Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors.

Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 µM for BD1 but >100 µM for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.

Mechanism study of toluene removal using iron/nickel bimetallic catalysts supported on biochar.

The present study utilized rice husk biomass as a carrier to synthesize rice husk biochar loaded with iron and nickel. Mono-metallic and bimetallic catalysts were prepared for the removal of toluene as the tar model. The efficiency of the catalysts for the removal of toluene was investigated, and finally, the removal mechanisms of mono-metallic and bimetallic catalysts for toluene were revealed. The experimental results showed that the bimetallic-loaded biochar catalysts had excellent toluene removal performance, which was closely related to the ratio of loaded Fe and Ni. Among them, the catalyst DBC-Fe2.5 %-Ni2.5 % (2.5 wt% iron loading and 2.5 wt% nickel loading) obtained through secondary calcination at 700 °C achieved the highest toluene removal efficiency of 92.76 %. The elements of Fe and Ni in the catalyst were uniformly dispersed on the surface and in the pores of the biochar, and the catalyst had a layered structure with good adsorption. Under the interaction of Fe and Ni, the agglomeration and sintering of Ni were reduced, and the surface acidity of the catalyst was increased, the surface acidity was favorable for toluene removal. The iron­nickel catalyst did not form significant alloys when calcined at 400 °C, whereas strong metal interactions occurred at 700 °C, resulting in the formation of Fe0.64Ni0.36 alloy and NiFe2O4 alloy. This NiFe alloy had abundant active sites to enhance the catalytic cracking of toluene and provide lattice oxygen for the reaction. Furthermore, the functional groups on the catalyst surface also had an impact on toluene removal. The catalyst prepared in this paper reduces the cost of tar removal, can be applied to the removal of industrial pollutant tars, reduces the pollution of the environment, and provides theoretical guidance and technical reference for the efficient removal of tar.

Characterization of Root and Foliar-Applied Iron Oxide Nanoparticles (α-Fe2O3, γ-Fe2O3, Fe3O4, and Bulk Fe3O4) in Improving Maize (Zea mays L.) Performance.

Iron (Fe) oxide nanoparticles (NPs) improve crop growth. However, the comparative effect of root and foliar-applied different sources of Fe oxide NPs on plant performance at morphological and physiological levels still needs to be discovered. In this study, we characterized the growth and physiological responses of hydroponic-cultured maize seedlings to four sources of Fe (i.e., α-Fe2O3, γ-Fe2O3, Fe3O4 NPs, and bulk Fe3O4) and two application methods (root vs. foliar). Results showed that Fe concentration in root and shoot increased by elevating the level of NPs from 100 mg L-1 to 500 mg L-1. Overall, the responses of maize seedlings to different sources of Fe oxide NPs were as follows: Fe3O4 > γ-Fe2O3 > α-Fe2O3 > bulk Fe3O4. The application of Fe at concentrations ranging from 100 mg L-1 to 500 mg L-1 had no significant effects on various growth parameters of maize, including biomass, chlorophyll content, and root length. Iron oxide NPs increased the plant biomass by 23-37% by root application, whereas it was 5-9% by foliar application. Chlorophyll contents were increased by 29-34% and 18-22% by foliar and root applications, respectively. The non-significant response of reactive oxygen species (i.e., superoxide dismutase, catalase, and peroxidase) suggested optimum maize performance for supplementing Fe oxide NPs. A confocal laser scanning microscope suggested that Fe oxide NPs entered through the epidermis and from the cortex to the endodermis. Our results provide a scientific basis that the root application of Fe3O4 at the rate of 100 mg L-1 is a promising approach to obtain higher maize performance and reduce the quantity of fertilizer used in agriculture to minimize environmental effects while improving crop productivity and quality. These findings demonstrated the tremendous potential of Fe NPs as an environmentally friendly and sustainable crop approach.

Optimal biochar amendment rate reduced the yield-scaled N2O emissions from Ultisols in an intensive vegetable field in South China.

Nitrous oxide (N2O) emissions, vegetable yields, and soil microbial properties were studied in response to different rates of rice-straw biochar applied to an intensive vegetable soil (Ultisol) in South China. The study was conducted over a one-year period as a block-designed field experiment (n = 3) with two successive crops and five harvests in total. Biochar was applied at rates of 0, 10, 20, 30 and 40 Mg ha-1 and splits of nitrogen (N) fertilizer were added in the form of urea (1010 kg N in total). References without biochar and N fertilization were included. Biochar significantly decreased the cumulative annual N2O emissions by 34-67%, which concurred with decreased denitrification enzyme activity and increased nosZ gene abundance in the vegetable soil. The absolute N2O mitigation increased with increasing flux rates, which were positively correlated to soil temperature and water-filled pore space. Conversely, weak increases of N2O emissions were recurrently induced by biochar when the soil temperature was lower than 20 °C and the absolute fluxes were low. A significant 17-29% increase in vegetable yield was induced by biochar, which also ameliorated soil fertility by increasing the soil carbon content and the cation exchange capacity. Overall, biochar significantly decreased the yield-scaled N2O emissions by 44-71% with the lowest yield-scaled N2O emissions for the intermediate biochar application rate of 20 Mg ha-1. Higher biochar application rates failed to further decrease the yield-scaled N2O emissions, but rather caused weak increases. Based on the present results, a biochar application rate of 20 Mg ha-1 combined with N fertilization seemed to be recommendable to achieve highest vegetable yield with lowest N2O emissions in intensive vegetable production in South China.

Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin.

Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.