Study on the Relationships between Microscopic Cross-Linked Network Structure and Properties of Cyanate Ester Self-Reinforced Composites.

Bisphenol A dicyanate (BADCy) resin microparticles were prepared by precipitation polymerization synthesis and were homogeneously dispersed in a BADCy prepolymer matrix to prepare a BADCy self-reinforced composites. The active functional groups of the BADCy resin microparticles were characterized by Fourier transform infrared (FT-IR) spectroscopy. The results of an FT-IR curve showed that the BADCy resin microparticles had a triazine ring functional group and also had an active reactive group -OCN, which can initiate a reaction with the matrix. The structure of the BADCy resin microparticles was characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). From the TEM results, the BADCy resin microparticles dispersed in the solvent were nano-sized and distributed at 40-60 nm. However, from the SEM results, agglomeration occurred after drying, the BADCy resin particels were micron-sized and distributed between 0.3 µm and 0.6 µm. The BADCy resin prepolymer was synthesized in our laboratory. A BADCy self-reinforced composite was prepared by using BADCy resin microparticles as a reinforcement phase. This corresponds to a composite in which the matrix and reinforcement phase are made from different morphologies of the same monomer. The DSC curve showed that the heat flow of the microparticles is different from the matrix during the curing reaction, this means the cured materials should be a microscopic two-phase structure. The added BADCy resin microparticles as reaction sites induced the formation of a more complete and regular cured polymer structure, optimizing the cross-linked network as well as increasing the interplay between the BADCy resin microparticles and prepolymer matrix. Relative to the neat BADCy resin material, the tensile strength, flexural strength, compressive strength and impact strength increased by 98.1%, 40.2%, 27.4%, and 85.4%, respectively. A particle toughening mechanism can be used to explain the improvement of toughness. The reduction in the dielectric constant showed that the cross-linked network of the self-reinforced composite was more symmetrical and less polar than the neat resin material, which supports the enhanced mechanical properties of the self-reinforced composite. In addition, the thermal behavior of the self-reinforced composite was characterized by thermogravimetric analysis (TGA) and dynamic mechanical thermal analysis (DMTA). The results of DMTA also establishes a basis for enhancing mechanical properties of the self-reinforced composite.

Design of a new pH-activatable cell-penetrating peptide for drug delivery into tumor cells.

Cell-penetrating peptides (CPPs) have been considered as potential drug delivery vectors due to their remarkable membrane translocation capacity. However, lack of specificity and extreme systemic toxicity hamper their successful application for drug delivery. Here, we designed a new pH-activatable CPP, LHHLLHHLHHLLHH-NH2 (LH), by substitution of all lysines and two leucines of LKKLLKLLKKLLKL-NH2 (LK) with histidines. As expected, histidine-rich LH could be activated and penetrate into cells at pH 6.0, whereas its membrane transduction activity could be shielded at pH 7.4. In contrast, LK showed no obviously different cellular uptake at both pH conditions. Importantly, LH was significantly less cytotoxicity compared with LK at both pH values, suggesting a better safety for further application. In addition, after conjugation of camptothecin (CPT) with LH, this conjugate displayed remarkably pH-dependent antitumor activity than free CPT and LK-CPT. This study provides a new tumor pH-responsive CPP with low toxicity for selective anticancer drug delivery.

Anti-atherosclerotic effect of Fermentum Rubrum and Gynostemma pentaphyllum mixture in high-fat emulsion- and vitamin D3-induced atherosclerotic rats.

BACKGROUND: The mixture of Hongqu and gypenosides (HG) is composed of Fermentum Rubrum (Hongqu, in Chinese) and total saponins of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan, in Chinese) in a 3.6:1 weight ratio. Both Hongqu and Jiaogulan are considered valuable traditional Chinese medicines (TCMs); they have been commonly used in China for the treatment of hyperlipidemia and related diseases for centuries. The aim of the current study was assess the anti-atherosclerotic effect of HG. METHODS: Sixty-four Wistar rats were randomly divided into eight groups: normal, model, positive control (simvastatin, 1 mg/kg), Hongqu-treated (72 mg/kg), gypenoside (total saponin)-treated (20 mg/kg), and three doses HG-treated (50, 100, and 200 mg/kg). All of the rats were fed a basal diet. Additionally, the model group rats were intragastrically administered a high-fat emulsion and intraperitoneally injected with vitamin D3. The serum lipid profiles, oxidative stress, inflammatory cytokine, and hepatic antioxidant levels were then determined. Furthermore, the liver histopathology and arterial tissue were analyzed, and the expression of hyperlipidemia- and atherosclerosis (AS)-related genes was measured using reverse transcription-polymerase chain reaction. RESULTS: The AS rat model was established after 80 days. Compared to the model group, the HG-treated groups showed an obvious improvement in the serum lipid profiles, oxidative stress, and inflammatory cytokine levels, and showed markedly increased hepatic total antioxidant capacity. Moreover, the expression of genes related to lipid synthesis and inflammation reduced and that of the genes related to lipid oxidation increased in the liver and arterial tissue, which also reflected an improved health condition. CONCLUSION: the anti-atherosclerotic effects of HG were superior to those of simvastatin, Hongqu, and the gypenosides. Therefore, HG may be a useful anti-atherosclerotic TCM preparation.

