Search

Aims/introduction Recent data showed that dipeptidyl peptidase 4 (DPP-4) inhibitors exert a lipid-lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non-diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol-lowering action. Materials and methods Male apolipoprotein E (ApoE)-deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14 C-labeled cholesterol (14 C-Chol). In additional experiments, effects of exendin-4 in mice and of anagliptin in DPP-4-deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice. Results The serum total and non-high-density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE-deficient mice. The cholesterol-lowering effect was predominantly observed in the chylomicron fraction. The plasma 14 C-Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14 C-Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP-4 activity, and exendin-4 had no effect on the 14 C-Chol transport in ApoE-deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport-related microsomal triglyceride transfer protein, acyl-coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin. Conclusions These findings suggest that anagliptin might exert a cholesterol-lowering action through DPP-4-dependent and glucagon-like peptide 1-independent suppression of intestinal cholesterol transport.

To determine the role of cholesterol synthesis in pancreatic b-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) spe- cifically in b-cells (TgRIP-SREBP-2) was developed and ana- lyzed. Expression of nuclear human SREBP-2 in b-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was pri- marily due to defects in glucose- and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esteri- fied cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated ex- pression of HMG-CoA synthase and reductase and LDL re- ceptor, with suppression of endogenous SREBPs. Genes involved in b-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of b-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken together, these results indicate that activation of SREBP-2 in b-cells caused severe diabetes by loss of b-cell mass with accumula- tion of cholesterol, providing a new lipotoxic model and a potential link of disturbed cholesterol metabolism to impair- ment of b-cell function.—Ishikawa, M., Y. Iwasaki, S. Yatoh, T. Kato, S. Kumadaki, N. Inoue, T. Yamamoto, T. Matsuzaka, Y. Nakagawa, N. Yahagi, K. Kobayashi, A. Takahashi, N. Yamada, and H. Shimano. Cholesterol accumulation and diabetes in pancreatic b-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity. J. Lipid Res. 2008. 49: 2524-2534.

The γ-Ga2O3-Al2O3 solid solutions prepared by the glycothermal reaction of the mixtures of aluminum isopropoxide and gallium acetylacetonate had extremely high activities for selective catalytic reduction of NO with methane as a reducing agent (CH4-SCR). With the increase in the Al content incorporated in the spinel structure, the catalytic activity increased. The active sites for this reaction were concluded to be the tetrahedral Ga ions with octahedral Al ions in the next-nearest-neighbor sites. Methane activation on the catalysts was the key-step of CH4-SCR. The solid-solution catalysts showed high durability under steaming conditions.

The reaction of mixtures of aluminum isopropoxide and gallium acetylacetonate in 1,4-butanediol or 1,5-pentanediol at high temperatures (glycothermal reaction) directly gave the γ-Ga2O3–Al2O3 solid solutions, which had high catalytic activities for selective reduction of NO using methane as the reducing agent. However, the reaction with a higher Al/(Ga+Al) charged ratio yielded the glycol derivative of boehmite as a by-product and the catalytic activity of the solid solution decreased. Therefore, synthesis of the solid solution using various glycols was examined and it was found that solid solutions with high Al contents without contamination of the glycol derivative of boehmite were obtained by using 1,6-hexanediol as a reaction medium. The solid solution exhibited a higher NO conversion than that synthesized in other glycols.

Gd- and Mg-substituted barium titanate crystals (Ba1− x Gd x )(Ti1− x /2Mg x /2)O3 with the Gd composition range of x > 0.1 show no ferroelectric phase transition. To discuss atomic thermal fluctuations in such unusual barium titanate crystals with cubic symmetry, accurate crystal structure analyses were performed by the maximum entropy method (MEM)/Rietveld method with the split-atom model and anharmonic temperature factor model using high-energy synchrotron radiation X-ray diffraction data. The off-centered positions of Gd ions at the Ba site in the probability density function were clearly observed at a low temperature but smeared in the high-temperature region by the over-barrier motion of Gd ions.

A convenient method was developed for the highly sensitive, quantitative determination of glutathione (GSH) using high performance gel filtration chromatography and fluorescence detection after N-(7-dimethylamino-4-methyl coumarinyl)-maleimide modification of the peptides. The fluorescence detection method is highly sensitive and sub pmol GSH contents were detectable. This method is applicable for determining the GSH content of micro samples from higher plant roots.

