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.     

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.     

Hydrogen absorption by Pd-coated ZrNi prepared by using Barrel-Sputtering System

To improve the durability of hydrogen storage materials against surface poisoning by impurity gases, effectiveness of Pd-coating layer prepared by using a Barrel-Sputtering System was examined for ZrNi powder. The effectiveness of Pd-coating was evaluated by activation temperature, at which Pd/ZrNi poisoned by air could be activated to absorb hydrogen. Characterization of Pd-coated ZrNi (denoted as Pd/ZrNi) by scanning electron microscopy, electron probe microanalysis and X-ray diffraction showed that a uniform Pd-coating layer was formed with the barrel-sputtering system. It was found that the poisoned Pd/ZrNi sample could be activated even at 423 K to absorb hydrogen at room temperature. This exhibits remarkable contrast to bare ZrNi, which could be only activated appreciably above 1073 K. It is concluded that the Pd-coating by barrel sputtering is quite effective to avoid the effect of surface poisoning of powdery hydrogen storage materials. However, the activation at excessively high temperature resulted in the loss of high activity to absorb hydrogen. It was concluded that this phenomenon was associated with reactions between Pd and ZrNi to form PdZr and other byproducts.     

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.     

Solution structure of bromelain inhibitor IV from pineapple stem: structural similarity with Bowman-Birk trypsin/chymotrypsin inhibitor from soybean

Bromelain inhibitor VI from pineapple stem (BI-VI) is a unique double-chain inhibitor with an 11-residue light chain and a 41-residue heavy chain by disulfide bonds and inhibits the cysteine proteinase bromelain competitively. The structure of BI-VI in aqueous solution was determined using nuclear magnetic resonance spectroscopy and simulated annealing-based calculations. Its three-dimensional structure was shown to be composed of two distinct domains, each of which is formed by a three-stranded antiparallel beta-sheet. Unexpectedly, BI-VI was found to share a similar folding and disulfide bond connectivities not with cystatin superfamily inhibitors which inhibit the same cysteine proteinases but with the Bowman-Birk trypsin/chymotrypsin inhibitor from soybean (BBI-I). BBI-I is a 71-residue inhibitor which has two independent inhibitory sites toward the serine proteinases trypsin and chymotrypsin. These structural similarities with BBI-I suggest that they have evolved from a common ancestor and differentiated in function during a course of molecular evolution.     

Annealing behavior of Ar ion irradiated Bi2Sr2Can-1CunO4+2n superlattice and intergrowth films

Artificially layered Bi₂Sr₂Ca_n–1Cu_nO_4+n films were synthesized by sequential sputter deposition of BiO, SrCu_0.5O_1.5 and CaCuO₂ layers. Annealing behavior of these films which were irradiated by Ar ions was studied. Defect assisted improvement of their crystalline perfection is expected which might results in the improvement of the superconducting properties of these films. An artificial film, such as an intergrowth of 2223 and 2234 phases, and superstructure films of (2245)₁(2201)₁ and (2234)₁(2212)₁, were irradiated by Ar ions (150 keV, 2–10×10¹² ions/cm₂) and annealed at 730 °C. An improvement of superconducting transition temperatures were observed.     

High-frequency ultrasonic cleaning tank utilizing oblique incidence

Transmission characteristics of a double-structured tank, used for high-frequency (1 MHz range) ultrasonic cleaning of semiconductor wafers and substrates, were improved by utilizing oblique incidence of ultrasonic waves. As the sound transmittivity through a plate in water varies with the angle of incidence, the bottom of the Pyrex glass inner container was slanted at the angle where strong transmission occurred. In the slant-bottom container, an intensive and uniform sound pressure distribution was measured with a polyvinylidene fluoride (PVDF) hydrophone probe. In comparison with the conventional horizontal-bottom container, it was shown that the distributions as well as amplitude of sound pressure were remarkably improved by slanting the bottom of the inner container at the proper angle     

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.