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.     

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.     

Direct digital design of computed torque controllers

Direct digital design of computed torque controllers for a robot manipulator is discussed in this article. A simple discrete-time model of the robot manipulator obtained by Euler's method is used for the design. Taking account of computation delay in the digital processor, we propose predictor-based designs of the PD and PID type controllers. The PID-type controller is designed based on a modified version of the discrete-time integral controller proposed by Mita. For both controllers, the feedback gains can be determined easily by using simple formulas. A simulation example is presented to illustrate the relevance of the proposed designs and the robustness of PID-type controller against physical parameter variations. © 1994 John Wiley & Sons, Inc.     

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.     

Catalytic decomposition of HCFC22 (CHClF2)

The catalytic decomposition of CHClF₂ was studied over various acidic metal oxides in a fixed-bed reactor. The Cr₂O₃ZrO₂ exhibited the highest activity. The presence of water vapor in the reaction system suppresses the transformation of oxides to fluorides, progresses the formation of CO₂, and it improves the catalysts life.     

A case of venous aneurysm

A 70-year-old woman was referred to our hospital with a complaint of a soft mass at the right elbow. Venography demonstrated that the mass was connected with vein. This mass was surgically removed and histologically a marked reduction of both elastic fibers and the adventitia were observed in the aneurysmal wall. Venous aneurysm (VA) is different form varicose veins by many features. It was considered that congenital fragility of the venous walls was associated with the onset of VA. We classified VA into type-I VA (cystic ectasia) and type II (fusiform ectasia).     

Human peripheral eosinophils express functional interferon-gamma receptors (IFN-gammaR)

In order to determine whether or not IFN-gammaR is associated with regulatory mechanisms on human eosinophil function, we examined the expression of functional IFN-gammaR on human peripheral eosinophils. In this study, peripheral blood eosinophils were obtained from seven normal controls and 12 patients (bronchial asthma, n = 9, and hypereosinophilic syndrome (HES), n = 3), and the purity of eosinophils was 97.11 +/- 2.31%, n = 19. We first showed that anti-IFN-gammaR alpha-chain MoAb reacted with all tested eosinophils of both normal controls and patients by flow cytometry analysis. We also showed expression of mRNA for the alpha-chain of IFN-gammaR in all purified eosinophils of six individuals. Further, to characterize IFN-gammaR on eosinophils, we did binding experiments with 125I-IFN-gamma on purified peripheral eosinophils. The linear Scatchard plot indicated a single type of high-affinity binding sites (dissociation constant (Kd) = 3.89-4.95 x 10(-10) M, numbers of binding sites = 183-233/cell, n = 3). To determine whether IFN-gammaR on eosinophils is functional, we examined surface eosinophilic cationic protein (ECP) and CD69 induction after IFN-gammaR ligation with recombinant human IFN-gamma (rhIFN-gamma) on eosinophils by flow cytometry. rhIFN-gamma stimulation significantly induced both ECP and CD69 expression on the 2-18 h-cultured eosinophils in a dose-dependent manner. Further, the effects of rhIFN-gamma stimulation were significantly blocked by both a neutralizing anti-IFN-gamma MoAb and a blocking anti-IFN-gammaR MoAb. These results suggest that human peripheral eosinophils express functional IFN-gammaR.