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Phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks) regulate several important cellular and subcellular processes including cell proliferation and differentiation. LY294002 was originally reported to be a selective inhibitor of PI3K-Akt. Later, it showed that this compound also inhibits several other molecules. In this study, we investigated the effect of LY294002 on the growth of suspension (MV4-11 and TF-1a) and tissue (Hep-G2) cells. In exponential phase, MV4-11 cells, but not TF-1a and Hep-G2 cells, expressed a low level of PI3Kp85 and addition of LY294002 inhibited the phosphorylation of PI3Kp85. LY294002 also significantly inhibited the proliferation of MV4-11, TF-1a and Hep-G2 cell and caused formation of cell clusters/aggregates measured by MTT and BrdU assays, and observed under an inverted microscope, respectively. Surprisingly, we found that LY294002 markedly repressed the activation of mitogen-activated protein kinase (MAPK) signal molecules, MEK and ERK, in all these cells. The inhibition of MEK and ERK was confirmed by using MEK stimulators, GM-CSF and phorbol 12-myristate 13-acetate, and MEK-specific inhibitor, PD98059. Although transforming growth factor beta (TGFβ) also inhibited the growth of Hep-G2 cells, it had no effect on the activity of MEK and ERK. The clusters/aggregates found in LY294002-treated cells were not detectable in TGFβ-treated cells. Our data suggest that LY294002 may directly inhibit the activation of MEK and ERK by its ability to bind to the ATP-binding site of the MAPK molecules.

The development of protein adsorbents with high adsorption performance has attracted great attention due to the important role of these adsorbents in protein separation and purification. Herein, cellulose-based composite membranes were prepared through a combination of cellulose fiber (CF) and 2,2,6,6-tetramethylpiperidine-1-oxyl oxidized cellulose nanofiber (CNF) in alkaline/urea aqueous solution and regeneration from a tape casting method. Taking advantage of the functional carboxyl groups in CNF, the obtained cellulose-based composite membranes display a good protein adsorption property, with a capacity of 241.6 mg g−1, by using bovine serum albumin as a model protein. Meanwhile, the adsorption performance of cellulose-based composite membranes can be optimized by regulating the blending ratios of CNF and CF, buffer pH, initial protein concentrations and temperature, and the mechanical property of cellulose-based composite membranes can be adjusted by changing the ratio of CNF and CF. These effective and economic membranes may act as promising candidates for protein adsorption in protein separation and purification fields.

In this study, regenerated cellulose-based macrogels with abundant carboxyl groups and interconnected microporous structures were synthesized from cellulose fibers (CFs)/cellulose nanofibers (CNFs) and utilized as stable, efficient, and recyclable platforms for enzyme immobilization. CNFs with different carboxyl contents were prepared by a TEMPO (2, 2, 6, 6 -tetramethylpiperidine-1-oxyl radical)-medium oxidation system. The cellulose-based macrogels were prepared by dissolving CFs and CNFs in a NaOH/urea aqueous solution and a followed extrusion process. The carboxyl groups within the macrogels were then activated by an N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC·HCl)/Nhydroxysuccinimide (NHS) system, which provides these macrogels with efficient binding sites for enzyme immobilization. The three-dimensional network structures of the macrogels facilitate the enzymes to infiltrate into the core of the macrogels and be fixed on the abundant pore walls. The immobilized enzymes maintain activity at a higher pH than free enzymes. Moreover, the immobilized enzymes have higher temperature tolerance, and their optimal reaction temperature is about 10 °C higher than that of free enzymes. The immobilized enzymes retain 24% of the initial activity after repeated use for 7 times. The microporous regenerated cellulose-based macrogels show potential in the fields of enzyme immobilization and biocatalysis.

The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers. This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3. The washout period was 7 days. Series of plasma samples were collected after each dose to determine concentrations of blonanserin and its metabolite N-desethyl blonanserin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis and compared between periods by standard average bioequivalence ANOVA. Adverse events were monitored throughout the study. All subjects completed the study. High-fat meals significantly increased blonanserin exposure (AUCt) 2.58-fold (90% CI 2.21, 3.02), relative to the reference period. Co-administration of blonanserin with grapefruit juice remarkably prolonged elimination half-life of blonanserin (from 9.7 to 21.4 h) and significantly increased exposures to blonanserin and N-desethyl blonanserin by 5.82-fold (90% CI 4.57, 7.42) and 1.81-fold (90% CI 1.65, 1.98), respectively. These results suggested that blonanserin was largely metabolised in the intestinal tract before becoming systemically available, and both food and grapefruit juice enhanced exposure to blonanserin and N-desethyl blonanserin. Grapefruit juice increased bioavailability and may have reduced systemic clearance of blonanserin. Further intestinal CYP3A4 and hepatic CYP3A4 might be postulated to explain the delayed elimination of blonanserin. Dose adjustment of blonanserin is needed on the basis of co-intake of known strong CYP3A4 inhibitor. Patients taking high-dose blonanserin also need to be cautious about the ingestion of grapefruit juice.

