Giant piezoresponse in nanoporous (Ba,Ca)(Ti,Zr)O3 thin film.

Lattice strain effects on the piezoelectric properties of crystalline ferroelectrics have been extensively studied for decades; however, the strain dependence of the piezoelectric properties at nano-level has yet to be investigated. Herein, a new overview of the super-strain of nanoporous polycrystalline ferroelectrics is reported for the first time using a nanoengineered barium calcium zirconium titanate composition (Ba0.85Ca0.15)(Ti0.9Zr0.1)O3 (BCZT). Atomic-level investigations show that the controlled pore wall thickness contributes to highly strained lattice structures that also retain the crystal size at the optimal value (<30 nm), which is the primary contributor to high piezoelectricity. The strain field derived from geometric phase analysis at the atomic level and aberration-corrected high-resolution scanning transmission electron microscopy (STEM) yields of over 30% clearly show theoretical agreement with high piezoelectric properties. The uniqueness of this work is the simplicity of the synthesis; moreover the piezoresponse d 33 becomes giant, at around 7500 pm V-1. This response is an order of magnitude greater than that of lead zirconate titanate (PZT), which is known to be the most successful ferroelectric over the past 50 years. This concept utilizing nanoporous BCZT will be highly useful for a promising high-density electrolyte-free dielectric capacitor and generator for energy harvesting in the future.

Magnetic Hydrogel Composite for Wastewater Treatment.

Nanocomposite hydrogels are highly porous colloidal structures with a high adsorption capacity, making them promising materials for wastewater treatment. In particular, magnetic nanoparticle (MNP) incorporated hydrogels are an excellent adsorbent for aquatic pollutants. An added advantage is that, with the application of an external magnetic field, magnetic hydrogels can be collected back from the wastewater system. However, magnetic hydrogels are quite brittle and structurally unstable under compact conditions such as in fixed-bed adsorption columns. To address this issue, this study demonstrates a unique hydrogel composite bead structure, providing a good adsorption capacity and superior compressive stress tolerance due to the presence of hollow cores within the beads. The gel beads contain alginate polymer as the matrix and MNP-decorated cellulose nanofibres (CNF) as the reinforcing agent. The MNPs within the gel provide active adsorption functionality, while CNF provide a good stress transfer phenomenon when the beads are under compressive stress. Their adsorption performance is evaluated in a red mud solution for pollutant adsorption. Composite gel beads have shown high performance in adsorbing metal (aluminium, potassium, selenium, sodium, and vanadium) and non-metal (sulphur) contaminations. This novel hybrid hydrogel could be a promising alternative to the conventionally used toxic adsorbent, providing environmentally friendly operational benefits.

Construction of AC/DC magnetic syringe device for stimulated drug release, injection and ejection of nanocarriers and testing cytotoxicity in vitro.

Iron nanoparticles are used as a targeted drug delivery system. The nanocarrier itself can be genotoxic, trigger oxidative stress or cell death. Therefore, we developed an AC/DC magnetic syringe for injecting, stimulating drug release and safe removing of the nanocarrier. Alongside we optimized the method for nanoparticles' drug release kinetics and testing cytotoxicity in vitro.•This paper presents detailed instructions for construction of AC/DC magnetic syringe device for stimulated drug release, injection and ejection of magnetic nanoparticles; nanoparticles preparation; adsorbing methylene blue on nanoparticles; determination of drug release kinetics from nanocarriers on the example of methylene blue•Gomori´s Prussian blue reaction for differentiated SH-SY5Y human neuroblastoma cell line; MTT viability assay optimized for differentiated SH-SY5Y human neuroblastoma cell line and antioxidant enzymes activities assay and lipid peroxidation methods are optimized for cell analyses cell cultivation for nanoparticles cytotoxicity testing in vitro.•Those protocols are the first step toward further testing the effect of nanoparticles in vivo, on brain tissue.

AC/DC magnetic device for safe medical use of potentially harmful magnetic nanocarriers.

