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     

Difference between human and guinea pig Hageman factors in activation by bacterial proteinases: cleavage site shift due to local amino acid substitutions may determine the activation efficiency of serine proteinase zymogens

Human and guinea pig Hageman factors have been subjected to the action of pseudomonal elastase and serratial E15 proteinase. The pseudomonal elastase cleaved 22-24% of the human molecule at Arg353-Val354, and the remainder at Gly357-Leu358 resulting in the generation of about 20% of potential activity as activated Hageman factor, compared with trypsin activation, while it hydrolyzed Arg340-Ile341 bond in guinea pig molecule and generated about 75% of activity as activated Hageman factor. The serratial proteinase did not hydrolyze the essential cleavage site (Arg353-Val354) of the human zymogen but Gly356-Gly357 (30%) and Gly357-Leu358 (70%) bonds. Both products showed no activity. The guinea pig zymogen, in contrast, was cleaved mostly at Arg340-Ile341 (70%) and less abundantly at Gly344-Leu345 (30%), generating about 85% of the whole potential activity as activated Hageman factor. From the high correspondence between the proportions of activation and of hydrolysis at the essential cleavage site in activation, it was concluded that hydrolysis of the bonds different from the essential bond did not cause activation, even when the spatial separation was only 3 or 4 residues. Considering the amino acid differences between human and guinea pig Hageman factors, -Met351-Thr-Arg-Val-Val-Gly-Gly-Leu-Val-Ala360- and -Leu338-Ser-Arg-Ile-Val-Gly-Gly-Leu-Val-Ala347-, respectively, it was realized that even the minor amino acid substitutions caused the cleavage site shift which resulted in significant differences in activation efficiency of the proteinase zymogens.     

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.     

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     

Development of 170 GHz/500 kW gyrotron

A development of 170GHz/500kW level gyrotron was carried out as R&D work of ITER. The oscillation mode is TE_31,8. In a short pulse experiment, the maximum power of 750kW was achieved at 85kV/40A. The efficiency was 22%. In the depressed collector operation, 500kW/36%/50ms was obtained. The maximum efficiency of 40% was obtained at P_RF=470kW whereas the power decrease by the electron trapping was observed. Pulse extension was done up to 10s at P_RF=170kW with the depressed collector operation. The power was limited by the temperature increase of the output window.