The proportion of the isotropic strain (ISO) in a microelectromechanical system (MEMS)-elastomer hybrid configuration was enlarged from 6.99% to 98.30% to support various applications that require not only isotropic strains but also large ISOs. This achievement was realized by relocating the applied forces in a typical MEMS configuration and by modifying the shape (cross, square, and octagon) of the elastomer attached to the MEMS. The proposed configuration significantly improved the ISO, almost completely covering the active area of interest in the elastomer. Comprehensive structural analysis revealed that the proposed configuration and its enlarged ISO enhanced the color purity of a filter based on surface plasmon resonance.

A tunable surface plasmon resonance (SPR) structure driven by microelectromechanical system (MEMS) is proposed and analyzed in this work. The MEMS isotropically expands the suspended SPR structures of nanometer metal disks scattered on a polydimethylsiloxane (PDMS) diaphragm, to different extents on the xy-plane; filtering the incident white light into various colors under control of applied voltage. This symmetrical MEMS design and its isotropic structure modulation of SPR prevailed other MEMS color filters in modulation capability, operation variety, and shows independency of polarization.

Ilaprazole is a novel proton pump inhibitor that has been marketed as an oral therapy for acid-related diseases in China and Korea. This study aimed to compare the gastroprotective effects of intravenous and enteral ilaprazole in rat models. The rats were divided into 7–8 groups receiving vehicle, esomeprazole, and different doses of intravenous and enteral ilaprazole. The rats were then exposed to indomethacin (30 mg/kg, i.g.), or water-immersion stress and gastric lesions were examined. The effects of different treatments on histamine (10 μmol/kg/h)-induced acid secretion were also observed. Intravenous ilaprazole exhibited high antiulcer activity in a dose-dependent manner. Ilaprazole at a dose of 3 mg/kg decreased ulcer number and index to the same extent as 20 mg/kg esomeprazole. Moreover, the potency of intravenous ilaprazole is superior to that of intragastric ilaprazole. In anesthetized rats, the inhibitory effect of intravenous ilaprazole on histamine-induced acid secretion is faster and longer-lasting than that of intraduodenal ilaprazole. Intravenous ilaprazole is more potent than oral ilaprazole against indomethacin- or stress-induced gastric lesions, with faster and longer inhibition of acid secretion.

The different refining processes of lime mud, including water washing, drying and adding auxiliaries from chemical recovery of black liquor from reed pulp mill were studied in the article. The convenient and effective technologies of refining lime mud for CaCO3used as papermaking fillers with less water consumption were optimized and discussed. The experimental results showed that the brightness of the CaCO3refined is 84~86%(ISO), and water consumption is about 30~50 ton for one ton’s lime mud by the washing processes, and the brightness of the CaCO3refined is 88~89%(ISO) by the drying processes, and the lowest water consumption is about 3~6 tons for one ton’s lime mud by the adding auxiliaries peocess. With the optimum process, the carbonizing temperature is about 50°C, and the brightness of CaCO3refined is 91.5%(ISO). Total water consumption in the processes is only about 5~10 tons for one ton lime mud.

Tie2 is an endothelial receptor tyrosine kinase. An amino-acid substitution of tryptophan for arginine at residue 849 (Tie2-R849W) leads to a ligand-independent activation of its kinase activity. This mutation has been associated with familial venous malformations (VMs), manifested by variable thickness or lack of smooth-muscle cells in the veins of patient lesions. The underlying mechanism for Tie2-R849W action in endothelial cells remains elusive. In this study, we used adenoviral infection to differentiate the effects of ectopic Tie2 (wild type, kinase-dead K855A, or constitutively active R849W) expression on endothelial cellular behaviors and Tie2-mediated downstream targets. Ectopic Tie2 reduced endothelial cell proliferation and serum withdrawal-induced apoptosis, while stimulating migration. When comparing R849W with K855A and its wild-type counterpart, a functional tyrosine kinase activity was required only for migration, and constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures formed on Matrigel. We further demonstrated that Tie2-R849W chronically induced STAT1 tyrosine phosphorylation and the promoter activity of STAT1-responsive IFN-regulatory factor 1 (IRF1). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Additional studies are needed to study the role of STAT1 activation in VMs.

To investigate the drug interactions between ilaprazole, a new proton pump inhibitor, and clarithromycin following ilaprazole, clarithromycin and amoxicillin combination therapy.Twelve healthy Chinese volunteers were recruited in a randomized, open-label, 3-period crossover study. All subjects were administered ilaprazole (5 mg), clarithromycin (500 mg) or a triple therapy, including ilaprazole (5 mg), clarithromycin (500 mg) and amoxicillin (1 g), twice daily for 6 consecutive days. On the 7th day, the drugs were given once, and blood samples were collected and analyzed using a well-validated HPLC/MS/MS method.Following the triple therapy, the peak concentration (C(max)) and the area under the concentration-time curve from 0 h to 12 h (AUC(0→12)) of ilaprazole were significantly decreased, as compared with the single medication group (C(max):1025.0±319.6 vs 1452.3±324.6 ng/mL; AUC(0→12): 9777.7±3789.8 vs 11363.1±3442.0 ng·h/mL). Similar changes were found for ilaprazole sulfone (C(max): 5.9±0.5 vs 9.3±1.7 ng/mL; AUC(0→12): 201.4±32.1 vs 277.1±66.2 ng·h/mL). The triple therapy significantly elevated the C(max) of clarithromycin (3161.5±702.2 vs 2541.9±476.2 ng/mL).The H pylori eradication therapy with clarithromycin, amoxicillin and ilaprazole may cause pharmacokinetic interactions that decrease the amount of ilaprazole and its metabolites and elevate that of clarithromycin.

