Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction.

Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinity Kd of 4.56 µM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.

Qualitative analysis of a two-group SVIR epidemic model with random effect.

In this paper, we investigate the dynamical behavior of a two-group SVIR epidemic model with random effect. Firstly, the two-group SVIR epidemic model with random perturbation of natural death rate is established. The existence and uniqueness of positive solution are proved by using stopping time theory and the Lyapunov analysis method. Secondly, a property of the system solution is obtained by using the law of strong numbers and the continuous local martingale. Finally, a new combination of Lyapunov functions is applied. The solution of the model we obtained is oscillating around a steady state if the basic reproduction number is less than one, which is the disease-free equilibrium of the corresponding deterministic model. A numerical simulation is presented to verify our theoretical results.

Preparation and characterization of angiopep-2 functionalized Ginsenoside-Rg3 loaded nanoparticles and the effect on C6 Glioma cells.

The purpose of this work was to prepare and characterize Angiopep-2 functionalized ginsenoside-Rg3 loaded nanoparticles (ANG-Rg3-NP) and evaluate the therapeutic effect on C6 glioma cells. Nanoparticles were prepared by the emulsion solvent evaporation method. Angiopep-2 was functionalized to nanoparticles via a maleimide-thiol covalent binding reaction to obtain ANG-Rg3-NP. The prepared nanoparticles were evaluated for size, zeta potential, morphology, stability, encapsulation efficiency, loading capacity, and release properties. The cytotoxicity study and targeting effect of ANG-Rg3-NP were evaluated by MTT assay. The study of cellular uptake in C6 glioma cells was performed by fluorescence microscopy and by using a microplate reader. The prepared ANG-Rg3-NP was observed to be uniformly spherical in shape with a particle size at 147.1 ± 2.7 nm. The encapsulation efficiency and loading capacity reached 80.6 ± 3.0% and 27.2 ± 1.4%, respectively. Additionally, ANG-Rg3-NP exhibited a desirable sustained release behavior. In vitro cytotoxicity study indicated that ANG-Rg3-NP could inhibit the proliferation of C6 glioma cells in a concentration-dependent manner. Also, the functionalization of Angiopep-2 made nanoparticles cross the blood-brain barrier more easily and accelerated the cellular uptake of nanoparticles. The ANG-Rg3-NP was a promising brain drug delivery carrier for the treatment of glioma.

Spatiotemporal patterns and source attribution of nitrogen pollution in a typical headwater agricultural watershed in Southeastern China.

Excessive nitrogen (N) discharge from agriculture causes widespread problems in aquatic ecosystems. Knowledge of spatiotemporal patterns and source attribution of N pollution is critical for nutrient management programs but is poorly studied in headwaters with various small water bodies and mini-point pollution sources. Taking a typical small watershed in the low mountains of Southeastern China as an example, N pollution and source attribution were studied for a multipond system around a village using the Hydrological Simulation Program-Fortran (HSPF) model. The results exhibited distinctive spatio-seasonal variations with an overall seriousness rank for the three indicators: total nitrogen (TN) > nitrate/nitrite nitrogen (NOx--N) > ammonia nitrogen (NH3-N), according to the Chinese Surface Water Quality Standard. TN pollution was severe for the entire watershed, while NOx--N pollution was significant for ponds and ditches far from the village, and the NH3-N concentrations were acceptable except for the ponds near the village in summer. Although food and cash crop production accounted for the largest source of N loads, we discovered that mini-point pollution sources, including animal feeding operations, rural residential sewage, and waste, together contributed as high as 47% of the TN and NH3-N loads in ponds and ditches. So, apart from eco-fertilizer programs and concentrated animal feeding operations, the importance of environmental awareness building for resource management is highlighted for small farmers in headwater agricultural watersheds. As a first attempt to incorporate multipond systems into the process-based modeling of nonpoint source (NPS) pollution, this work can inform other hydro-environmental studies on scattered and small water bodies. The results are also useful to water quality improvement for entire river basins.