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.     

Cover Image,Volume 69, Issue 3

The cover image is based on the Mini‐Review Well‐defined, environment‐friendly synthesis of polypeptides based on phosgene‐free transformation of amino acids into urethane derivatives and their applications by Takeshi Endo et al., https://doi.org/10.1002/pi.5952 . Cover image © Takeshi Endo Images.

     

Glycoconjugated polymer 6. Synthesis of poly[styrene-<Emphasis Type="Italic">block</Emphasis>-(styrene-<Emphasis Type="Italic">graft</Emphasis>-amylose)] via potato phosphorylase-catalyzed polymerization

Summary The potato phosphorylase-catalyzed polymerization of α-D-glucose-1-phosphate (G-1-P) onto poly[styrene-block-(4-vinylbenzyl maltohexaoside)] (1) was performed at the molar ratios of [G-l-P]₀ and [maltohexaose]₀ of 35, 80, and 250. The product was found to be soluble in dimethyl sulfoxide, which was a good solvent for amylose, and showed the complex-formation with iodine, indicating that the product was assignable to poly[styrene-block-(styrene-graft-amylose)] (2). The quantitative analysis of the liberated phosphoric acid gave the average degree of polymerization o f the glucose unit (n) as 27, 5 1, and 180 for 2-I, 2-II, and 2-III, respectively. Received: 29 November 2002/Accepted: 22 December 2002 Correspondence to Toyoji Kakuchi     

Biphasic effect of hydrogen peroxide on field potentials in rat hippocampal slices

In the CA1 region of rat hippocampal slices, H2O2 (0.294-2.94 mM) caused initial augmentation, and subsequent long-lasting depression, of population spikes and excitatory postsynaptic potentials. The effect of H2O2 may not be mediated by its degradation product, hydroxyl radicals, because an iron chelator deferoxamine did not block the effect. A catalase inhibitor 3-amino-1,2,4-triazole only modestly attenuated the initial augmentation, suggesting that the effect of H2O2 is not attributable to catalase-dependent O2 generation, either. An N-methyl-D-aspartate receptor antagonist DL-2-amino-5-phosphonovaleric acid had no influence on the effect of H2O2, whereas a gamma-aminobutyric acid type A receptor channel blocker picrotoxin attenuated long-lasting depression, indicating that gamma-aminobutyric acid-mediated inhibition is altered during the depression phase. The initial augmentation but not subsequent depression was attenuated by a phospholipase A2/C inhibitor 4-bromophenacyl bromide, suggesting the involvement of lipid signaling molecule(s) in the enhancement of excitatory synaptic transmission. These results suggest that H2O2 regulates hippocampal synaptic transmission via multiple mechanisms.     

Active sites of Cu-ZSM-5 for the decomposition of acrylonitrile

The catalytic decomposition of acrylonitrile (AN) over Cu-ZSM-5 prepared with various Cu loadings was investigated. AN conversion, during which the nitrogen atoms in AN were mainly converted to N₂, increased as Cu loading increased. N₂ selectivities as high as 90–95% were attained. X-ray diffraction measurements (XRD) and temperature-programmed reduction by H₂ (H₂-TPR) showed the existence of bulk CuO in Cu-ZSM-5 with a Cu loading of 6.4 wt% and the existence of highly dispersed CuO in Cu-ZSM-5 with a Cu loading of 3.3 wt%. Electron spin resonance measurements revealed that Cu-ZSM-5 contains three forms of isolated Cu²⁺ ions (square-planar, square-pyramidal, and distorted square-pyramidal). The H₂-TPR results suggested that in Cu-ZSM-5 with a Cu loading of 2.9 wt% and below, Cu⁺ existed even after oxidizing pretreatment. The activity of AN decomposition over Cu/SiO₂ suggested that CuO could form N₂, but, independent of the CuO dispersion, nitrogen oxides (NO_x) were formed above 350 °C. Cu⁺ and the square-pyramidal and distorted square-pyramidal forms of Cu²⁺ showed low activity for AN decomposition. Temperature-programmed desorption of NH₃ suggested that N₂ formation from NH₃ proceeded on Cu²⁺, resulting in the formation of Cu⁺. The Cu⁺ ions were oxidized to Cu²⁺ at around 300 °C. Thus, high N₂ selectivity over Cu-ZSM-5 with a wide range of temperature was probably attained by the reaction over the square-planar Cu²⁺, which can be reversibly reduced and oxidized.     

Heat transfer mechanism of a swirling impinging jet in a stagnation region

Heat transfer characteristics of a swirling impinging jet have been experimentally examined using a combined particle image velocimetry (PIV) and laser‐induced fluorescence (LIF) technique for simultaneous measurement of velocity and temperature fields. The present study shows that the radial width of the jet stretches with increasing swirl intensity, and that the stretching phenomenon contributes to the maximum local heat transfer coefficient. At the stagnation region, the flow near the heated surface is mixed intermittently by reverse flows toward upstream, and spatial distributions of temperature are correlated with instantaneous velocity vector maps. The dynamic behavior of recirculation zones, attributed to swirl number Sw and impinging distance, mainly determines the turbulent heat transfer at the stagnation region. © 2003 Wiley Periodicals, Inc. Heat Trans Asian Res, 32(8): 663–673, 2003; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/htj.10120     

Prediction of spectral reflectance factor distribution of automotive paint finishes

It is necessary to determine the accurate reflectance of painted surfaces for the review of paint finishes by computer graphics (CG) before actual painting of the exterior color of automobiles, and for quality control during production and inspection processes. We have optimized a method for measuring reflectance by using a statistical technique. We have found that the reflectance of a painted surface is best measured at an incident angle of 60° and at five aspecular angles of 10°, 18°, 28°, 40°, and 90°. Our method makes it possible to accurately reproduce reflection characteristics of paint finishes containing special flake pigments, such as pearl mica. Also it was proved that our method can apply not only to solid and metallic coatings but to all painted surfaces. © 2005 Wiley Periodicals, Inc. Col Res Appl, 30, 275–282, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20125     

Determination of three dimensional in situ stress from core discing based on analysis of principal tensile stress

To determine all of the components of in situ stress from core discing, both the directions and magnitudes of the principal in situ stresses must be determined for a disc of a given thickness. In this study, we analyzed the direction and magnitude of tensile stress below an HQ core stub for 11 core lengths using stress conditions under which core discing is likely to occur. First, based on an analysis of the direction of tensile stress below the core stub, we propose a method for determining directions of in situ stress from the height distribution at the periphery of the end surface of a disc. This method can be used with a disc of any thickness. Next, based on an analysis of the magnitude of tensile stress in the central part of a core, we propose a linear criterion for core discing, which can be applied to a core of any length. This criterion was in good agreement with an empirical formula obtained previously in laboratory experiments. By combining information on the direction of in situ stress and the linear criterion for core discing, we propose a method for determining all of the components of in situ stress from core discing under the assumption that vertical stress is given by the overburden stress. Finally, these methods were applied to discs obtained from a field where hydraulic fracturing was performed to measure horizontal stresses. The results showed that the azimuths of the principal stresses estimated from core discing were consistent with those of the principal horizontal stresses determined by hydraulic fracturing and that while the magnitudes of the principal horizontal stresses estimated from core discing showed a large scatter, they were similar to those determined by hydraulic fracturing.