In addition to the prevention of cardiovascular diseases by lowering plasma LDL cholesterol, recent studies suggest that statins could have some impact on insulin action. To estimate the direct effects of statins on insulin secretion from pancreatic beta-cells, MIN6 cells were treated with pravastatin, simvastatin, or atorvastatin. Basal insulin secretion at low glucose concentration was unexpectedly increased at very high doses of simvastatin or atorvastatin after 24- and 48-hour incubation. Insulin secretion at high glucose was not significantly changed, and thus, net glucose-stimulated insulin secretion was apparently decreased by these lipophilic statins. The changes in insulin secretion were highly associated with increased endogenous SREBP activities in response to HMG-CoA inhibition as estimated by SRE-luciferase assays, and finally after 48-hour incubation, accompanied by impaired cell viability as estimated by MTT assays. In contrast, these changes were much less prominent by the addition of pravastatin. Meanwhile, glucose-stimulated insulin secretion of islets isolated from C57BL/6 mice was not significantly changed by any of the statins. Overall, taken up by beta-cells, statins can affect insulin secretion through either HMG-CoA inhibition or cytotoxicity, as observed by the addition of extraordinary high doses of lipophilic statins, but not hydrophilic statins, to the medium.

Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.

To protect space structures from debris impact, the new types of shield using a self-sealing materials are suggested. A hole by debris impact on shield will be fixed with the self-sealing materials by melting, sealing and solidification. Time to seal impact hole was experimentally simulated. If time to seal impact hole was assumed to be about 5 s, viscosity of self-sealing materials should be about 0.5 Pa s. In addition, glasses with supercooled liquids at elevated temperatures were also suggested as candidate materials for sealing, because low values of viscosity were obtained below melting points. From these results, boride ceramics, high temperature polymer materials including a liquid-crystal and light metallic glasses were suggested as the candidate materials for the self-sealing system.

Barium titanate BaTiO3 is a ferroelectric oxide with low dielectric loss and high permittivity, which makes it a good insulator for industrial uses. However, the pure barium titanate is not always used for electronic devices. Gd- and Mg-doping in barium titanate is effective for the dielectrics in multilayer ceramic capacitors MLCCs, for example, to attain the uniform temperature-variation of dielectric constants in the wide temperature-range where MLCCs are practically used, while the Curie temperature is significantly decreased [1]. In this study, the structural characteristics of Gd- and Mg-substituted barium titanate (Ba,Gd)(Ti,Mg)O3 (BGTM) in the cubic phase were investigated to clarify the effects of Gd- and Mg-substitution on the crystal structure and the chemical bonding. Synchrotron radiation x-ray powder diffraction measurements were carried out using the BGTM samples with the Mg content of x = 0 ~ 0.1. Lattice parameters, substitution sites of the Gd and Mg ions, thermal parameters, and electron charge density distributions in the crystals were analyzed by using the maximum entropy method (MEM)/Rietveld method. The Curie temperature decreased with increasing x. The phase transition did not take place in BGTM with x > 0.05. The Gd ion was confirmed to be substituted for the Ba ion with larger thermal vibration amplitude than that of the Ba ion. The amplitude was almost independent of the Gd content. It was revealed that the Gd ion occupied the off-centered positions slightly form the Ba-site along the directions at lower temperatures. Difference in thermal behaviors of the Gd and Ba ions can be attributed to the size difference between the smaller Gd ion and the larger Ba ion. The Mg ion was observed on the Ti-site. The substitution of the Mg ion for the Ti ion suppresses the ferroactivity of the Ti ion, which causes the lowering of the Curie temperature.

To evaluate vascular endothelial growth factor (VEGF) levels in relation to disease activity in rheumatoid arthritis (RA), VEGF in the serum of 155 patients with RA and 75 healthy control subjects was quantified by our highly sensitive enzyme-linked immunosorbent assay. VEGF levels were found to correlate with the articular index (AI) and Lansbury's activity index (LI). Patients with RA had a mean serum VEGF concentration of 153.5+/-111.8 pg/ml, which was significantly higher than control subjects (104.8+/-65.7 pg/ml; P0.01). VEGF concentration was elevated significantly according to disease progression as expressed by stages I to IV and correlated with AI (r=0.530, P0.0001) and LI (r=0.688, P0.0001) in stages I and II as well as with the conventional erythrocyte sedimentation rate or serum C-reactive protein concentration. Serum VEGF levels may therefore be valuable as a marker of disease activity in patients with early RA, and this cytokine may play a significant role in the pathophysiology of RA.

An influence of the argon-ion etching on Tc is investigated for high-Tc Bi1.6Pb0.4Sr2Ca2Cu3Ox. The etching doesn’t decrease the Tc for 7.0 ks. However, excess etching greatly decreases the Tc. Thus, a critical etching time (te C) to maintain high Tc above 100 K is defined and determined. The te C is 8.5 ks for the argon-ion etching.

Boronization with decaborane which is solid at room temperature has been successfully applied to the Compact Helical System (CHS) experiment. The effect of boronization on neutral-beam-injection (NBI)-heated plasma has been compared with the optimized case of titanium gettering. The concentration of oxygen has been reduced by a factor of 2 with boronization. Metal impurities can also be completely suppressed. Plasma performance has been improved in the high-density region with \barn e> 5×1019 m-3. The effective lifetime covers at least 200 NBI discharges while the favorable condition with titanium gettering has an effective lifetime of only 20∼30 discharges.