Isocotoin suppresses hepatitis E virus replication through inhibition of heat shock protein 90.

Hepatitis E virus (HEV) causes 14 million infections and 60,000 deaths per year globally, with immunocompromised persons and pregnant women experiencing severe symptoms. Although ribavirin can be used to treat chronic hepatitis E, toxicity in pregnant patients and the emergence of resistant strains are major concerns. Therefore there is an imminent need for effective HEV antiviral agents. The aims of this study were to develop a drug screening platform and to discover novel approaches to targeting steps within the viral life cycle. We developed a screening platform for molecules inhibiting HEV replication and selected a candidate, isocotoin. Isocotoin inhibits HEV replication through interference with heat shock protein 90 (HSP90), a host factor not previously known to be involved in HEV replication. Additional work is required to understand the compound's translational potential, however this suggests that HSP90-modulating molecules, which are in clinical development as anti-cancer agents, may be promising therapies against HEV.

Brain Activity during Methamphetamine Anticipation in a Non-Invasive Self-Administration Paradigm in Mice.

The ability to sense time and anticipate events is critical for survival. Learned responses that allow anticipation of the availability of food or water have been intensively studied. While anticipatory behaviors also occur prior to availability of regularly available rewards, there has been relatively little work on anticipation of drugs of abuse, specifically methamphetamine (MA). In the present study, we used a protocol that avoided possible CNS effects of stresses of handling or surgery by testing anticipation of MA availability in animals living in their home cages, with daily voluntary access to the drug at a fixed time of day. Anticipation was operationalized as the amount of wheel running prior to MA availability. Mice were divided into four groups given access to either nebulized MA or water, in early or late day. Animals with access to MA, but not water controls, showed anticipatory activity, with more anticipation in early compared to late day and significant interaction effects. Next, we explored the neural basis of the MA anticipation, using c-FOS expression, in animals euthanized at the usual time of nebulization access. In the dorsomedial hypothalamus (DMH) and orbitofrontal cortex (OFC), the pattern of c-FOS expression paralleled that of anticipatory behavior, with significant main and interaction effects of treatment and time of day. The results for the lateral septum (LS) were significant for main effects and marginally significant for interaction effects. These studies suggest that anticipation of MA is associated with activation of brain regions important in circadian timing, emotional regulation, and decision making.