Efficient Cellular Release of Rift Valley Fever Virus Requires Genomic RNA

The Rift Valley fever virus is responsible for periodic, explosive epizootics throughout sub-Saharan Africa. The development of therapeutics targeting this virus is difficult due to a limited understanding of the viral replicative cycle. Utilizing a virus-like particle system, we have established roles for each of the viral structural components in assembly, release, and virus infectivity. The envelope glycoprotein, Gn, was discovered to be necessary and sufficient for packaging of the genome, nucleocapsid protein and the RNA-dependent RNA polymerase into virus particles. Additionally, packaging of the genome was found to be necessary for the efficient release of particles, revealing a novel mechanism for the efficient generation of infectious virus. Our results identify possible conserved targets for development of anti-phlebovirus therapies

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40–60 pM 2 weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target

A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells

Abstract A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer