The Novel Immunosuppressive Protein Kinase C Inhibitor Sotrastaurin Has No Pro-Viral Effects on the Replication Cycle of Hepatitis B or C Virus

The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients

Mitochondrially Associated Hepatitis B Virus X Protein Constitutively Activates Transcription Factors STAT-3 and NF-κB via Oxidative Stress

The hepatitis B virus X protein (HBx) plays essential roles in viral replication and the generation of hepatocellular carcinoma. In spite of a large number of suggestive cellular targets and functions, a clear picture of its mechanism(s) of action has remained elusive. In this report, we continue to characterize its recently described mitochondrial association and further examine its impact on mitochondrial functions. HBx was previously shown to bind to a voltage-dependent anion channel (VDAC3) and alter the mitochondrial transmembrane potential (ΔΨ(m)). Here we show that, as a consequence of association with mitochondria, HBx constitutively induces activation of transcription factors, which include STAT-3 and NF-κB. This induction of activation was sensitive to the antioxidants N-acetyl l-cysteine and pyrrolidine dithiocarbamate, as well as to overexpression of Mn-superoxide dismutase. These results therefore implicate a potential role of reactive oxygen species (ROS) in a process that ultimately leads to the activation of STAT-3 and NF-κB. Evidence is also presented for the HBx-induced generation of ROS. The ability of HBx to induce the activation of STAT-3 and NF-κB was demonstrated by mobility shift and reporter gene expression assays with lysates from HBx-transfected HepG2 cells. A C-terminal HBx deletion mutant, HBxΔ99, failed to bind VDAC3 and activate STAT-3 and NF-κB. These studies shed new light on the physiological significance of HBx's mitochondrial association and its role in inducing oxidative stress which can contribute to the liver disease pathogenesis associated with the hepatitis B virus infection

El concepto de valencia: su construcción histórica y epistemológica y la importancia de su inclusión en la enseñanza The valence concept: its historical and epistemological construction and its importance to teaching

El objetivo de éste escrito es reconocer la importancia de la historia y la filosofía de los modelos, teorías y conceptos científicos en la enseñanza de las ciencias, en particular en la enseñanza del concepto de valencia, además de la forma como es presentado éste en los libros de texto. El estudio histórico y epistemológico de este concepto fue realizado desde los criterios establecidos por los autores, aplicado a algunos de los libros de texto utilizados en educación básica y media del sistema educativo Colombiano.<br>The aim of this article is to promote a better understanding about the important role played by both the history and the philosophy of the science on the teaching of the scientific concepts, theories and models, in particular on the teaching of "the valency" concept; and, how is it presented in textbooks. Thus, a historic and epistemological study of this concept was done in order to define the main criteria to analyze different textbooks that are used at both secondary and university levels of the education in the Colombian system