FTY720, given i.v. or orally at 0.03 mg/kg or more, significantly prolonged skin allograft survival in a dose-dependent manner and showed more potent immunosuppressive activity than cyclosporin A ...(CsA) or tacrolimus (FK506) in MHC-incompatible rat strains of WKAH donors and F344 recipients. However, unlike CsA or FK506, FTY720 up to 1000 nM did not affect IL-2 production in allogeneic MLC. Within 3 to 24 h after a single oral administration of FTY720 at 0.1 to 1 mg/kg, the number of lymphocytes in the rats was markedly decreased in the peripheral blood and thoracic duct lymph and partially in spleen. By contrast, the number of lymphocytes in peripheral lymph nodes (PLN), mesenteric lymph nodes (MLN), and Peyer's patches (PP) was significantly increased at the same time. Intravenous transfusion of calcein-labeled rat lymphocytes into rats revealed that FTY720 significantly accelerated lymphocyte homing to PLN, MLN, and PP, dose dependently. Since FTY720-induced lymphocyte homing was completely blocked by simultaneous treatment of the calcein-labeled lymphocytes with mAbs against CD62L, CD49d, and CD11a before the transfusion, the acceleration of lymphocyte homing by FTY720 appears to be mediated by lymphocyte-homing receptors. These findings indicate that FTY720 sequesters circulating mature lymphocytes into PLN, MLN, and PP by acceleration of lymphocyte homing and thereby decreases the number of lymphocytes in peripheral blood, thoracic duct lymph, and spleen. Based on these observations, sequestration of circulating mature-lymphocytes is presumed to be a main mechanism of the immunosuppressive activity of FTY720.
Ethacrynic acid, a loop diuretic drug, caused lipid peroxidation in isolated rat hepatocytes. The thiobarbituric acid reactive substances (TBARS) formation showed a good correlation with the leakage ...of glutamic–oxaloacetic acid transaminase (GOT) from the hepatocytes. The addition of antioxidants such as
N,
N′-diphenyl-
p-phenylenediamine (DPPD) and promethazine to the isolated rat hepatocyte suspension containing ethacrynic acid prevented the lipid peroxidation and decreased the GOT leakage to some extent. SKF-525A inhibited the oxidative metabolism of ethacrynic acid and decreased the TBARS formation, suggesting that the lipid peroxidation was caused by the oxidative metabolim. The intracellular reduced glutathione markedly decreased in the hepatocyte suspension containing ethacrynic acid and the hepatocellular protein sulfhydryls were decreased, which was negatively correlated with the GOT leakage. Thus the ethacrynic acid-induced hepatotoxicity was found to be related to the lipid peroxidation and the decrease of cellular protein sulfhydryls.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Isothermal crystallization of polybutene-1 melt under shear flow was observed with an optical microscope by using a device newly developed by our group. Firstly, our coaxial cylinder-type apparatus ...(shear flow direct observation system (SF-DOS)) to observe crystallization directly under shear flow is explained in detail. Secondly to examine the accuracy of the measurement with the new device and to establish an appropriate procedure for the elimination of overshoot in temperature profiles, various examinations were performed in terms of temperature distribution, stability, and the velocity gradient by comparing the results from isothermal DSC measurements. The precise investigation suggested that the temperature distribution was proved to be very small (within 0.5°C) and the establishment of the procedure eliminated the overshooting of temperature profiles. Finally, we observed isothermal crystallization of polybutene-1 with the new device at various temperatures between 102°C and 140°C under shear rates of up to 0.7 s
–1. When the shear strain became higher and the temperature became lower, narrow bands of oriented region formed after a certain time along the flow direction even at high temperature. This tendency was also observed in a polystyrene melt; therefore, it was interpreted that the narrow bands were considered to be the highly deformed region, which was generated by high shear stress. In the narrow bands, spherulites nucleated. After a certain amount of time, spherulites were also generated randomly outside of the narrow bands. Under very low shear rate, where the narrow bands did not exist, the spherulites appeared randomly.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We here report on some modifications of the Primitive Chain Network (PCN) model, originally proposed in Y. Masubuchi et al., J. Chem. Phys. 115, 4387 (2001), which both refine the model and make it ...suitable for predicting nonlinear rheological response in fast flows. Simulation results are compared with some existing viscoelastic data on monodisperse polystyrene melts Schweizer et al., J. Rheol. 48, 1345 (2004); Bach et al., Macromolecules 36, 5174 (2003), by using as single adjustable parameter (to be assigned once and for all) a basic relaxation time which relates to the coarse graining of the PCN model. Essentially quantitative prediction of linear viscoelasticity is achieved. Without further parameters, the nonlinear behavior of the polystyrene melts in start-up of shear and uniaxial elongational flow is also reproduced by the simulations. Specifically, the viscosity growth functions are quantitatively predicted, whereas transient elongational viscosities are reasonably reproduced only up to extensional rates of the order of the reciprocal Rouse time. At higher elongation rates, although the strain hardening effect is correctly captured by the simulations, steady state values are not. Notwithstanding this latter limitation, the simulation model appears adequate to portray the rheological behavior of entangled melts, both in the linear and the nonlinear range.
