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.     

Hepatoblastoma in an adult associated with c-met proto-oncogene imbalance

A rare case of hepatoblastoma in a 61-year-old Japanese housewife is described. This liver tumor mainly consisted of two tissue components: embryonal hepatocytes and primitive mesenchymal tissue. Fetal hepatocytes with alpha-fetoprotein production, gland formation, cartilage and osteoid were also found in a small portion. Molecular analysis by slot blot method revealed increased copy numbers of c-met and K-sam proto-oncogenes and cyclin D1 genes. These findings suggest that alterations of these oncogenes might play a role in the development of adult hepatoblastoma.     

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.     

Effect of chromium content on remarkably rapid nitriding in austenitic Fe-Ni-Cr alloys

Remarkably rapid nitriding which is independent of diffusion theory based on the thermal activation process, was observed during nitriding of austenitic Fe-Ni-Cr steels containing 16 and 19 mass% chromium. Increase of the chromium content in the alloys yielded increasing thickness of the nitrided layer, i.e. the internal nitriding theory did not hold in the nitriding. No rapid nitriding was observed in steels containing less than 13 mass% chromium. Hence the limiting concentration of chromium for the rapid nitriding will lie between 13 and 16 mass% chromium. A solution to the problem of abnormalities arising during nitriding of practical austenitic stainless steels which have been investigated since 1972, has been presented experimentally by nitriding various chromium-containing steels. Based on the experimental results, the origin of the rapid nitriding is discussed in connection with the free-energy function of Cr₂N and CrN to temperature. In particular, a plateau of nitrogen concentration measured in the nitrided layers leads to the conclusion that a forced nitrogen diffusion in the layer resulted in the rapid nitriding.     

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.     

Light scattering studies on crystallization in polyethylene terephthalate

The light scattering from the spherulites of polyethylene terephthalate grown near the glass transition temperature has been investigated. The Hv scattering profiles can be reproduced by the sum of the ideal spherulite scattering with the distribution of spherulite radius and the isotropic scattering from randomly oriented crystallites. The ratio of optical anisotropies in the isotropic scattering to the ideal spherulite scattering is obtained by the method established to eliminate the effects of the number density of spherulites and the coefficient depending on the experimental conditions. It is found that the anisotropy ratio is almost independent of the crystallization time and of temperature above 106 °C, while it is larger at a crystallization temperature of 103 °C. The spherulitic structure is discussed in terms of the anisotropy ratio.     

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.     

Properties of Va metal-B films prepared by r.f.-sputtering

Ta_100-x B _x alloy films were prepared by r.f.-sputtering in the chemical composition range 45 x 77. Ta_100-x B _x (45 x 58) films consist of the amorphous phase, while the TaB₂ crystal phase was observed in Ta_100-x B _x (66 x 77) films. A remarkable preferred orientation with the (001) plane of TaB₂ parallel to the film surface was observed in Ta₃₄B₆₆. The d.c. electrical conductivity of Ta_100-x B _x (45 x 77) films decreases with increasing boron content in the range 6.7 × 10³ to 1.3 × 10^3–1 cm^–1. The micro-Vickers hardness of Ta_100-x B _x (45 x 77) films was in the range 2200 to 2600 kg mm^–2.