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.     

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.     

Synthesis and characterization of poly(N-propionyl)iminoethylene

Summary The cationic polymerization of 2-ethyl-2-oxazoline using CH₃I as initiator at different monomer/initiator ratios, temperatures, solvents and times of polymerization was carried out. The effect of these variables on the polymerization yield and viscosity of the polymers was studied. The poly(N-propionyl)iminoethylene was hydrolyzed in acid medium obtaining a linear poly(ethyleneimine) (PEI). All the polymers were characterized by elemental analysis, IR,¹H NMR, and¹³C NMR spectroscopy.     

Reactivity of platinum nanoaggregates in catalytic reduction of U(VI) with hydrazine in acid solutions

Catalysts Pt/SiO₂ with different size of Pt nanoaggregates were studied in catalytic reduction of U(VI) with hydrazine in solutions of H₂SO₄, HClO₄, and HNO₃. The catalytic activity of the surface Pt atoms of Pt/SiO₂ in this reaction monotonically increases with an increase in the size of metal crystallites on the support, i.e., the negative size effect is observed. Catalytic reduction of U(VI) with hydrazine in H₂SO₄ solutions is significantly faster than in HClO₄ and HNO₃, and in HClO₄ it is slightly faster than in HNO₃. The results were interpreted within the framework of the concept of the energetic nonuniformity of the surface atoms and of the mechanisms of catalytic reduction of U(VI) with hydrazine in acid solutions.     

Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K+ in rat hippocampus

Spreading depression (SD) is known to be involved in the N-methyl-D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K+ perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 microM) and nitrobenzylthioinosine (NBI) (50 microM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEg and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR+NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR+NBI were blocked by application of a selective antagonist of adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the A1 receptor in rat hippocampus.     

Distributions of multi-estimates for multistage stochastic inclusions

The problems of constructing recursive relations for conditional and unconditional distributions of random informational sets are considered. These sets, which are called multi-estimates in the paper, appear naturally in the problems of estimation of states and parameters of multistage stochastic inclusions.     

A novel technique for a DC brushless motor without position sensors

A dc brushless motor is a kind of synchronous motor driven by an inverter and requires sensors to detect the rotor position. As one of the methods, the induced voltages of a brushless motor have been utilized in practice. However, there are some problems in this method, e.g., the motor can obtain insufficient torque due to the low induced voltages in a low-speed range. This paper proposes a new method which controls the inverter angular frequency ω₁ by using inherent characteristics wherein the torque current i_r is almost proportional to the internal phase angle φ where the primary flux of a synchronous motor is controlled to be constant. If the parameters of a motor are given exactly, the speed regulation is quite small and the transient characteristics with high response and high starting torque are obtained. Furthermore, it is possible to operate a synchronous motor in the field-weakening range. Here, the principle of the control method and the performance characteristics of a dc brushless motor having no position sensors are discussed. The simulation and the experimental results of the tested machine show that the proposed method is very useful for practical applications.     

Selective control of the observables in the ensemble of quantum mechanical molecular systems

A new approach to synthesize algorithms for selective control of the observables in quantum mechanical systems in the presence of additional constraints during the whole period of control is proposed. Analytic results of achieving the goal of control under some additional assumptions were obtained. It was demonstrated that the error in achieving the goal of control is proportionate to the error in prescribing the initial state of system and the error in realizing the control action. Numerical results for the problem of selective control for energy of hydrogen molecules (H₂) with different isotopes are represented. The proposed algorithms are easy to design.