Continuing our previous research work on a drug delivery system based on combined AC/DC magnetic fields, we have developed a prototype AC/DC magnetic syringe device for stimulation of drug release from drug carriers, with the options of injecting/removing drug carriers. The porous Fe3O4 carrier, in a dose-dependent manner, causes acute oxidative damage and reduces the viability of differentiated SH-SY5Y human neuroblastoma cells, indicating the necessity for its removal once it reaches the therapeutic concentration at the target tissue. The working mechanism of the device consists of three simple steps. First, direct injection of the drug adsorbed on the surface of a carrier via a needle inserted into the targeted area. The second step is stimulation of drug release using a combination of AC magnetic field (a coil magnetised needle with AC current) and permanent magnets (DC magnetic lens outside of the body), and the third step is removal of the drug carriers from the injected area after the completion of drug release by magnetising the tip of the needle with DC current. Removing the drug carriers allows us to avoid possible acute and long term side effects of the drug carriers in the patient's body, as well as any potential response of the body to the drug carriers.

Enhancement of thermoelectric properties of La-doped SrTiO3 bulk by introducing nanoscale porosity.

Electron-doped SrTiO3 is a well-known n-type thermoelectric material, although the figure of merit of SrTiO3 is still inferior compared with p-type metal oxide-based thermoelectric materials due to its high lattice thermal conductivity. In this study, we have used a different amount of the non-ionic surfactant F127 during sample preparation to introduce nanoscale porosities into bulk samples of La-doped SrTiO3. It has been observed that the porosities introduced into the bulk sample significantly improve the Seebeck coefficient and reduce the thermal conductivity by the charge carrier and phonon scattering respectively. Therefore, there is an overall enhancement in the power factor (PF) followed by a dimensionless figure of merit (zT) over a wide scale of temperature. The sample 20 at% La-doped SrTiO3 with 600 mg of F127 surfactant (SLTO 600F127) shows the maximum PF of 1.14 mW m-1 K-2 at 647 K which is 35% higher than the sample without porosity (SLTO 0F127), and the same sample (SLTO 600F127) shows the maximum value of zT is 0.32 at 968 K with an average enhancement of 62% in zT in comparison with the sample without porosity (SLTO 0F127).

Chemical Synthesis of Porous Barium Titanate Thin Film and Thermal Stabilization of Ferroelectric Phase by Porosity-Induced Strain.

Barium titanate (BaTiO3, hereafter BT) is an established ferroelectric material first discovered in the 1940s and still widely used because of its well-balanced ferroelectricity, piezoelectricity, and dielectric constant. In addition, BT does not contain any toxic elements. Therefore, it is considered to be an eco-friendly material, which has attracted considerable interest as a replacement for lead zirconate titanate (PZT). However, bulk BT loses its ferroelectricity at approximately 130 °C, thus, it cannot be used at high temperatures. Because of the growing demand for high-temperature ferroelectric materials, it is important to enhance the thermal stability of ferroelectricity in BT. In previous studies, strain originating from the lattice mismatch at hetero-interfaces has been used. However, the sample preparation in this approach requires complicated and expensive physical processes, which are undesirable for practical applications. In this study, we propose a chemical synthesis of a porous material as an alternative means of introducing strain. We synthesized a porous BT thin film using a surfactant-assisted sol-gel method, in which self-assembled amphipathic surfactant micelles were used as an organic template. Through a series of studies, we clarified that the introduction of pores had a similar effect on distorting the BT crystal lattice, to that of a hetero-interface, leading to the enhancement and stabilization of ferroelectricity. Owing to its simplicity and cost effectiveness, this fabrication process has considerable advantages over conventional methods.

Discovery of oxazole-based PDE4 inhibitors with picomolar potency.

Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.

Discovery of a highly potent series of oxazole-based phosphodiesterase 4 inhibitors.

Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.

A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation.

