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Micelles are highly attractive nano-drug delivery systems for targeted cancer therapy. While they have been demonstrated to significantly alleviate the side-effects of their cargo drugs, the therapy outcomes are usually suboptimal partially due to ineffective drug release and endosome entrapment. Stimulus-responsive nanoparticles have allowed controlled drug release in a smart fashion, and we want to use this concept to design novel micelles. Herein, we reported pH-sensitive paclitaxel (PTX)-loaded poly (ethylene glycol)-phenylhydrazone-dilaurate (PEG-BHyd-dC12) micelles (PEG-BHyd-dC12/PTX). The micelles were spherical, with an average particle size of ∼135 nm and a uniform size distribution. The pH-responsive properties of the micelles were certified by both colloidal stability and drug release profile, where the particle size was strikingly increased accompanied by faster drug release as pH decreased from 7.4 to 5.5. As a result, the micelles exhibited much stronger cytotoxicity than the pH-insensitive counterpart micelles against various types of cancer cells due to the hydrolysis of the building block polymers and subsequent rapid PTX release. Overall, these results demonstrate that the PEG-BHyd-dC12 micelle is a promising drug delivery system for cancer therapy.

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Opening of large conductance calcium-activated and voltage-dependent potassium (BKCa) channels hyperpolarizes plasma membranes of smooth muscle (SM) to cause vasodilation, underling a key mechanism for mediating uterine artery (UA) dilation in pregnancy. Hydrogen sulfide (H2S) has been recently identified as a new UA vasodilator, yet the mechanism underlying H2S-induced UA dilation is unknown. Here, we tested whether H2S activated BKCa channels in human UA smooth muscle cells (hUASMC) to mediate UA relaxation. Multiple BKCa subunits were found in human UA in vitro and hUASMC in vitro, and high β1 and γ1 proteins were localized in SM cells in human UA. Baseline outward currents, recorded by whole-cell and single-channel patch clamps, were significantly inhibited by specific BKCa blockers iberiotoxin (IBTX) or tetraethylammonium, showing specific BKCa activity in hUASMC. H2S dose (NaHS, 1–1000 µM)-dependently potentiated BKCa currents and open probability. Co-incubation with a Ca2+ blocker nifedipine (5 µM) or a chelator (ethylene glycol-bis (β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM) did not alter H2S-potentiated BKCa currents and open probability. NaHS also dose-dependently relaxed phenylephrine pre-constricted freshly prepared human UA rings, which was inhibited by IBTX. Thus, H2S stimulated human UA relaxation at least partially via activating SM BKCa channels independent of extracellular Ca2+.

The endometrium becomes receptive to the embryo only in the mid-luteal phase, but not in the other stages of the menstrual cycle. Endometrial factors play an important role in implantation. Women with recurrent miscarriage and recurrent implantation failure have both been reported to have altered expression of receptivity markers during the window of implantation. We aimed to compare the gene expression profiles of the endometrium in the window of implantation among women with unexplained recurrent implantation failures (RIF) and unexplained recurrent miscarriages (RM) by RNA sequencing (RNA-Seq). In total 20 patients (9 RIF and 11 RM) were recruited. In addition 4 fertile subjects were included as reference. Endometrium samples were precisely timed on the 7th day after luteal hormone surge (LH + 7). All the 24 endometrium samples were extracted for total RNA. The transcriptome was determined by RNA-Seq in the first 14 RNA samples (5 RIF, 6 RM and 3 fertile). Differentially expressed genes between RM and RIF were validated by quantitative real-time PCR (qPCR) in all 24 RNA samples (9 RIF, 11 RM and 4 fertile). Transcriptomic profiles of RM and RIF, but not control samples, were separated from each other by principle component analysis (PCA) and support vector machine (SVM). Complementary and coagulation cascades pathway was significantly up-regulated in RIF while down-regulated in RM. Differentially expressed genes and in complement and coagulation cascade pathway between RM and RIF were further validated by qPCR. This study compared endometrial transcriptome among patients with RIF and RM in the window of implantation; it identified differential molecular pathways in endometrium between RIF and RM, which potentially affect the implantation process.

a An ab initio simulation of the UV/Visible spectra of substituted chalcones Abstract:The electronic absorption spectra of 29 phenyl-ring substituted chalcones have been investigated with the time-dependent density functional theory (TD-DFT) and polarizable continuum TD-DFT (PCM-TD-DFT). It turns out that the hybrid PBE1PBE functional with the 6-31G basis set provide reliable λ max when the solvent effects are included in the model. Comparisons with experimental values lead to a mean absolute error of 12 nm (0.136 eV). Moreover, the observed substituent effects are reproduced by calculation qualitatively. The λ max of substituted chalcone in phenyl ring A is less sensitive to substitution than that in ring B. The linear correlation of Hammett's substituent constants (σ P ) with LUMO energies is better with respect to HOMO energies. The calculation reveals that the maximum absorption band mainly results from the π→π* transition from HOMO to LUMO. The analysis of the electron density plots of frontier molecular orbitals show that most transitions should be of valence excitation nature.

The neurodegeneration induced by manganese has been attributed to its ability to undergo redox cycling, and catalysis of reactive oxygen species (ROS) formation, as with other transition metals. However, the characterization of manganese as a pro-oxidant is confounded by increasing evidence that the metal may scavenge superoxide anions and protect cells from oxidative damage. The current study was designed to address conflicting reports pertaining to the oxidative capacity of manganese. We found that the metal has distinctive redox dynamics in which the divalent reduced form, unlike iron, possessed no intrinsic oxidative capacity. The apparent ability of Mn 2+ to promote the formation of ROS within a cortical mitochondrial-synaptosomal fraction was quenched by the depletion of contaminating nanomolar concentrations of trivalent metals. The addition of manganic ions at trace concentrations dose-dependently restored the oxidative capacity attributed to divalent manganese, whereas the presence of the ferric ion retarded the rate of ROS generation. This result was paralleled by the spectrophotometric demonstration that the kinetics of iron oxidation is accelerated by trivalent but not divalent manganese. The markedly different capacities of the lower and higher valence states of manganese to promote free-radical formation in cortical fractions and to modulate the process of iron oxidation may account for earlier contradictory reports of anti-and pro-oxidant properties of manganese.