Intramolecular cyclization of the antimicrobial peptide Polybia-MPI with triazole stapling: influence on stability and bioactivity.

Cationic antimicrobial peptides have attracted increasing attention as a novel class of antibiotics to treat infectious diseases caused by pathogenic bacteria. However, susceptibility to protease is a shortcoming in their development. Cyclization is one approach to increase the proteolytic resistance of peptides. Therefore, to improve the proteolytic resistance of Polybia-MPI, we have synthesized the MPI cyclic analogs C-MPI-1 (i-to-i+4) and C-MPI-2 (i-to-i+6) by copper(I)-catalyzed azide-alkyne cycloaddition. Compared with MPI, C-MPI-1 displayed sustained antimicrobial activity and had enhanced anti-trypsin resistance, while C-MPI-2 displayed no antimicrobial activity. The relationship between peptide structure and bioactivity was further investigated by probing the secondary structure of the peptides by circular dichroism. This showed that C-MPI-1 adopted an α-helical structure in aqueous solution and, interestingly, had increased α-helical conformation in 30 mM sodium dodecyl sulfate and 50% trifluoroethyl alcohol compared with MPI. C-MPI-2 that was not α-helical in structure, suggesting that the propensity for α-helix conformation may play an important role in cyclic peptide design. In addition, scanning electron microscopy, propidium iodide uptake, and membrane permeabilization assays indicated that MPI and the optimized analog C-MPI-1 had membrane-active action modes, indicating that the peptides would not be susceptible to conventional resistance mechanisms. Our study provides additional insight into the influence of intramolecular cyclization at various positions on peptide structure and biological activity. In conclusion, the design and synthesis of cyclic analogs via click chemistry offer a new strategy for the development of stable antimicrobial agents. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Design of novel antimicrobial peptide dimer analogues with enhanced antimicrobial activity in vitro and in vivo by intermolecular triazole bridge strategy.

Currently, antimicrobial peptides have attracted considerable attention because of their broad-sprectum activity and low prognostic to induce antibiotic resistance. In our study, for the first time, a series of side-chain hybrid dimer peptides J-AA (Anoplin-Anoplin), J-RR (RW-RW), and J-AR (Anoplin-RW) based on the wasp peptide Anoplin and the arginine- and tryptophan-rich hexapeptide RW were designed and synthesized by click chemistry, with the intent to improve the antimicrobial efficacy of peptides against bacterial pathogens. The results showed that all dimer analogues exhibited up to a 4-16 fold increase in antimicrobial activity compared to the parental peptides against bacterial strains. Furthermore, the antimicrobial activity was confirmed by time-killing kinetics assay with two strains which showed that these dimer analogues at 1, 2×MIC were rapidly bactericidal and reduced the initial inoculum significantly during the first 2-6h. Notably, dimer peptides showed synergy and additivity effects when used in combination with conventional antibiotics rifampin or penicillin respectively against the multidrug-resistant strains. In the Escherichia coli-infected mouse model, all of hybrid dimer analogues had significantly lower degree of bacterial load than the untreated control group when injected once i.p. at 5mg/kg. In addition, the infected mice by methicillin-resistant (MRSA) strain could be effectively treated with J-RR. All of dimer analogues had membrane-active action mode. And the membrane-dependent mode of action signifies that peptides functions freely and without regard to conventional resistant mechanisms. Circular dichroism analyses of all dimer analogues showed a general predominance of α-helix conformation in 50% trifluoroethanol (TFE). Additionally, the acute toxicities study indicated that J-RR or J-AR did not show the signs of toxicity when adult mice exposed to concentration up to 120mg/kg. The 50% lethal dose (LD50) of J-AA was 53.6mg/kg. In conclusion, to design and synthesize side chain-hybrid dimer analogues via click chemistry may offer a new strategy for antibacterial therapeutic option.

Cell penetrating peptide TAT can kill cancer cells via membrane disruption after attachment of camptothecin.

Attachment of traditional anticancer drugs to cell penetrating peptides is an effective strategy to improve their application in cancer treatment. In this study, we designed and synthesized the conjugates TAT-CPT and TAT-2CPT by attaching camptothecin (CPT) to the N-terminus of the cell penetrating peptide TAT. Interestingly, we found that TAT-CPT and especially TAT-2CPT could kill cancer cells via membrane disruption, which is similar to antimicrobial peptides. This might be because that CPT could perform as a hydrophobic residue to increase the extent of membrane insertion of TAT and the stability of the pores. In addition, TAT-CPT and TAT-2CPT could also kill cancer cells by the released CPT after they entered cells. Taken together, attachment of CPT could turn cell penetrating peptide TAT into an antimicrobial peptide with a dual mechanism of anticancer action, which presents a new strategy to develop anticancer peptides based on cell penetrating peptides.