Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.     

Radiophotoluminescence phenomenon in copper-doped aluminoborosilicate glass

Radiophotoluminescence phenomena have been widely investigated on various types of materials for dosimetry applications. We report that an aluminoborosilicate glass containing 0.005 mol% copper exhibits intense photoluminescence in the visible region induced by X-ray and γ-ray irradiation. The luminescence is assigned to the 3d⁹4s¹ → 3d¹⁰ transition of Cu⁺. The proportionality of the intensity of the induced photoluminescence to the irradiation dose was confirmed up to 0.5 kGy using ⁶⁰Co γ-ray irradiation. Based on the spectroscopic results, a potential mechanism was proposed for the enhancement of the photoluminescence. The exposure to the ionizing radiation generates electron-hole pairs in the glass, and the electrons are subsequently captured by the Cu²⁺ ions, which are converted to Cu⁺ and emit the luminescence. For the glass containing 0.01 mol% copper, the pronounced enhancement of the photoluminescence was not observed because the reverse reaction, ie, the capture of the holes by the Cu⁺ ions, becomes prominent. The photoluminescence induced by the irradiation was stably observed for the glasses kept at room temperature and even for the glasses heat-treated at 150°C. However, the induced photoluminescence could be eliminated by the heat treatment at a temperature at 500°C, and the glass returned to the initial pre-irradiation state. The Cu-doped aluminoborosilicate glass is a potential candidate for use in dosimetry applications.     

Monomeric, monovalent derivative of Maackia amurensis leukoagglutinin. Preparation and application to the study of cell surface glycoconjugates by flow cytometry

A stable subunit of Maackia amurensis leukoagglutinin (MMAL) was prepared by the selective reduction of disulfide bridges between the subunits followed by alkylation with 4-vinylpyridine. MMAL failed to precipitate fetuin, whereas it retained its ability to bind to the same glycoprotein coated on a plastic plate, indicating the monovalency of this derivative. This binding to immobilized fetuin was inhibited by a haptenic sugar, Neu5Ac alpha 2-3lactose, with the same inhibitory potency as against the native M. amurensis leukoagglutinin. Microscopic observation as well as flow cytometric analyses showed that Chinese hamster ovary cells were clearly stained with fluorescein isothiocyanate-labeled MMAL without any detectable agglutination. This staining was inhibited by the addition of fetuin or by the sugar chains of fetuin. Differences in the types of sialylated glycoconjugates on the cell surface of several cell lines were detected by the combined use of fluorescein isothiocyanate-labeled MMAL and the monomeric derivative of elderberry bark lectin (specific for the Neu5Ac alpha 2-6Gal/GalNAc sequence) by flow cytometry. These results demonstrate the usefulness of these monovalent derivatives of sialylated oligosaccharide-specific lectins as probes for the analysis of cell surface glycoconjugates containing sialic acid by the technique of flow cytometry.     

Subsurface structures in initial stage of FeSi2 growth studied by high-resolution Rutherford backscattering spectroscopy

The initial stage of iron silicide formation is investigated by high-resolution Rutherford backscattering spectroscopy. During the Fe deposition on Si(001) at 470 °C, the formation of FeSi₂ is confirmed by the surface peak analysis. Initially, FeSi₂ grows epitaxially so that one of the major crystallographic axes is parallel to the <111> axis of the Si substrate. With increasing Fe deposition, the deviation between the major crystallographic axis of the silicide region and Si<111> increases although the electron diffraction pattern is independent of the amount of Fe deposition. Therefore, the subsurface crystallographic structure of iron silicide is transformed from a cubic-like to a low-symmetry structure.     

Improvement of Mechanical Properties of Machinable Glass-Ceramics through Postmachining Heat Treatments

A mica-based machinable glass-ceramic has been converted to a glass-ceramic containing cordiertie and body-centered cubic chondrodite through heat treatment at temperatures higher than that used for the crystallization of mica. The machinability is lost, microhardness increases, and the thermal expansion coefficient decreases with the change of the crystalline phase from mica to cordierite and chondrodite.     

Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K+ in rat hippocampus

Spreading depression (SD) is known to be involved in the N-methyl-D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K+ perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 microM) and nitrobenzylthioinosine (NBI) (50 microM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEg and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR+NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR+NBI were blocked by application of a selective antagonist of adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the A1 receptor in rat hippocampus.     

A novel technique for a DC brushless motor without position sensors

A dc brushless motor is a kind of synchronous motor driven by an inverter and requires sensors to detect the rotor position. As one of the methods, the induced voltages of a brushless motor have been utilized in practice. However, there are some problems in this method, e.g., the motor can obtain insufficient torque due to the low induced voltages in a low-speed range. This paper proposes a new method which controls the inverter angular frequency ω₁ by using inherent characteristics wherein the torque current i_r is almost proportional to the internal phase angle φ where the primary flux of a synchronous motor is controlled to be constant. If the parameters of a motor are given exactly, the speed regulation is quite small and the transient characteristics with high response and high starting torque are obtained. Furthermore, it is possible to operate a synchronous motor in the field-weakening range. Here, the principle of the control method and the performance characteristics of a dc brushless motor having no position sensors are discussed. The simulation and the experimental results of the tested machine show that the proposed method is very useful for practical applications.     

A copper/polyimide Metal-base packaging technology

A unique substrate MCPM (Mitsubishi Copper Polyimide Metal-base) technology has been developed by applying our basic copper/polyimide technology.¹ This new substrate technology MCPM is suited for a high-density, multi-layer, multi-chip, high-power module/package, such as used for a computer. The new MCPM was processed using a copper metal base (110 × 110 mm), full copper system (all layers) with 50-μm fine lines. As for pad metallizations for the IC assembly, we evaluated both Ni/Au for chip and wire ICs and solder for TAB ICs. The total number of assembled ICs is 25. To improve the thermal dispersion, copper thermal vias are simultaneously formed by electro-plating. This thermal via is located between the IC chip and copper metal base, and promotes heat dispersion. We employed one large thermal via (4.5 mm^?) and four small vias (1.0 mm^?) for each IC pad. The effect of thermal vias and/or base metal is simulated by a computer analysis and compared with an alumina base substrate. The results show that the thermal vias are effective at lowering the temperature difference between the IC and base substrate, and also lowering the temperature rise of the IC chip. We also evaluated the substrate’s reliability by adhesion test, pressure cooker test, etc.