Diol or Hydrogen Peroxide-responsive Micellar Systems and Their Rheological Properties.

External stimuli-responsive worm-like micelles (WLMs) have the potential for a wide range of applications. In particular, sugar (a polyol compound)-responsive WLMs have the potential for use in smartdrug release systems. Phenylboronic acid (PBA) functions as a cis-diol sensor in a similar manner it does as a glucose sensor.

Phenylboronate-salicylate ester cross-linked self-healing hydrogel composed of modified hyaluronan at physiological pH.

Several hydrogels with boronate/diol ester cross-linking have been reported. However, multiple synthetic steps or expensive reagents are required to modify some diol moieties into polymers. Therefore, diol-modified polymers, which are easily and inexpensively prepared a single-step process, are required for the formation of boronate esters.

Anomalous glucose-responsive rheological changes in a boronic acid-modified hyaluronan.

Herein, we report anomalous glucose (Glc)-responsive gelation/solation in 3-aminophenylboronic acid-modified hyaluronic acid. With 5-20 mM Glc, gelation occurred, resulting in the formation of crosslinks Glc, which could reversibly bind to the two boronic acid sites. Solation was induced at Glc concentrations of >80 mM.

Diol responsive viscosity increase in a cetyltrimethylammonium bromide/sodium salicylate/3-fluorophenylboronic acid micelle system.

We report a novel smart micellar system utilising a phenylboronic acid (PBA) derivative whose viscosity increases on adding diol compounds such as sugar or sugar alcohol. We prepared a typical worm-like micelle (WLM) system in 100 mM cetyltrimethylammonium bromide (CTAB)/70 mM sodium salicylate (NaSal), which showed high zero-shear viscosity ( ). Upon the addition of 20 mM 3-fluorophenylboronic acid (3FPBA) to the WLM system, decreased by 1/300 that of the system without 3FPBA.

Delivery of acetaminophen to the central nervous system and the pharmacological effect after intranasal administration with a mucoadhesive agent and absorption enhancer.

Acetaminophen, a central antipyretic and analgesic drug, is one of the most commonly used drugs among individuals of all ages throughout the world. This study pharmacokinetically and pharmacodynamically investigated the transport of acetaminophen to the central nervous system and systemic circulation after intranasal (i.n.

The Enhancing Effects of S-Allylcysteine on Liver Regeneration Are Associated with Increased Expression of mRNAs Encoding IGF-1 and Its Receptor in Two-Thirds Partially Hepatectomized Rats.

Two-thirds partial hepatectomy (PHx) was performed in rats, and the differences in effects between S-allylcysteine (SAC) and other sulfur-containing compounds on regeneration of the remaining liver and restoration of the injury were examined. Three days after two-thirds PHx, rats treated with 300 mg/kg/d, per os (p.o.

Galectin-2 Has Bactericidal Effects against in a β-galactoside-Dependent Manner.

is associated with the onset of gastritis, peptic ulcers, and gastric cancer. Galectins are a family of β-galactoside-binding proteins involved in diverse biological phenomena. Galectin-2 (Gal-2), a member of the galectin family, is predominantly expressed in the gastrointestinal tract.

Effect of Selective Serotonin (5-HT) Receptor Agonist BW723C86 on Epidermal Growth Factor/Transforming Growth Factor-α Receptor Tyrosine Kinase and Ribosomal p70 S6 Kinase Activities in Primary Cultures of Adult Rat Hepatocytes.

Serotonin (5-hydroxytryptamine; 5-HT) can induce hepatocyte DNA synthesis and proliferation by autocrine secretion of transforming growth factor (TGF)-α through 5-HT receptor/phospholipase C (PLC)/Ca and a signaling pathway involving epidermal growth factor (EGF)/TGF-α receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase 2 (ERK2)/mammalian target of rapamycin (mTOR). In the present study, we investigated whether 5-HT or a selective 5-HT receptor agonist BW723C86, would stimulate phosphorylation of TGF-α RTK and ribosomal p70 S6 kinase (p70S6K) in primary cultures of adult rat hepatocytes. Western blotting analysis was used to detect 5-HT- or BW723C86 (10 M)-induced phosphorylation of EGF/TGF-α RTK and p70S6K.

Enhancement Effect of Poly-L-ornithine on the Nasal Absorption of Water-Soluble Macromolecules in Rats.

The transnasal route for the delivery of water-soluble macromolecules, such as bioactive peptides and proteins, has attracted interest, although the use of permeation enhancers is required due to the poor permeabilities of these macromolecules across the nasal mucosa. With polycationic compounds, such as poly-L-arginine and chitosan, the nasal absorption of hydrophilic macromolecules is molecular weight- and concentration-dependently enhanced without causing cytotoxicity. In the present study, we evaluated the effect of various molecular weights and concentrations of poly-L-ornithine (PLO), a polycationic compound, on the nasal absorption and the damage to the nasal mucosa in vivo.