Ilaprazole is a new proton pump inhibitor designed for the treatment of gastric ulcers, and limited data is available on the metabolism of the drug. In this article, the structural elucidation of urinary metabolites of ilaprazole in human was described by HPLC-ESI-MS/MS and stopped-flow HPLC-NMR experiments. Urinary samples were precipitated by sodium carbonate solution, and then extracted by liquid–liquid extraction after adding ammonium acetate buffer solution. The enriched sample was separated using a C18 reversed-phase column with the mobile phase composed of acetonitrile and 0.05 mol/L ammonium acetate buffer solution in a gradient solution, and then directly coupled to ESI-MS/MS detection in an on-line mode or 1H-NMR (500 MHz) spectroscopic detection in a stopped-flow mode. As a result, four sulfide metabolites, ilaprazole sulfide (M1), 12-hydroxy-ilaprazole sulfide (M2), 11,12-dihydroxy-ilaprazole sulfide (M3) and ilaprazole sulfide A (M4), were identified by comparing their MS/MS and NMR data with those of the parent drug and available standard compounds. The main biotransformation reactions of ilaprazole were reduction and the aromatic hydroxylation of the parent drug and its relative metabolites. The result testified that HPLC-ESI-MS/MS and HPLC-NMR could be widely applied in detection and identification of novel metabolites. Copyright © 2010 John Wiley & Sons, Ltd.

The purpose of the study was to assess the impact of CYP2C19 genotypes, CYP3A phenotypes and gender-related difference on the pharmacokinetics of new proton pump inhibitor ilaprazole. Twenty-four healthy Chinese volunteers (age 24.0  1.9 years) were enrolled in an open-label study stratified for gender (12 males and 12 females) and their CYP2C19 genotype (12 of CYP2C19*1/*1 and 12 of CYP2C19*1/*2 or *1/*3). After a single 10-mg dose of ilaprazole was administrated, blood samples were collected at time 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36h from all subjects. Ilaprazole and its metabolite sulfone-ilaprazole plasma concentrations were measured using the well-validated HPLC/MS/MS method. CYP3A phenotype was determined by the classic CYP3A probe drug midazolam one week after the clinical trial. The kinetics characteristics of ilaprazole and sulfone-ilaprazole were significantly influenced by gender. The clearance/systemic bioavailability (CL/F) of ilaprazole was much lower in female than in male (2.5  1.0 versus 3.7  1.6 h-1, P = 0.029), difference became more significant even after corrected by body weight (P = 0.008). However, the differences on half-life, AUC0-36 and AUC0→∞ of ilaprazole between genders were not significantly after normalized by body weight. As for sulfone ilaprazole, larger AUC0→36 and AUC0→∞ were detected in female when compared with male (406.8  126.3 vs. 246.7  70.0 ng • h/ml, P = 0.007, and 606.7  224.5 vs. 332.0  117.1 ng • h/ml, P = 0.001), discrepancies were still significant after corrected by total body weight, P value were 0.017 and 0.010 respectively. The pharmacokinetics parameters of ilaprazole and ilaprazole sulfone were neither different across CYP2C19 genotype groups nor related to CYP3A phenotype. CL/F of ilaprazole were much smaller in women than in men even after adjusted by body weight, indicating great effect of gender on the pharmacokinetics of ilaprazole. CYP2C19 genotypes and CYP3A phenotypes did not affect the pharmacokinetics of ilaprazole or sulfone-ilaprazole.

Bismuth ruthenate and erbia-stabilized bismuth oxide (ESB) composites were studied as prospective cathode materials for solid oxide fuel cells (SOFCs) operating at intermediate temperatures (IT). Phase chemistry between bismuth ruthenate and ESB was studied using differential thermal analysis and X-ray diffraction (XRD). Symmetrical cells were fabricated on gadolinium-doped ceria electrolytes and studied by electrochemical impedance spectroscopy. Bi 2 Ru 2 O 7 -ESB composite electrodes showed area specific resistance values significantly lower than single-phase bismuth ruthenate electrodes, with the best performance from composite electrodes containing 31.25-43.75 wt % ESB. At 700°C, composite electrodes containing 31.25-43.75 wt % ESB exhibited an area specified resistance of 0.08-0.11 Ω cm 2 as compared to 1.78 Q cm 2 for Bi 2 Ru 2 0 7 . Introduction of the ESB phase reduced the rate limiting charge transfer and surface-diffusion steps in the oxygen reduction reaction, resulting in improved electrode performance.