Sch527123 [2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]ben-zamide] is a potent, selective antagonist of the human CXCR1 and CXCR2 receptors (Gonsiorek et al., 2007). Here we describe its pharmacologic properties at rodent CXCR2 and at the CXCR1 and CXCR2 receptors in the cynomolgus monkey, as well as its in vivo activity in models demonstrating prominent pulmonary neutrophilia, goblet cell hyperplasia, and mucus production. Sch527123 bound with high affinity to the CXCR2 receptors of mouse (K(d) = 0.20 nM), rat (K(d) = 0.20 nM), and cynomolgus monkey (K(d) = 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC(50) approximately 3-6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (K(d) = 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC(50) approximately 1000 nM). Oral treatment with Sch527123 blocked pulmonary neutrophilia (ED(50) = 1.2 mg/kg) and goblet cell hyperplasia (32-38% inhibition at 1-3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppressed the pulmonary neutrophilia (ED(50) = 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED(50) =<0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppressed the pulmonary neutrophilia (ED(50) = 1.3 mg/kg), goblet cell hyperplasia (ED(50) = 0.7 mg/kg), and increase in BAL mucin content (ED(50) = <1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In cynomolgus monkeys, Sch527123 reduced the pulmonary neutrophilia induced by repeat bronchoscopy and lavage (ED(50) = 0.3 mg/kg). Therefore, Sch527123 may offer benefit for the treatment of inflammatory lung disorders in which pulmonary neutrophilia and mucus hypersecretion are important components of the underlying disease pathology.

Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist.

In neutrophils, growth-related protein-alpha (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42:2874-2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the pharmacology of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [(3)H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K(d) = 3.9 +/- 0.3 nM), the compound is CXCR2-selective (K(d) = 0.049 +/- 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.

Human cord blood-derived mast cells synthesize and release I-309 in response to IgE.

Mast cells are the central mediating cells of allergic reactions. Binding of allergen specific IgE to high affinity IgE receptor (Fcepsilon RI) and subsequent binding of allergen by the IgE causes receptor cross-linking and activation. In a study examining the differential gene expression in human cord blood-derived mast cells (CBMCs) mediated by activation of Fcepsilon RI both with IgE and IgE followed by cross-linking with alpha-IgE, the chemokine I-309 was found to be upregulated. I-309 is the ligand for the CCR8 receptor and is responsible for chemoattraction of TH2 type T-cells. Interestingly, I-309 RNA and protein levels were elevated not only in response to IgE/alpha-IgE activation but also by IgE alone. In addition, the I-309 levels were augmented by growth of the CBMCs in the presence of the proinflammatory cytokine IL-4. GM-CSF and MIP-1alpha secretion was also induced by IgE. These results suggest that IgE, through the production and release of cytokines such as I-309, GM-CSF and MIP-1alpha could promote an inflammatory reaction in the absence of antigen stimulation of mast cells.

SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist.

Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor.

We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.

Microarray profile of differentially expressed genes in a monkey model of allergic asthma.

BACKGROUND: Inhalation of Ascaris suum antigen by allergic monkeys causes an immediate bronchoconstriction and delayed allergic reaction, including a pulmonary inflammatory infiltrate. To identify genes involved in this process, the gene-expression pattern of allergic monkey lungs was profiled by microarrays. Monkeys were challenged by inhalation of A. suum antigen or given interleukin-4 (IL-4) treatment; lung tissue was collected at 4, 18 or 24 h after antigen challenge or 24 h after IL-4. Each challenged monkey lung was compared to a pool of normal, unchallenged monkey lungs. RESULTS: Of the approximately 40,000 cDNAs represented on the microarray, expression levels of 169 changed by more than 2.5-fold in at least one of the pairwise probe comparisons; these cDNAs encoded 149 genes, of which two thirds are known genes. The largest number of regulated genes was observed 4 h after challenge. Confirmation of differential expression in the original tissue was obtained for 95% of a set of these genes using real-time PCR. Cluster analysis revealed at least five groups of genes with unique expression patterns. One cluster contained genes for several chemokine mediators including eotaxin, PARC, MCP-1 and MCP-3. Genes involved in tissue remodeling and antioxidant responses were also identified as regulated by antigen and IL-4 or by antigen only. CONCLUSION: This study provides a large-scale profile of gene expression in the primate lung following allergen or IL-4 challenge. It shows that microarrays, with real-time PCR, are a powerful tool for identifying and validating differentially expressed genes in a disease model.

8-Methoxyquinolines as PDE4 inhibitors.

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

Synthesis and profile of SCH351591, a novel PDE4 inhibitor.

The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).