Mechanistic study of idiosyncratic drug-induced hepatitis (DIH) continues to be a challenging problem because of the lack of animal models. The inability to produce this type of hepatotoxicity in ...animals, and its relative rarity in humans, may be linked to the production of anti-inflammatory factors that prevent drug-protein adducts from causing liver injury by immune and nonimmune mechanisms. We tested this hypothesis by using a model of acetaminophen (APAP)-induced liver injury in mice. After APAP treatment, a significant increase was observed in serum levels of interleukin (IL)-4, IL-10, and IL-13, cytokines that regulate inflammatory mediator production and cell-mediated autoimmunity. When IL-10 knockout (KO) mice were treated with APAP, most of these mice died within 24 to 48 hours from liver injury. This increased susceptibility to APAP-induced liver injury appeared to correlate with an elevated expression of liver proinflammatory cytokines, tumor necrosis factor (TNF)-α, and IL-1, as well as inducible nitric oxide synthase (iNOS). In this regard, mice lacking both IL-10 and iNOS genes were protected from APAP-induced liver injury and lethality when compared with IL-10 KO mice. All strains, including wild-type animals, generated similar amounts of liver APAP-protein adducts, indicating that the increased susceptibility of IL-10 KO mice to APAP hepatotoxicity was not caused by an enhanced formation of APAP-protein adducts. In conclusion, these findings suggest that an important feature of the normal response to drug-induced liver injury may be the increased expression of anti-inflammatory factors such as IL-10. Certain polymorphisms of these factors may have a role in determining the susceptibility of individuals to idiosyncratic DIH. (HEPATOLOGY .)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The electrorheological (ER) effect of urethane-modified polypropylene glycol (UPPG)/dimethylsiloxane (DMS) blends was investigated by rheological measurement and observation of the domain structure ...under shear flow. It was found that: (i) the cause of an ER effect is in close association with the domain composition under no electric field; the ER effect appears when UPPG forms droplets, while when it forms a continuous phase, the ER effect does not appear; (ii) UPPG droplets elongate and bridge between the electrodes when an electric field is applied and the bridges remain even under the shear; and (iii) the ER effect is positive in the case that the viscosity of UPPG is larger than that of DMS and negative in the case that the viscosity of UPPG is smaller than that of DMS. The cause of both positive and negative ER effects for UPPG/DMS blends is the connection of UPPG between electrodes under the electric field.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Recent experimental data suggest that the idiosyncratic nature of drug-induced liver disease (DILD) may be due in part to a deficiency of one or more hepatoprotective factors. In this study we have ...investigated whether interleukin (IL)-6 may also be one of these factors. Following the induction of liver injury with acetaminophen (APAP), a time-dependent increase in liver mRNA expression of IL-6 and its family members IL-11, leukemia inhibitory factor, and oncostatin M was observed in wild type (WT) mice, suggesting a possible hepatoprotective role played by this cytokine family. Indeed, mice lacking IL-6 (
IL-6
−/−) were more susceptible than were WT mice to APAP-induced liver injury. The increased susceptibility of the
IL-6
−/− mice was associated with a deficiency in the expression of hepatic heat shock protein (HSP)25, 32, and 40 as well as inducible HSP70 following APAP treatment. These results suggest that IL-6 and possibly other family members may protect the liver from injury, at least in part, by up-regulating the hepatic expression of several cytoprotective HSPs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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