Apoptosis of A549 cells by small interfering RNA targeting survivin delivery using poly-β-amino ester/guanidinylated O-carboxymethyl chitosan nanoparticles

Gene-based therapeutics has emerged as a promising approach for human cancer therapy. Among a variety of non-viral vectors, polymer vectors are particularly attractive due to their safety and multivalent groups on their surface. This study focuses on guanidinylated O-carboxymethyl chitosan (GOCMCS) along with poly-β-amino ester(PBAE) for siRNA delivery. Binding efficiency of PBAE/siRNA/GOCMCS nanoparticles were characterized by gel electrophoresis. The siRNA-loaded nanoparticles were found to be stable in the presence of RNase A, serum and BALF respectively. Fine particle fraction (FPF) which was determined by a two-stage impinger (TSI) was 57.8% ± 2.6%. The particle size and zeta potential of the nanoparticles were 153.8 ± 12.54 nm and + 12.2 ± 4.94 mV. In vitro cell transfection studies were carried out with A549 cells. The cellular uptake was significantly increased. When the cells were incubated with siSurvivin-loaded nanoparticles, it could induce 26.83% ± 0.59% apoptosis of A549 cells and the gene silencing level of survivin expression in A549 cells were 30.93% ± 2.27%. The results suggested that PBAE/GOCMCS nanoparticle was a very promising gene delivery carrier.

Reaction mechanism and kinetics of CO oxidation over a CuO/Ce0.75Zr0.25O2-δ catalyst

The CuO/Ce0.75Zr0.25O2-δ and Ce0.75Zr0.25Oδ catalysts were prepared by the sol-gel method, and Cu0.07Ce0.75Zr0.25O2-δ was obtained by treating CuO/Ce0.75Zr0.25O2-δ with nitric acid to remove the well-dispersed CuO on the surface. Various characterizations were used to reveal the different active sites, such as surface-dispersed CuO and Cu-Ce-Zr-Oδ solid solutions in CuO/Ce0.75Zr0.25O2-δ, Cu-Ce-Zr-Oδ solid solutions in Cu0.07Ce0.75Zr0.25O2-δ and Ce-Zr-Oδ solid solutions in Ce0.75Zr0.25Oδ. The Raman and O2-TPD results showed that the concentration of oxygen vacancies in Cu-Ce-Zr-Oδ solid solutions was higher than that in Ce-Zr-Oδ solid solutions. CO oxidation testing suggested that the catalytic activity decreases in the order of CuO/Ce0.75Zr0.25O2-δ > Cu0.07Ce0.75Zr0.25O2-δ > Ce0.75Zr0.25Oδ. Combined with the in situ diffuse-reflectance Fourier transform (in situ DRIFT) results, the reaction sensitivity followed the order of CO linear chemisorption onto dispersed CuOx species (Mars-van Krevelen mechanism) > carbonate species onto a Cu-Ce-Zr-Oδ solid solution (Langmuir-Hinshelwood mechanism) > carbonate species onto a Ce-Zr-Oδ solid solution (Langmuir-Hinshelwood mechanism). Kinetic studies suggested that the power-law rate expressions and apparent activation energies were r = 6.02 × 10−7×PCO0.68PO20.03 (53 ± 3 kJ/mol) for CuO/Ce0.75Zr0.25O2-δ, r = 5.86 × 10−7×PCO0.8PO20.07 (105 ± 5 kJ/mol) for Cu0.07Ce0.75Zr0.25O2-δ and r = 5.7 × 10−7×PCO0.75PO20.12 (115 ± 6 kJ/mol) for Ce0.75Zr0.25Oδ. The Mars-van Krevelen mechanism should be the crucial reaction pathway over CuO/Ce0.75Zr0.25O2-δ in CO interfacial reactions, although the Langmuir-Hinshelwood mechanism cannot be ignored, and the Langmuir-Hinshelwood mechanism mainly occurred over the Cu0.07Ce0.75Zr0.25O2-δ and Ce0.75Zr0.25Oδ catalysts, where the contribution from the Mars-van Krevelen mechanism was negligible due to the absence of surface CuOx species.

Catalytic self-sustained combustion of toluene and reaction pathway over CuxMn1-xCe0.75Zr0.25/TiO2 catalysts

Epigenetic modification in histone deacetylase deletion strain of Calcarisporium arbuscula leads to diverse diterpenoids

Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporium arbuscula had led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes and isolation of ten compounds. Further investigation of the crude extract of C. arbuscula ΔhdaA strain resulted in the isolation of twelve new diterpenoids including three cassanes ( 1 - 3 ), one cleistanthane ( 4 ), six pimaranes ( 5 - 10 ), and two isopimaranes ( 11 and 12 ) along with two know cleistanthane analogues. Their structures were elucidated by extensive NMR spectroscopic data analysis. Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2 (matrix metalloproteinases family) in human breast cancer (MCF-7) cells.

mTOR inhibitor INK128 attenuates systemic lupus erythematosus by regulating inflammation-induced CD11b+Gr1+ cells

