No abstract

In addition to being a structural protein that packages the viral genomic RNA, hepatitis C virus (HCV) core protein possesses regulatory functions. In this report, we demonstrate that the HCV core protein could enhance the gene transactivation activity of the tumor suppressor p53, regardless of whether p53 was derived from an exogenous or an endogenous gene. The activation of p53 by the HCV core protein was supported by the observation that the HCV core protein could enhance the expression of p21(waf1/Cip1), a downstream effector gene of p53, in a p53-dependent manner. Further studies indicated that the HCV core protein could also suppress hepatocellular growth via p53. The HCV core protein and p53 could bind to each other in vitro, which was evidenced by the coimmunoprecipitation, the GST pull-down, and the Far-Western blot assays. The deletion-mapping analysis indicated that the carboxy-terminal sequence of p53 located between amino acids 366 and 380 was required for the core protein binding. These results raised the possibility that the HCV core protein might activate p53 through direct physical interaction. The persistent perturbation of p53 activity by the HCV core protein during chronic infection may have important consequences in HCV pathogenesis.

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self‐assembled micelles that are consisted of reactive oxygen species (ROS)‐responsive and fibrin‐binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood–brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.

Hepatitis C virus (HCV) F protein is a newly discovered HCV gene product that is expressed by translational ribosomal frameshift. Little is known about the biological properties of this protein. By performing pulse-chase labeling experiments, we demonstrate here that the F protein is a labile protein with a half-life of <10 min in Huh7 hepatoma cells and in vitro. The half-life of the F protein could be substantially increased by proteasome inhibitors, suggesting that the rapid degradation of the F protein is mediated by the proteasome pathway. Further immunofluorescence staining and subcellular fractionation experiments indicate that the F protein is primarily associated with the endoplasmic reticulum. This subcellular localization is similar to those of HCV core and NS5A proteins, raising the possibility that the F protein may participate in HCV morphogenesis or replication.

Current strategies for Alzheimer's disease (AD) treatments focus on pathologies in the late stage of the disease progression. Poor clinical outcomes are displayed due to the irreversible damages caused by early microglia abnormality which triggers disease development before identical symptoms emerge. Based on the crosstalk between microglia and brain microenvironment, a reactive oxygen species (ROS)‐responsive polymeric micelle system (Ab‐PEG‐LysB/curcumin (APLB/CUR)) is reported to normalize the oxidative and inflammatory microenvironment and reeducate microglia from an early phase of AD. Through an β‐amyloid (Aβ) transportation‐mimicked pathway, the micelles can accumulate into the diseased regions and exert synergistic effects of polymer‐based ROS scavenging and cargo‐based Aβ inhibition upon microenvironment stimuli. This multitarget strategy exhibits gradual correction of the brain microenvironment, efficient neuroprotection, and microglia modulation, leading to decreased Aβ plaque burdens and consequently enhanced cognitive functions in APPswe/PSEN1dE9 model mice. The results indicate that microglia can be exploited as an early target for AD treatment and their states can be controlled via microenvironment modulation.