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.     

Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis

T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cirrhosis (PBC). In the previous study, we identified the immunodominant T-cell epitope on the E2 component of pyruvate dehydrogenase complex (PDC-E2) in patients with PBC who have HLA-DRB4*0101. In this report, we revealed that the frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared with healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4*01 (DR53) by using HLA-DR-transfected L cells. These results together with the evidence that the immunodominant B-cell epitope overlaps with the human T-cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC at least in patients who have HLA-DR53. Therefore, we analyzed the T-cell receptor (TCR) Vbeta sequence of the five different T-cell clones and the three T-cell clones derived from three patients with PBC and healthy subjects, respectively, which are reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53. The Vbeta- and the Jbeta-gene usages were diverse among the T-cell clones (Vbeta11-Jbeta1.4, Vbeta8-Jbeta1.2, Vbeta12-Jbeta2.1, Vbeta10-Jbeta1.5, and Vbeta20-Jbeta2.1) in patients with PBC. By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T-cell clones. Moreover, RGXG motif was found in three clones generated from two patients. In healthy subjects, the Vbeta- and the Jbeta-gene usages were also diverse, and GXG and RGXG motif were found. These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy would be possible using these motifs.     

Effects of cysteinyl-leukotriene receptor antagonist, thromboxane A2 receptor antagonist, and thromboxane A2 synthetase inhibitor on antigen-induced bronchoconstriction in patients with asthma

BACKGROUND: Leukotriene (LT) and thromboxane A2 (TXA2) receptor antagonists have been used in the treatment of asthma. OBJECTIVES: We examined the effects of an LT receptor antagonist, TXA2 receptor antagonist, and TXA2 synthetase inhibitor on bronchoprovocation test (BPT) in patients with mild-to-moderate atopic asthma. METHODS: BPT was performed four times in each of six asthmatics. Development of the immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) was confirmed on the first BPT (BPT1). After a 7-day washout period, an LT receptor antagonist (pranlukast, 450 mg/d), TXA2 receptor antagonist (seratrodast, 80 mg/d), or TXA2 synthetase inhibitor (ozagrel, 800 mg/d) was administered orally over 7 days at random using a cross-over method (BPT2-4). Blood levels of LTB4, LTC4, LTD4, 11-dehydrothromboxane B2, eosinophil cationic protein, and histamine were measured at reaction phases of pre-BPT, IAR, and LAR. RESULTS: Administration of pranlukast suppressed IAR by 80.5% (p < 0.0001) and LAR by 54.6% (p = 0.0391). Ozagrel significantly suppressed IAR by 39.5% (p = 0.0413), but the fall in FEV1 was >20% (21.56+/-4.173%). Seratrodast did not suppress IAR or LAR. Blood levels of chemical mediators did not correlate with the suppressive effects of the tested drugs. CONCLUSIONS: The LT receptor antagonist was considered to be the most effective. LT might play a more important role in the pathogenesis of asthma than TXA2. Our data showed that measurement of blood levels of chemical mediators is not useful in identifying the pathogenic mechanisms of asthma.     

Adsorption of urea,creatinine, and uric acid from three solution types using spherical activated carbon and its recyclability

In this paper, we propose that the urinary toxins from the wastewater be adsorbed on an adsorbent such as spherical activated carbon and the latter be regenerated by subjecting it to high temperatures to recycle activated carbon and also to recycle the water used in dialysis. We studied the adsorption of artificial waste dialysate, which is a mixed solution of urea, creatinine, and uric acid, and the separate solutions for each of these and found that their extents of adsorption onto the spherical activated carbon material were nearly identical. The amount of adsorption was approximately 1.4 mg·g^-1 for urea, 18 mg·g^-1 for creatinine, and 20 mg·g^-1 for uric acid. The urea, creatinine, and uric acid adsorbed onto the spherical activated carbon decomposed on heat treatment at 500℃, and the adsorption capacity of the spherical activated carbon was regenerated. Our study successfully demonstrated that the spherical activated carbon can be recycled in the waste dialysate treatment process.     

Effect of platelet-activating factor on lipoprotein lipase and blood lipids

We investigated the effect of platelet-activating factor (PAF) and of the PAF specific antagonist CV-6209 on plasma lipid metabolism, and particularly on post-heparin plasma lipolytic activity in male Wistar rats. Lipoprotein lipase (LPL) activity was enhanced by intravenous injection of PAF before intravenous injection of heparin when the PAF dose was low (0.2 μg/kg). PAF activated hepatic triacylglycerol lipase (HTGL) activity dose-dependently. Plasma triacylglycerols (TG) significantly decreased with the activation of LPL and/or HTGL. Plasma total cholesterol (TC) and phospholipid (PL) levels decreased at a low dose of PAF (0.2 μg/kg), but increased when higher doses were used. The PAF antagonist CV-6209 partially reversed the PAF induced effects on HTGL, TC and PL. Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, Tokyo, Japan, May 1989.     

