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     

AFM observation of polyethylene single crystals: selective handedness of screw dislocations in a chair type

The three-dimensional morphology of polyethylene single crystals grown from dilute solution has been examined by atomic force microscopy. Single crystals were deposited on a soft ground of aqueous solution of poly(vinyl alcohol) (PVA) to avoid the collapse of thin lamellar crystals with thickness of 10 nm. The observation of single crystals on dried PVA clarifies the morphology of a chair type crystal as well as well-known hollow pyramidal type. It has been confirmed that the screw dislocations in the chair type follow a selection rule of the handedness in a manner to relieve the distortion in the chair type.     

Iodine-123-BMIPP myocardial washout and cardiac work during exercise in normal and ischemic hearts

Due to the changes in the frequency of penicillin-resistant strains of S. pneumoniae, it is necessary to perform surveillance studies of bacterial resistance. Isolates from the upper respiratory tract of asymptomatic children have been useful. There is no information about the difference between isolates from children with and without upper respiratory tract infection (URTI). The objective of the authors in this paper is to establish the prevalence of carrier-state, serotype and antimicrobial resistance of S. pneumoniae isolates from children with and without acute upper respiratory tract infection (URTI) in a rural area in Mexico. A cross-sectional comparative study was performed in Tlaxcala, Mexico. Children from one month 5 years of age were included. Nasopharyngeal swabs were obtained. Identification was done by international microbiology standards. Serotyping was done by the capsular Quellung test. The susceptibility testing was performed by the agar dilution method. Four-hundred and fifty patients were included. S. pneumoniae was isolated in 134 children (29.7%). Frequency of carriers was greater in patients with URTI (107/323) than without URTI (27/127) (33.1% vs. 21.1% p = 0.012, OR 1.84, IC 95% 1.1-3.08). The six most frequent serotypes were: 6B (16.4%); 19F (11.9%); 19A (6.7%); 14, 23F, and 35 (5.2% each), with no difference among the groups. Only 3% of the strains had high level resistance to penicillin, and 12.6% had intermediate resistance, and for ampicillin 4%, amoxicillin 4%, amoxicillin-clavulanate 4%, ceftriaxone 3%, cefotaxime 1.5%, erythromycin 6%, miocamycin 3%, chloramphenicol 4%, and vancomycin 0%. Trimethoprim-sulfamethoxazole resistance was very high (42%). In conclusion, colonization is higher in children with URTI. Five of the most frequent serotypes identified in this study were the same as those identified in patients with S. pneumoniae invasive diseases in Mexico City. In Tlaxcala, Mexico, beta-lactams could be the drug of choice for the treatment of S. pneumoniae lower respiratory tract infections. It is necessary to perform clinical assays to evaluate the efficacy of trimethoprim-sulfamethoxazole due to the high resistance in vitro.     

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.     

Wide-span optical frequency comb generator for accurate opticalfrequency difference measurement

An optical frequency comb (OFC) generator was realized for accurate optical frequency difference measurement of 1.5 μm wavelength semiconductor lasers by using a high frequency LiNbO₃ electrooptic phase modulator which was installed in a Fabry-Perot cavity. It was confirmed that the span of the OFC was wider than 4 THz. By using semiconductor lasers whose spectrum linewidths were narrowed to 1 kHz and a sensitive optical balanced-mixer-receiver for measuring beat signal between the sideband of the comb and the laser, we demonstrated a frequency difference measurement up to 0.5 THz with a signal-to-noise ratio higher than 61 dB, and a heterodyne optical phase locking with a heterodyne frequency of 0.5 THz in which the residual phase error variance was less than 0.01 rad². The maximum measurable frequency difference, which was defined as the sideband frequency with the signal-to-noise ratio of 0 dB, was estimated to be 4 THz     

A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4

The availability of an analgesic compound devoid of the side effects associated with the commonly used opioid and nonsteroidal antiinflammatory drugs would be useful during the perioperative period. Although adenosine has analgesic and anesthetic-sparing properties, it also produces dose-dependent cardiovascular depression. Inhibitors of adenosine kinase may be able to provide analgesia without producing acute cardiovascular or respiratory depression. This preliminary study investigated the effects of a novel adenosine kinase-inhibiting drug, GP683, on the minimum alveolar anesthetic concentration (MAC) of desflurane in dogs. Seven mongrel dogs were administered one of three different GP683 dose regimens (or the solvent) by intravenous infusion on separate occasions according to a cross-over study design. After determining the baseline desflurane MAC value, GP683 was infused at 75, 150, or 300 microg x kg(-1) x min(-1) for 5 min as a loading dose, followed by 15, 30, or 60 microg x kg(-1) x min(-1) for an additional 85 min to maintain a stable plasma drug level. The desflurane MAC was redetermined 30-90 min after starting the study drug or vehicle infusion, and 30-90 min and 120-180 min after termination of the infusion. Cardiovascular variables and plasma concentrations of GP683 were determined at specific intervals before, during, and after the MAC determinations. The three GP683 dose regimens produced 22%, 31%, and 50% decreases in the desflurane MAC, respectively. In addition, there was good correlation between the decrease in desflurane MAC and the plasma GP683 concentration (r = -0.78). Although the mean arterial pressure (MAP) was decreased up to 25% by the highest infusion rate of GP683, adjustments in the desflurane concentration to an equi-MAC value resulted in normalization of the MAP values. Furthermore, GP683 produced no changes in heart rate. In conclusion, the adenosine kinase-inhibiting drug, GP683, produced dose-dependent decreases in the desflurane MAC of dogs without producing untoward hemodynamic changes. IMPLICATIONS: An investigational drug (GP683) that can increase the levels of an important endogenous substance in the body (adenosine) has been found to decrease the anesthetic requirement in dogs without producing adverse effects on the cardiovascular system.     

Measurements of distribution of self-bias potential on an RF-plane electrode in plasma etching devices

The self-bias potential (V_dc) induced on an RF-powdered electrode (153 mm Ø) in a plasma is measured using electrical probes which are buried in, de-insulated from, and RF-connected to the electrode. The configuration of the probes allows to study the distribution of V_dc discretely on the electrode. The potential is homogeneous in the absence of external magnetic field. In the presence of a homogeneous magnetic field parallel to the electrode, it is reduced and a monotonous gradient takes place in its distribution due to the plasma shift induced by E × B drift. When the magnetic field is rotated along the axis of the RF-electrode at a frequency less than 50 Hz, the distribution, which is almost identical to the one in a static field, rotates with the magnetic field. On the coordinate system rotating with the magnetic field, the probes are regarded to be rotating. The potential distribution is obtained as a continuous function of the azimuthal angle. Thus the rotation of the field provides information for the experimental interpolation.