Association of upregulated activity of KATP channels with impaired insulin secretion in UCP1-expressing insulinoma cells

Insulin-secreting MIN6 cells overexpressing uncoupling protein-1 (UCP1) were studied regarding insulin secretion in response to various secretagogues. Overexpression of UCP1 prevented an increase of cytosolic ATP levels induced by glucose. In contrast, glucose utilization was not affected, nor was glycerol phosphate flux. The UCP1-expressing cells showed an inability to increase cytosolic Ca2+ concentration ([Ca2+]i) in response to glucose or α ketoisocaproate and this resulted in less insulin secretion, whereas initial reduction in [Ca2+]i occurring upon either nutrient addition was not affected. Moreover, the effectiveness of tolbutamide on [Ca2+]i increase was reduced and the dose-response relations for insulin secretion induced by the agent was shifted toward the right in the UCP1-expressing cells. The resting membrane potential of the UCP1-expressing cells was significantly hyperpolarized by 6.2 mV compared with control cells. In the perforated and conventional whole-cell patch-clamp configurations, the conductance density of ATP-sensitive K+ (KATP) channels of the UCP1-expressing cells was 6-fold and 1.7-fold greater than that of the control cells, respectively. The sensitivity of KATP channels for tolbutamide was not different between two groups, indicating that in intact cells more than 6-fold higher concentrations of tolbutamide were required to reduce the KATP channel currents of UCP1-expressing cells to the same levels as of the control cells. The current density of the voltage-dependent Ca2+ channels was not influenced. In conclusion, UCP1-expressing cells showed a refractoriness to respond to tolbutamide as well as nutrients. An upregulated activity of KATP channels was associated with unresponsiveness to the agent in the cells with impaired mitochondrial function

Slerry -Erosion Behavior of Alminum-Silicon Carbide Composite Alloys

Composite materials have good mechanical properties such as high strength, high hardness and high wear resistance. They are widely used in the fields of automobiles, civil engineering and many other machine industries. Hopefully it will be used more wide engineering fields such as ship industry and slurry sucking up pumps, in which high resistance for slurry-erosion should be required. And also mechanical properties of the materials are known to depend on the microstructure. In this paper, relationships among microstructure, mechanical properties and slurry-erosion behavior are discussed on the specimens of pure Al, dispersion hardend Al alloys ( Al-Si alloys ), solution hardend alloys ( Al-Mg alloy, Al-Cu alloy ) and SiC particles inserted Al alloys for developing a material for slurry sucking up pump. Based on the experimental results, it was revealed that slurry-erosion resistance of the SiC particles inserted Al alloy shows about seven times higher than that of the dispersion hardend alloys and the solution hardend alloys. It was concluded that the SiC particles inserted Al alloys are a promising materials for the slurry sucking up pump

Change in phenoloxidase and its precursor during silkworm (a80 strain) development

The changes in phenoloxidase and its precursor, so-called prophenoloxidase, of the silkworm, Bombyx mori （a80 strain）were examined using detection assay with or without detergent to distinguish PO and pro-PO in hemolymph （Yamamoto, et al., 1999）. Little or no phenoloxidase activity was detected in hemolymph at the silkworm development during the final larval instar and pupal stage. On the other hand, prophenoloxidase was detected for same time frame. In males, after prophenoloxidase increased slightly at day 4, it decresed to a minimum level at spinning and increased to a maximum level on the day of pupation and decreased gradually to day 5 after pupation. In females, prophenoloxidase decreased gradually to a minimum level on day of spinning and a slight increase was observed at day 8 and it increased to maximum level between day 2 and 3 after pupation and decreased thereafter. Prophenoloxidase mRNA expression was preceded a day or two before, when comparing the change of phenoloxidase mRNA with its product

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF₁) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF₁ receptor antagonists. In a structure–activity relationship study, 4-chloro-<i>N</i>²-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-<i>N</i>⁷,<i>N</i>⁷-dipropyl-1<i>H</i>-benzimidazole-2,7-diamine <b>29g</b> had the most potent binding activity against a human CRF₁ receptor and the antagonistic activity (IC₅₀ = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF₁ receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus–pituitary–adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound <b>29g</b> after oral administration in mice. Thus, the newly designed benzimidazole <b>29g</b> showed in vivo CRF₁ receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF₁ receptor antagonist drug discovery research