Influence of ammonium salt on electrowinning of copper from ammoniacal alkaline solutions

In order to develop an energy-saving copper recycling process from wastes, electrochemical measurements were conducted in ammoniacal alkaline solutions containing Cu(I) ions and an ammonium salt of sulfate, chloride or nitrate. The results of each system were then compared. The polarization measurements suggested that the voltage required for the electrode process is lower in the chloride and nitrate systems than that in the sulfate system. The cathode current efficiency during the copper electrodeposition varied from 39 to 97% and increased with current density in the chloride and sulfate systems. In the nitrate system, the lowest cathode current efficiency of 30% was observed because of nitrate ion reduction. Based on these results, the power consumption required for the electrowinning stage of the copper recycling process was calculated. Among these three systems, the chloride system showed the lowest power consumption of 500 kWh t⁻¹ at the current density of 200 A m⁻², which is about 25% of the conventional copper electrowinning process from a copper sulfate-sulfuric acid solution.     

Conformational studies of poly(N-methyl-l-alanine) by n.m.r. spectroscopy

Nuclear magnetic resonance (n.m.r.) and circular dichroism of $\text{poly}\text{(N-}\text{methyl-}\text{l}\text{-alanine}\text{)}$ in methylene $\text{chloride}\text{-d}{}_2\text{dichloroacetic acid}$ were investigated. In methylene chloride-d₂$\text{poly}\text{(N-}\text{methyl-}\text{l}\text{-alanine}\text{)}$ was found to consist of nearly all-trans amide bonds and assume a stable secondary structure. Trace amounts of cis amide bonds were also present. The addition of dichloroacetic acid destroyed the secondary structure and induced a drastic change of the n.m.r. spectrum, which was similar to that observed with the monomeric amide, $\text{N-}\text{acetyl}\text{-N-}\text{methyl-}\text{l}\text{-alanine}$ dimethylamide. In comparison of the polymer with the monomeric amide, it was concluded that the transition of $\text{poly}\text{(N-}\text{methyl-}\text{l}\text{-alanine}\text{)}$ was caused by the isomerization of amide bonds. The complex n.m.r. spectrum was interpreted in terms of the distribution along the polymer chain of various non-planar amide links as well as planar cis and trans amide links. The difference of the mechanism of conformational transition between poly(amino acid) and poly(imino acid) is also discussed.     

Swarm robotic network using Lévy flight in target detection problem

One approach in swarm robotics is homogeneous system which is embedded with sensing, computing, mobile and communication components. In this study, a target detection problem, which is one of navigation problems, was employed. Once a robot detects a target, robots immediately communicate with a base station via intermediate relay robots due to the multi-hop transmission of wireless communication. Therefore, this control task is completed with connectivity of the network. In a target detection problem, we must improve the performance of exploration as well as connectivity of the network. This study investigates the performances of the two types of random walk algorithm in navigation while loosely ensuring connectivity of the robotic network based on our previous study.     

Emergency response to the nuclear accident at the Fukushima Daiichi Nuclear Power Plants using mobile rescue robots

On March 11, 2011, a massive earthquake (magnitude 9.0) and accompanying tsunami hit the Tohoku region of eastern Japan. Since then, the Fukushima Daiichi Nuclear Power Plants have been facing a crisis due to the loss of all power that resulted from the meltdown accidents. Three buildings housing nuclear reactors were seriously damaged from hydrogen explosions, and, in one building, the nuclear reactions became out of control. It was too dangerous for humans to enter the buildings to inspect the damage because radioactive materials were also being released. In response to this crisis, it was decided that mobile rescue robots would be used to carry out surveillance missions. The mobile rescue robots needed could not be delivered to the Tokyo Electric Power Company (TEPCO) until various technical issues were resolved. Those issues involved hardware reliability, communication functions, and the ability of the robots' electronic components to withstand radiation. Additional sensors and functionality that would enable the robots to respond effectively to the crisis were also needed. Available robots were therefore retrofitted for the disaster reponse missions. First, the radiation tolerance of the electronic componenets was checked by means of gamma ray irradiation tests, which were conducted using the facilities of the Japan Atomic Energy Agency (JAEA). The commercial electronic devices used in the original robot systems operated long enough (more than 100 h at a 10% safety margin) in the assumed environment (100 mGy/h). Next, the usability of wireless communication in the target environment was assessed. Such tests were not possible in the target environment itself, so they were performed at the Hamaoka Daiichi Nuclear Power Plants, which are similar to the target environment. As previously predicted, the test results indicated that robust wireless communication would not be possible in the reactor buildings. It was therefore determined that a wired communication device would need to be installed. After TEPCO's official urgent mission proposal was received, the team mounted additional devices to facilitate the installation of a water gauge in the basement of the reactor buildings to determine flooding levels. While these preparations were taking place, prospective robot operators from TEPCO trained in a laboratory environment. Finally, one of the robots was delivered to the Fukushima Daiichi Nuclear Power Plants on June 20, 2011, where it performed a number of important missions inside the buildings. In this paper, the requirements for the exploration mission in the Fukushima Daiichi Nuclear Power Plants are presented, the implementation is discussed, and the results of the mission are reported.