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.     

Volumetric Change and Surface Properties of Temperature-Sensitive Polyvinylalcohol (PVA) Hydrogel

Polyvinylalcohol (PVA) polymer gel is a temperature sensitive polymeric gel, with a critical transition temperature (with H₂O) of 310 K. At higher than 310 K, this temperature sensitive polymer gel shrinks because of discharging water, whereas at lower temperatures, the gel swelled because of absorbing water. The reversibility of the gel's volume change was confirmed by temperature swing. The adsorption behavior of an organic compound onto the PVA polymer gel in water was tested at various temperatures. The amount of adsorbed organic compound increased remarkably at temperatures higher than about 310 K. Then, it was confirmed that the organic compound in PVA polymer gel could be reversibly adsorbed and desorbed by a temperature change between 293 and 323 K. The mechanism of adsorption of the organic compound onto the PVA polymer gel could be explained by hydration and dehydration of polymer gel.     

Stability,cure properties,and applicability as one part adhesives of systems of divalent metal salts of mono(hydroxyethyl) phthalate–anhydride–bisepoxide

Heterogeneous curable compositions of divalent metal salts of mono(hydroxyethyl) phthalate–anhydride–bisphenol A diglycidyl ether (BADG) systems were prepared by merely mixing these components at room temperature. Stability at room temperature and cure properties at high temperature of the compositions were investigated for evaluating their applicability as one part adhesive. It was found that the systems containing Mg were generally more stable than those containing Ca. Similarly, at 150°C the Ca-containing systems showed generally shorter gelation time than the Mg-containing ones, due to the fact that the Ca salt dissolves more rapidly and enters into the addition reaction with the anhydride, leading to the faster appearance of the catalytic activities of the Ca carboxylate group. Among the various combinations of components, the metal salt–succinic anhydride (SA)–BADG systems were stable at room temperature for more than 6 months and rapidly cured at high temperature, showing excellent adhesive properties. This result indicates that the SA-containing systems should be of interest in applications to one part adhesives.     

Galvanic cell measurements on supersaturated activities of oxygen in Fe-Al-M (M=C, Te, Mn, Cr, Si, Ti, Zr, and Ce) melts

Using a mullite (3Al₂O₃ · 2SiO₂)-tube and ZrO₂-9 mol pct MgO-plug type solid electrolyte galvanic cells, the activities of supersaturated oxygen in Fe-0.0017 to 0.41 mass pct Al-M (M=C, Te, Mn, Cr, Si, Ti, Zr, and Ce) alloys were measured as a function of total Al or M contents at 1873 K in an alumina crucible. Based on these results, the effects of alloying elements on the supersaturated oxygen activity with respect to alumina precipitation were studied. In the Fe-Al-M (M=C, Te, Mn, Cr, and Si) alloys, the supersaturated oxygen activities for a given Al level approach the equilibrium values with increasing contents of alloying elements. However, the oxygen activities for a given Al level are still supersaturated in the Fe-Al-M (M=Ti, Zr, and Ce) alloys even in the presence of considerable amounts of the alloying elements.     

Lipopolysaccharide primes human alveolar macrophages for enhanced release of superoxide anion and leukotriene B4: self-limitations of the priming response with protein synthesis

Human alveolar macrophages (AM) can produce potent reactive oxygen intermediates (ROI) and arachidonic acid metabolites (eicosanoids), which have important roles in host defense and the pathogenesis of some diseases of the lung. Bacterial lipopolysaccharide (LPS) is believed to cause profound lung injury and can prime mouse peritoneal macrophages for the enhanced secretion of ROI and eicosanoids. Therefore, we investigated the effect of LPS pretreatment on the ability of AM to release superoxide anions (O2-) and leukotriene B4 (LTB4). LPS can prime AM for the enhanced secretion of O2- and LTB4, regardless of whether they are derived from nonsmokers or smokers. Moreover, judging from the time-response characteristics, this priming for LTB4 release could be inhibited in the later stages of pretreatment, when the O2(-)-releasing capacity was enhanced. The priming inhibition was prevented, at least in part, by cycloheximide, but not by SOD and/or catalase. In addition, cycloheximide also inhibited the priming for O2- release. Hence, protein synthesis might be necessary for the priming for O2- release and for inhibiting the priming for LTB4 release. This phenomenon of self-limiting the priming response with LPS seems to be very important when we consider the high oxygen tension in the lungs and the many bacterial substances inspired into alveoli.     

Intramolecular triplet energy migration in poly(2-vinylnaphthalene) and poly(naphthylalkyl methacrylate)s in solid solution: Effects of side chain length

Summary The effect of side chain length on intramolecular triplet energy migration of naphthalene containing polymers was investigated by a delayed fluorescence (DF) spectroscopy for the solid solution of the polymers. The degree of triplet energy migration depends strongly on whether the chromophores are directly attached to the main chain or not.