ABSTRACTgpl30 is a ubiquitously expressed signaltransducing receptor component shared by interleukin 6, interleukin 11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1. To investigate physiological roles of gpl30 and to examine pathological consequences of a lack of gpl30, mice deficient for gpl30 have been prepared. Embryos homozygous for the gpl30 mutation progressively die between 12.5 days postcoitum and term. On 16.5 days postcoitum and later, they show hypoplastic ventricular myocardium without septal and trabecular defect. Cytokine signals are mediated through specific receptor complexes, whose components belong, in most cases, to a large group of proteins called the cytokine receptor family (1). These receptor complexes are usually composed of a ligandspecific receptor chain and a signal transducer common to multiple cytokines. gp130 was initially identified as a signal transducing receptor component that associates with the interleukin 6 receptor (IL-6R) when the receptor binds interleukin 6 (IL-6) (2). gp130 is also utilized as a critical signaling component in the receptor complexes for interleukin 11, leukemia inhibitory factor (LIF), oncostatin M, ciliary neurotrophic factor (CNTF), and cardiotrophin 1 (CT-1) (refs. 1 and 3 and references therein). The discovery of this shared signal transducer, gpI30, helps to explain how these different cytokines mediate overlapping biological functions. IL-6 binding to IL-6R induces homodimerization of gp130 (4), whereas stimulation by LIF, CNTF, oncostatin M, and CT-1 leads to heterodimerization of gpl 30 with a closely related protein, LIF receptor (3, 5). Homo-or heterodimerization of gpl30 triggers the activation of JAKI, JAK2, and TYK2, members of the JAK family of cytoplasmic tyrosine kinases that are associated with gpl30 (6-8). This leads to subsequent tyrosine phosphorylation and functional activation of a latent cytoplasmic transcription factor,

Background-High-frequency fractionated electrograms recorded during atrial fibrillation (AF) in the posterior left atrium (PLA) and elsewhere are being used as target sites for catheter ablation. We tested the hypothesis that highly periodic electric waves emerging from AF sources at or near the PLA give rise to the most fractionated activity in adjacent locations. Methods and Results-Sustained AF was induced in 8 isolated sheep hearts (0.5 mol/L acetylcholine). Endocardial videoimaging (DI-4-ANEPPS) and electric mapping of the PLA enabled spatial characterization of dominant frequencies (DFs) and a regularity index (ratio of DF to total power). Regularity index showed that fractionation was lowest within the area with the maximal DF (DFmax domain; 0.

Abstract-Heart failure (HF) commonly results in atrial fibrillation (AF) and fibrosis, but how the distribution of fibrosis impacts AF dynamics has not been studied. HF was induced in sheep by ventricular tachypacing (220 bpm, 6 to 7 weeks). Optical mapping (Di-4-ANEPPS, 300 frames/sec) of the posterior left atrial (PLA) endocardium was performed during sustained AF (burst pacing) in Langendorff-perfused HF (nϭ7, 4 mol/L acetylcholine; nϭ3, no acetylcholine) and control (nϭ6) hearts. PLA breakthroughs were the most frequent activation pattern in both groups (72.0Ϯ4.6 and 90.2Ϯ2.7%, HF and control, respectively). However, unlike control, HF breakthroughs preferentially occurred at the PLAs periphery near the pulmonary vein ostia, and their beat-to-beat variability was greater than control (

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Cisplatin (cis-diaminedichloroplatinum II, CDDP) is extensively used for the treatment of several cancers. Its major side effect; namely, nephrotoxicity, is a dose-limiting factor in CDDP therapy.1) The exact mechanisms of nephrotoxicity induced by CDDP are still not fully elucidated. However, lipid peroxidation and free radical generation in the renal tubular cells have been suggested to be responsible for CDDP-induced renal failure.2) Zhang et al. showed that CDDP significantly depletes glutathione (GSH) and increases lipid peroxidation in the mitochondria prepared from the rat renal cortical slices.3) In addition, the activities of superoxide dismustase (SOD) and catalase in the rat kidney tissues are significantly suppressed by CDDP. 4)Capsaicin (Cap) is the major pungent ingredient of hot red peppers. It has been used as a tool in the study of pain sensations which are caused by stimulation of Cap receptor or vanilloid receptor 1, an ion channel protein expressed by nociceptive primary afferent neurons. 5,6) On the other hand, Cap potentially inhibits the peroxidation of various lipids [7][8][9][10] and generates reactive oxygen species in rat peritoneal macrophages.11) However, the mechanism responsible for the potent inhibitory effects of Cap on lipid peroxidation in vivo is still unclear.Several studies have examined the effects of decreased lipid peroxidation and nephrotoxicity induced by CDDP using various agents including antioxidants. [12][13][14] The purpose of the present study was to investigate whether the administration of Cap exerts any protective effect against cisplatin-induced lipid peroxidation and nephrotoxicity in rats. MATERIALS AND METHODS ChemicalsCap with a purity of 98.6% was kindly supplied by Maruishi Pharmaceutical Co., Ltd. (Osaka, Japan). CDDP was purchased from Sigma (MO, U.S.A.). All other chemicals and reagents used were of analytical grade.Animals Male Sprague-Dawley rats weighing 200 to 250 g were purchased from Nippon SLC Inc. (Shizuoka, Japan). The rats had free access to standard rat chow and water ad libitum, were individually housed in metal cages, and kept in a room maintained at 23Ϯ2°C with a 12 h/12 h light/dark cycle. The study adhered to the guidelines of Osaka University of Pharmaceutical Sciences for the experimental use of animals.Animal Treatments The rats were divided at random into 4 groups of 4 or 5 animals each. The first group (control) received a vehicle (5% carboxymethyl cellulose sodium solution (CMC-Na), 5 ml/kg body wt., p.o.) used for Cap. The second group received Cap (10 mg/kg/d, p.o.) in 5% CMC-Na (5 ml/kg), and the third received 5% CMC-Na for 6 consecutive days injected with CDDP (5 mg/kg in physiological saline solution, i.p.). The fourth group received Cap (10 mg/kg/d, p.o.) in 5% CMC-Na for 6 consecutive days after CDDP injection (5 mg/kg, i.p.). For all groups, Cap or vehicle was given twice daily. The selected Cap concentration and the dose administration schedule without inducing any rat intestinal damage were chosen using data from our p...

