through JNK1/2 inhibition. This conclusion is supported by the fact that viral titers measured after infections of JNK1/2 knockout cells were not altered as compared to those of wild-type cells. In contrast, a decline in viral titers was verified when the infection of KO cells was carried out in the presence of the pharmacological inhibitor. SP600125 has been the focus of recent studies that have evaluated its action on diverse viral infections including DNA viruses. Our data support the notion that SP600125 can be regarded as a potential antipoxviral compound.

Objetivo: Verificar a aceitação da população na aquisição de medicamentos genéricos e os fatores que podem estar associados. Métodos: Trata-se de um estudo de caráter descritivo, conduzido com 393 indivíduos, de ambos os sexos, idade de 18 a 80 anos. Os usuários foram investigados quanto a aceitação e utilização dos medicamentos genéricos. Os dados obtidos foram introduzidos em planilha do software Excel versão 2013 e transportados aos softwares IBM® SPSS® Statistics versão 24.0. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. Resultados: Evidenciou-se que a maioria dos entrevistados (96,5%) afirmaram já ter utilizado algum medicamento genérico e 89,8 relatam ter atingido resultado eficaz nos tratamentos realizados com esses medicamentos e que após a utilização sentiu que houve o efeito desejado. Conclusão: Os medicamentos genéricos têm aceitação pela maior parte da população. E o grau de conhecimento sobre os medicamentos genéricos pela população aumentou. A população confia no farmacêutico para realizar a troca do medicamento de marca pelo genérico.

A depressão é o mais comum dos distúrbios afetivos (definidos como distúrbios do humor, e não desequilíbrios do pensamento ou da cognição); pode variar de alteração muito leve, beirando a normalidade, até a depressão mais grave, acompanhada de alucinações e delírios. De acordo com os últimos levantamentos da Organização Mundial