[Gender Differences in Projected Life Expectancy in Japan (2023-2047) Determined by Bayesian Age-Period-Cohort Analysis].

Objectives: In this study, we aimed to (1) determine the effects of age, period, and cohort on mortality rate trends between 1958 and 2012 in Japan and (2) assess gender differences in projected life expectancy (LE) for the 2023-2047 period.

Methods: A time trend study was conducted using age-period-cohort (APC) analysis. A Bayesian APC model was fitted to describe mortality rate trends for the 1958-2012 period and to project mortality rates for 2023-2047.

Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine.

We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4), in rats under closed and open systems.

Dietary nitrite supplementation attenuates cardiac remodeling in l-NAME-induced hypertensive rats.

Loss of nitric oxide (NO) bioavailability underlies the development of hypertensive heart disease. We investigated the effects of dietary nitrite on N-nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Sprague-Dawley rats were divided into five groups: an untreated control group, an l-NAME-treated group, and three other l-NAME-treated groups supplemented with 10 mg/L or 100 mg/L of nitrite or 100 mg/L of captopril in drinking water.

Preparation and Evaluation of PEGylated Poly-L-ornithine Complex as a Novel Absorption Enhancer.

Polycationic compounds, such as poly-L-arginine and poly-L-ornithine (PLO), enhance the nasal absorption of hydrophilic macromolecular drugs. However, the bio availability corresponding to the dose of these enhancers has not been obtained in an open system study, where an administered solution is transferred to the pharynx because they do not exhibit mucoadhesion/retention in the nasal cavity. In this study, we prepared PEGylated-poly-L-ornithine (PEG-PLO) and investigated the effects of PEGylation on in vitro adhesion/retention properties, permeation enhancement efficiency, and cytotoxicity.

Preparation of Bioadhesive Phosphorescent Particles and Their Use as Markers for Video-oculography of Mice.

Objective: To develop a bioadhesive phosphorescent particle that can be used as a marker in video-oculography to assess eye movements in the dark without drug treatment.

Methods: The marker was prepared by spray-coating a Sr4Al14O25: Eu2+, Dy3+ phosphor with a carboxyvinyl polymer. The morphologic, luminescent and adhesive properties were assessed.

Serotonin 5-HT2B Receptor-Stimulated DNA Synthesis and Proliferation Are Mediated by Autocrine Secretion of Transforming Growth Factor-α in Primary Cultures of Adult Rat Hepatocytes.

The mechanism of serotonin 5-HT2 receptor subtype-stimulated DNA synthesis and proliferation was investigated in primary cultures of adult rat hepatocytes to elucidate the intracellular signal transduction pathways. DNA synthesis and proliferation were detected in hepatocyte parenchymal cells grown in serum-free, defined medium containing 5-HT (10(-6) M) or the selective 5-HT2B receptor agonist BW723C86 (10(-6) M). In addition, exogenous transforming growth factor (TGF)-α (1.

Development of a Transnasal Delivery System for Recombinant Human Growth Hormone (rhGH): Effects of the Concentration and Molecular Weight of Poly-L-arginine on the Nasal Absorption of rhGH in Rats.

A novel system for delivering recombinant human growth hormone (rhGH) that is noninvasive and has a simple method of administration is strongly desired to improve the compliance of children. The aim of this study was to investigate the potential for the intranasal (i.n.

Signal Transduction Mechanism for Serotonin 5-HT2B Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes.

The involvement of serotonin (5-hydroxytryptamine; 5-HT) and the 5-HT2 receptor subtypes in the induction of DNA synthesis and proliferation was investigated in primary cultures of adult rat hepatocytes to elucidate the intracellular signal transduction mechanisms. Hepatocyte parenchymal cells maintained in a serum-free, defined medium, synthesized DNA and proliferated in the presence of 5-HT or a selective 5-HT2B receptor agonist, BW723C86, but not in the presence of 5-HT2A, or 5-HT2C receptor agonists (TCB-2 and CP809101, respectively), in a time- and dose-dependent manner. A selective 5-HT2B receptor antagonist, LY272015 (10(-7) M), and a specific phospholipase C (PLC) inhibitor, U-73122 (10(-6) M), as well as specific inhibitors of growth-related signal transducers-including AG1478, LY294002, PD98059, and rapamycin-completely inhibited 5-HT (10(-6) M)- or BW723C86 (10(-6) M)-induced hepatocyte DNA synthesis and proliferation.

[Age, period, and birth cohort-specific effects on cervical cancer mortality rates in Japanese women and projections for mortality rates over 20-year period (2012-2031)].

