RESUMO
The NS1 protein of influenza virus is a virulence factor that counteracts the PKR-mediated antiviral response by the host. As a consequence, influenza NS1 gene knockout virus delNS1 (an influenza A virus lacking the NS1 open reading frame) fails to replicate in normal cells but produces infectious particles in PKR-deficient cells. Because it is known that oncogenic ras induces an inhibitor of PKR, we addressed the question of whether the delNS1 virus selectively replicates in cells expressing oncogenic ras. We show that upon transfection and expression of oncogenic N-ras, cells become permissive for productive delNS1 virus replication, suggesting that the delNS1 virus has specific oncolytic properties. Viral growth in the oncogenic ras-transfected cells is associated with a reduction of PKR activation during infection. Moreover, treatment of s.c. established N-ras-expressing melanomas in severe combined immunodeficiency mice with the delNS1 virus revealed that this virus has tumor-ablative potentials. The delNS1 virus does not replicate in nonmalignant cell lines such as melanocytes, keratinocytes, or endothelial cells. The apathogenic nature of the delNS1 virus combined with the selective replication properties of this virus in oncogenic ras-expressing cells renders this virus an attractive candidate for the therapy of tumors with an activated ras-signaling pathway.
Assuntos
Genes ras/fisiologia , Vírus da Influenza A/fisiologia , Animais , Transformação Celular Viral/genética , Transformação Celular Viral/fisiologia , Chlorocebus aethiops , Ativação Enzimática , Genes ras/genética , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/metabolismo , Masculino , Melanoma/terapia , Melanoma/virologia , Camundongos , Camundongos SCID , Transfecção , Células Tumorais Cultivadas , Células Vero , Proteínas não Estruturais Virais/genética , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
The methanol extract obtained from the leaves and stems of Euphorbia hirta inhibited the activity of angiotensin converting enzyme (ACE) by 90 percent and 50 percent at 500 ug and 160 ug respectively using enzyme linked immunosorbent assay (ELISA). The effect of the extract on thirst was examined using Wistar rats. Intraperitoneal administration of 10mg/100mg body wt of the extract significantly (p<0.05) decreased the amount of water consumed by rats. This effect lasted for 2 h.(AU)