A new ion chromatographic method that is applicable to the direct determination of UV-absorbing inorganic anions in saline matrixes is described. An octadecylsilica column modified with a zwitterionic surfactant (3-(N,N-dimethylmyristylammonio)propanesulfonate) is used as the stationary phase, and an electrolytic solution is used as the eluent. Under these conditions, the matrix species (such as chloride and sulfate) are only retained weakly and show little or no interference. It is proposed that a binary electrical double layer (EDL) is established by retention of the eluent cations on the negatively charged (sulfonate) functional groups of the zwitterionic surfactant (forming a cation-EDL) and by retention of eluent anions on the positively charged (quaternary ammonium) functional groups of the zwitterionic surfactant (forming an anion-EDL). Sample anions are able to distribute into the cation-EDL and to form ion pairs with the EDL cations, while at the same time experiencing repulsion from the anion-EDL. Anions are therefore eluted in order of increased propensity to form ion pairs. The method has been applied to the determination of bromide, nitrate, and iodide in artificial seawater, giving detection limits of 0.75 ppb for bromide, 0.52 ppb for nitrate, and 0.8 ppb for iodide using UV absorbance detection at 210 nm and relative standard deviations of <1.2%. Real seawater samples have also been analyzed successfully.In a series of previous studies 1-7 employing stationary phases coated with zwitterionic surfactants (i.e., those containing both positively and negatively charged functional groups but carrying no formal net charge), it has been demonstrated that inorganic anions can be separated using pure water as eluent, with unique separation selectivity. This method has been termed electrostatic ion chromatography (EIC), and the separation has been attributed to a simultaneous electrostatic attraction and repulsion mechanism occurring at both the positive and the negative charges on the stationary phase. A drawback of EIC is that when the sample contains multiple anions and cations, each analyte anion may be eluted as more than one peak, with each peak being a specific combination of the anion with one of the cations of the sample. Recently, we showed 8 that addition of a small quantity of a suitable electrolyte to the eluent causes analyte anions to be eluted only as a single peak, irrespective of the number and type of cations in the sample. In the present study, we have investigated the separation mechanism in more detail and have applied the method to the determination of nitrate, bromide, and iodide in seawater.The determination of nitrate, bromide, and iodide in seawater is of importance to oceanographic research. 9-11 Ion-exchange chromatography (IEC) is generally inapplicable to this analysis for several reasons. First, the large amount of matrix ions (chloride, sulfate) saturate the active sites of the stationary phase and thereby impede the separation of the target analytes. Second, the high ionic...

Background The G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is a common cause of cystic fibrosis (CF). G551D-CFTR is characterized by an extremely low open probability despite its normal trafficking to the plasma membrane. Numerous small molecules have been shown to increase the activity of G551D-CFTR presumably by binding to the CFTR protein. Methods We investigated the effect of curcumin, genistein and their combined application on G551D-CFTR activity using the patch clamp technique. Results Curcumin increased G551D-CFTR whole-cell and single-channel currents less than genistein did at their maximally effective concentrations. However, curcumin further increased the channel activity of G551D-CFTR that had been already maximally potentiated by genistein, up to ~50% of the WT-CFTR level. In addition, the combined application of genistein and curcumin over a lower concentration range synergistically rescued the gating defect of G551D-CFTR. Conclusions The additive effects between curcumin and genistein not only support the hypothesis that multiple mechanisms are involved in the action of CFTR potentiators, but also pose pharmaceutical implications in the development of drugs for CF pharmacotherapy.

Multiwalled carbon nanotubes (MWCNTs) were used as the active elements for the first time for affinity-based elimination of ionic dyes. MWCNTs were encapsulated in cross-linked alginate (ALG) microvesicles using Ba2+ as the bridging ion. The Ba2+-alginate matrix constitutes a cage which holds the physically trapped MWCNTs. The cage carries negative charges on its surface. The cage restricts the access of anions of large molecular weight, such as humic acids, because of electrostatic repulsion. The cage also restricts the access of colloids of large size, because of size exclusion. Ionic dyes partition into the cage and then are captured by MWCNTs probably on the basis of van der Waals interactions occurring between the hexagonally arrayed carbon atoms in the graphite sheet of MWCNTs and the aromatic backbones of the dyes. As a result of these interactions the target species, namely, the ionic dyes, are eliminated efficiently by the MWCNTs of Ba2+-ALG/MWCNT composite adsorbents. The adsorptive capacities for elimination of acridine orange, ethidium bromide, eosin bluish, and orange G (the model species used for this study) were found as high as 0.44, 0.43, 0.33, and 0.31 micromol, respectively, for 1.0 mg of the caged MWCNTs. Adsorptive experiments with carbon nanofibers and activated carbons as the adsorbents were also performed. The MWCNT-based adsorbents provided the best capability for the affinity-based elimination of these targeted species. Biocompatibility experiments performed in vitro and in vivo provided promising results, suggesting potential applications of the caged MWCNTs in in situ environmental remediation.