Objectives: We aimed to determine the effects of age, period, and birth cohort on cervical cancer mortality rate trends in Japanese women, by age-period-cohort (APC) analysis. Additionally, we analyzed projected mortality rates.

Methods: We obtained data on the number of cervical cancer deaths in Japanese women from 1975-2011 from the national vital statistics and census population data.

L-ascorbic acid- and L-ascorbic acid 2-glucoside accelerate in vivo liver regeneration and lower serum alanine aminotransaminase activity in 70% partially hepatectomized rats.

The effects of L-ascorbic acid and its stable analogue L-ascorbic acid 2-glucoside on the restoration of liver mass and recovery of liver function after 70% partial hepatectomy (PH), were compared with other natural vitamin C analogues in rats in vivo. L-Ascorbic acid (100 mg/kg/d, intraperitoneally (i.p.

A mechanism enhancing macromolecule transport through paracellular spaces induced by Poly-L-Arginine: Poly-L-Arginine induces the internalization of tight junction proteins via clathrin-mediated endocytosis.

Purpose: Poly-L-arginine (PLA) enhances the paracellular permeability of the Caco-2 cell monolayer to hydrophilic macromolecules by disappearance of tight junction (TJ) proteins from cell-cell junctions. However, the mechanism of the disappearance of TJ proteins in response to PLA has been unclear. In this study, we investigated the mechanism of disappearance of TJ proteins from cell-cell junctions after the application of PLA to Caco-2 cell monolayers.

Evaluation of the effects of absorption enhancers on Caco-2 cell monolayers by using a pore permeation model involving two different sizes.

We applied a parallel pore permeation model based on the Renkin molecular sieving function by using two different-sized pathways to analyze the permeation-enhancing effects of poly-L-arginine (PLA) or a mixed system of spermine (SPM) and sodium taurocholate (STC). Four paracellular markers were simultaneously applied to Caco-2 cell monolayers, and a set of apparent permeability coefficient (P) values was used to obtain membrane parameters. For PLA treatment, the pore occupancy/length ratio (ε/L) of the large pathways increased while the pore radius (R) did not, suggesting that the number of large pathways for the relatively large hydrophilic molecules in the monolayers could be increased by the addition of PLA.

Aldehyde dehydrogenase 2 partly mediates hypotensive effect of nitrite on L-NAME-induced hypertension in normoxic rat.

Nitrite has become a topic of interest in the field of medical research because of its potential therapeutic role as an alternative source of nitric oxide (NO). While the bioconversion of nitrite to NO occurs via either nonenzymatic or enzymatic reduction under acidic or hypoxic conditions, little is known about its conversion to NO under normoxic conditions. Because of a recent report of aldehyde dehydrogenase 2 (ALDH2)-catalyzed glyceryl trinitrate (GTN) vasorelaxation by denitration of GTN to 1,2-glyceryl dinitrate (1,2-GDN) and nitrite, we therefore investigated a catalytic activity of ALDH2 for nitrite reduction and subsequent effect on N(ω)-nitro-l-arginine methyl ester (l-NAME)-induced hypertension in normoxic rat.

Poly-L-arginine-Induced internalization of tight junction proteins increases the paracellular permeability of the Caco-2 cell monolayer to hydrophilic macromolecules.

We investigated whether poly-L-arginine (PLA) enhances the paracellular permeability of the Caco-2 monolayer to hydrophilic macromolecules and clarified the disposition of tight junction (TJ) proteins. The transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran (FD-4) permeation were determined after treatment with PLA. TJ proteins were visualized using immunofluorescence microscopy after PLA exposure and depletion, and their expression levels were determined.

Effect of poly-L-arginine on intestinal absorption of hydrophilic macromolecules in rats.

We have already reported that poly-L-arginine (PLA) remarkably enhanced the in vivo nasal absorption of hydrophilic macromolecules without producing any significant epithelial damage in rats. In the present study, we examined whether PLA could enhance the absorption of a model hydrophilic macromolecule, fluorescein isothiocyanate-dextran (FD-4), across the intestinal mucosa, as well as the nasal mucosa, by an in situ closed-loop method using the rat intestine. PLA was found to enhance the intestinal absorption of FD-4 in a concentration-dependent manner within the concentrations investigated in this study, but segment-specific differences were found to be associated with this effect (ileum>jejunum>duodenum≧colon).

Relationships between the particle velocity and introduction of drug-loaded microparticles into the skin in a microparticulate bombardment system.

Recently, it has been suggested that a microparticulate bombardment system would be a very useful tool for the delivery of a variety of powdered drugs as an alternative to parenteral injection via a needle. However the relationship between the particle dynamics and introduction into the skin has not been researched using this system. In the present study, we analyzed the velocity of microparticles bombarded by the Helios(TM) gun system under various conditions using particle image velocimetry (PIV).