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by systemic chronic inflammation that can affect multiple major organ systems. Although the etiology of SLE is known to involve a variety of factors such as the environment, random factors and genetic susceptibility, the exact role of CD11b + Gr1 + myeloid cells in lupus progression is not fully understood. Myeloid-derived CD11b + Gr1 + cells are thought to be a heterogeneous group of immature myeloid cells with immune function. Some studies have reported that CD11b + Gr1 + cells and the activation of mTOR pathway are involved in the pathogenesis of systemic lupus erythematosus (SLE). However, it is still not clarified about the mechanism of influence of lupus microenvironment and mTOR signaling on CD11b + Gr1 + cells. In the present study, we found that the percentage of CD11b + Gr1 + cells increased prior to the abnormal changes of Th17, Treg, T and B cells during lupus development. TLR7 and IFN-α signaling synergized to promote CD11b + Gr1 + cell accumulation in an mTOR-dependent manner. Moreover, compared to a traditional mTOR inhibitor, INK128 inhibited more effectively the disease activity via regulating CD11b + Gr1 + cell expansion and functions. Furthermore, TLR7/IFN-α-modified CD11b + Gr1 + cells promoted unbalance of Th17/Tregs and were inclined to differentiate into macrophages via the mTOR pathway. In conclusion, CD11b + Gr1 + cells increased in the early stages of the lupus progression and mTOR pathway was critical for CD11b + Gr1 + cells in lupus development, suggesting the changes of inflammation-induced CD11b + Gr1 + cells initate lupus development. We also provide evidence for the first time that INK128, a second generation mTOR inhibitor, has a good therapeutic action on lupus development by regulating CD11b + Gr1 + cells.

Er Shen Wan extract alleviates polyuria and regulates AQP 2 and AVPR 2 in a rat model of spleen-kidney Yang deficiency–induced diarrhea

Er Shen Wan (ESW), has been empirically used for treating spleen-kidney Yang deficiency (SKYD) syndrome in Traditional Chinese medicine (TCM) for centuries and shows a variety of activities. The medicinal formula is a mixture of two component herbs, Psoraleae Fructus (PF, Bu-Gu-Zhi in Chinese) and Myristicae Semen (MS, Rou-Dou-Kou in Chinese). The current study was designed to evaluate ESWP antidiuretic treatment of polyuria and to explore potential mechanisms of renal water metabolism in the rat model of SKYD-induced diarrhea.

Structure-guided evolution of a 2-phenyl-4-carboxyquinoline chemotype into PPARα selective agonists: New leads for oculovascular conditions

Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure-activity relationships for the newly identified quinoline-based PPARα agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand-protein interactions and better complement the nature of the binding pocket. A focused subset of analogs was designed, synthesized, and assessed for PPARα agonism. Two key observations arose from this work 1) contrary to other PPARα agonists, incorporation of the fibrate "head-group" decreases PPARα selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPARα that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPARα agonism (EC 50  = ∼6 µM) than Y-0452 (EC 50  = ∼50 µM) and manifests >20-fold selectivity for PPARα over the PPARγ and PPARδ isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPARα agonism including PPARα upregulation, induction of target genes, and inhibition of cell migration.

Convergence analysis of modified PGSS methods for singular saddle-point problems

Recently, variants of shift-splitting iteration method have been proposed for solving singular saddle-point problems. However, these methods can only be proved to converge to one of the solutions of the consistent singular linear system, not knowing any further information about this solution. In this work, we consider a modified preconditioned generalized shift-splitting (MPGSS) iteration method for solving both consistent and inconsistent singular saddle-point problems. This method is proved to converge to the best least squares solution. Moreover, based on the iteration form, a preconditioner is obtained to accelerate Krylov subspace methods. Theoretical analysis shows that the preconditioned GMRES method also converges to the best least squares solution of the consistent singular saddle-point problem. In addition, numerical results are presented to show the effectiveness and robustness of the proposed iteration method and preconditioner.

The method of particular solutions for solving nonlinear Poisson problems

Based on the recent development in the method of particular solutions, we re-exam three approaches using different basis functions for solving nonlinear Poisson problems. We further propose to simplify the solution procedure by removing the insolvency condition when the radial basis functions are augmented with high order polynomial basis functions. We also specify the deficiency of some of these methods and provide necessary remedy. The traditional Picard method is introduced to compare with the recent proposed methods using MATLAB optimization toolbox solver for solving nonlinear Poisson equations. Ranking on these three approaches are given based on the results of numerical experiment.

A hierarchical porous Fe-N impregnated carbon-graphene hybrid for high-performance oxygen reduction reaction

A Fe-N impregnated carbon in a hybrid with in-situ grown graphene from hierarchical porous carbon has been obtained for high-performance oxygen reduction reaction (ORR) catalysis. This hybrid material combines the desirable characteristics for the ORR, including Fe-N active sites, high surface area, good electron conductivity, and hierarchical channels for mass diffusion. As a result, this catalyst exhibits a very positive reaction onset potential (−0.05 V vs. Ag/AgCl), a high ORR current density, and a complete four-electron ORR pathway, which are even better than a commercial 20% Pt/C catalyst. We further reveal the synergistic ORR enhancement from the controlled Fe-N impregnation in the doped carbon-graphene hybrid.