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.     

Isolation of antimicrobial agent from the marine algae Cystoseira hakodatensis

Cystoseira hakodatensis is an unutilised brown algae belonging to family Sargassaceae. A crude methanol extract from the algae showed inhibitory effects on the growths of Bacillus cereus and Bacillus licheniformis. To isolate the major antimicrobial agent, a sequential active‐guided isolation procedure was applied: liquid–liquid extraction, column chromatography and bio‐autography. A marked antimicrobial agent (active α) was isolated in hydrophobic fraction and was determined to phenolics without carbohydrates and proteins by phytochemical test. Regarding the antimicrobial potential, the isolated active α showed better inhibitory effects against B. cereus and B. licheniformis at 2 and 4 times of lower concentrations (62.5 and 31.3 μg mL^?1) in comparison with epigallocatechin gallate. These results showed that C. hakodatensis is a potential source of antimicrobial agent capable of preventing the growth of the two bacteria.     

Fabrication of lotus-type porous carbon steel by the continuous zone melting method and its mechanical properties

A lotus-type porous carbon steel with cylindrical pores was fabricated by the continuous zone melting method in a pressurized mixture of hydrogen and helium gases. The porosity increases with increasing partial pressure of the hydrogen gas, while the pore diameter remains almost constant, independent of the pressure. The ultimate tensile strength of the specimen with cylindrical pores parallel to the tensile direction is lower than the estimated value, assuming that the strength is decreased in proportion to the decrease of the cross-sectional area of the specimen, while the yield strength is higher than the estimated value. The compressive yield strength is also higher than the estimated value. The increase in yield strength is considered to be due to precipitation strengthening. The tensile strength is increased by quenching and tempering, while the elongation decreases. Such mechanical properties are discussed in terms of the microstructural analysis.     

Operant conditioning of hippocampal theta: Dissociating reward from performance deficits.

Dopaminergic blocking agents have been known to suppress intracranial self-stimulation, but whether the suppression results from a reduction in the rewarding value of stimulation or from motor deficits has remained controversial. We have resolved this controversy by developing an operant technique minimally dependent on motor activity; rats were trained to perform a bar-holding response for 3s or to produce hippocampal theta waves for 3s when the bar was retracted. Decamethonium bromide (a muscle relaxant) reduced bar holding without affecting theta production for brain stimulation. Pimozide (a dopaminergic blocking-agent) reduced both bar holding and theta production for stimulation, though rats were still capable of making the theta response at a rate comparable to the preinjection rate. Dopaminergic blocking at low doses reduces the rewarding value of brain stimulation at the level of the lateral hypothalamus. The method described in this report has wide applicability. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Establishment time of liquid flow in a bath agitated by bottom gas injection

The establishment time of gas-liquid two-phase flows in a cylindrical bath agitated by bottom gas injection through a central single-hole bottom nozzle was investigated. Because the turbulence intensity in the bath was comparable to or larger than the unity, the conventional definition of the flow establishment time based on the history of mean velocity was not suitable for the present case. In fact, it was difficult to determine the flow establishment time based on the well-known 90 or 99 pct criterion for the mean velocity. Accordingly, two methods of determining the flow establishment time by focusing on the turbulence components instead of the mean velocity components were proposed. Velocity measurements were made with a two-channel laser Doppler velocimeter. The flow establishment time was correlated as a function of gas flow rate. Close agreement was obtained by the two methods.     

A 0.1-μm delta-doped MOSFET fabricated with post-low-energyimplanting selective epitaxy

A simple fabrication technology for delta-doped MOSFETs, named post-low-energy implanting selective epitaxy (PLISE) is presented. The PLISE technology needs no additional photo-lithography mask, deposition step or etching step even for CMOS devices. The only additional step is growing undoped epitaxial channel layers by UHV-CVD after the channel implantation. With this technology, delta-doped NMOSFETs with 0.1-μm gate length were successfully fabricated. By optimizing the epi-layer thickness and the channel doping level, short-channel effects are suppressed enough to achieve 0.1-μm gate length. Moreover, the junction capacitance at zero bias is reduced by 50%     

Intestinal metaplasia with adherent Helicobacter pylori: a hybrid epithelium with both gastric and intestinal features

Helicobacter pylori seem to avoid areas of intestinal metaplasia in the gastric mucosa, but attachment of these bacteria to epithelium with the appearance of incomplete intestinal metaplasia has been documented. To characterize the nature of the epithelium to which H pylori was attached, we carried out an immunohistochemical study using monoclonal antibodies against gastric surface mucous cell mucins (M1), blood group-related carbohydrates antigens (Le(a), sialyl Le(a), Le(b), type 1H, and type 2H) and sialyl Tn antigen. The results of this study suggest that these areas of H pylori attachment represent a hybrid epithelium whose cells share characteristics of both gastric surface mucous cells and intestinal metaplastic cells. Whether all areas of incomplete intestinal metaplasia represent an intermediate stage between the normal gastric epithelium and the fully developed complete type of metaplasia remains to be determined.     

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.