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.     

Mass transfer in polycrystalline ytterbium monosilicate under oxygen potential gradients at high temperatures

Mass transfer in polycrystalline Yb₂SiO₅ wafers with precise composition control was evaluated and analyzed by oxygen permeation experiments at high temperatures using an oxygen tracer. Oxygen permeation proceeded due to mutual grain boundary diffusion of oxide ions and Yb ions without synergistic effects such as acceleration or suppression. The oxygen shielding properties of Yb₂SiO₅ were compared with those of the other line compounds such as Yb₂Si₂O₇ and Al₂O₃ based on the determined mass transfer parameters. It was found that the more preferentially an oxide ion diffuses in the grain boundary compared to the interior of the grain, the greater the effect of suppressing the movement of the oxide ion by applying an oxygen potential gradient becomes.     

Direct Observation of Pure Cu and Cu-Ag Anode Passivation in H2SO4-CuSO4 Aqueous Solution by Channel Flow Double Electrode and Optical Microscopy

Metallurgical and Materials Transactions B - The dissolution and passivation of pure Cu and Cu-5 wt pct Ag anodes in H2SO4-CuSO4 electrolyte were investigated by a direct...     

Carbon radicals generated by solid polymers: Electron spin resonance spectroscopy for detection of species in water

Radicals generated in plastic medical devices (solid phase) by γ-rays or electron-beam irradiation during sterilization are known to cause oxidation of protein drugs, resulting in a loss or reduction in drug efficacy. The generation of radical species in water by the radical species in solid polymers has not been proved. Using electron spin resonance (ESR) spectroscopy, we confirm the generation of new radicals in water by γ-ray irradiated cyclic olefin polymers (COP). ESR measurements are obtained using 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) as a spin probe and 5-(2,2-dimethyl-1,3-propoxycyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO) as a spin trap, in which the irradiated COP was immersed. The ESR signals indicate the TEMPOL radicals decline over time, suggesting the generation of new radicals. Conversely, the characteristic ESR signals of the adduct formed by the reaction between CYPMPO and the hydroxyl radical are observed. Thus, hydroxyl radicals are generated because of the migration of the radicals from COP to water. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48604.     

Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine

The histone methyltransferase SET7/9 methylates not only histone but also non‐histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2‐hydroxy group showed the most potent activity. On the other hand, a 3‐hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2‐hydroxycyproheptadine. These results are expected to be helpful for further structure‐based development of SET7/9 inhibitors.     

Dietary exposure to acrylamide in a group of Japanese adults based on 24-hour duplicate diet samples

Acrylamide is a probable human carcinogen and known human neurotoxin that can be generated in food through heating. Using a mathematical modelling approach, our previous study estimated long-term average dietary exposure to acrylamide in the Japanese people; however, the validity of these estimates remained unknown. Here, we aimed to obtain a more accurate estimate of acrylamide exposure that would reflect the usual practice of heat processing and consumption of foods in the population. We collected duplicate diet samples and dietary records during 24 h from a group of Japanese adults. A total of 110 duplicate diet samples were analysed for acrylamide by LC-MS/MS. Data from individual dietary records were used to examine the association between dietary acrylamide exposure and consumption of selected food groups (e.g., coffee, tea, confectioneries, and vegetables prepared at high temperature [deep-frying, stir-frying, sautéing, and baking]). Of the 110 homogenised diet samples, 108 contained detectable levels of acrylamide. Dietary exposure to acrylamide ranged from 8 to 1582 ng/kg body weight (bw)/day, with the mean value of 215 ng/kg-bw/day and median value of 143 ng/kg-bw/day. This mean value was higher than the value we previously estimated for Japanese adults using a mathematical approach. Multiple linear regression analysis showed log dietary acrylamide exposure was significantly associated with consumption of coffee and vegetables prepared at high temperature during 24-hr of sampling (adj. R² = 0.250, p < 0.001). We revealed significant difference in dietary acrylamide exposure between participants who had coffee and vegetables prepared at high temperature (median, 169 ng/kg-bw/day; range, 35–1224 ng/kg-bw/day, n = 42) and those who had none of them (median, 75 ng/kg-bw/day; range, 8–311 ng/kg-bw/day, n = 15) (Steel-Dwass test, p < 0.05).     

Rapid Reconstitution of Biosynthetic Machinery for Fungal Metabolites in Aspergillus oryzae: Total Biosynthesis of Aflatrem

Reconstitution of the biosynthetic machinery for fungal secondary metabolites in Aspergillus oryzae provides an opportunity both for stepwise determination of the biosynthetic pathways and the total biosynthesis of fungal natural products. However, to maximize the utility of the reconstitution system, a simple and rapid strategy for the introduction of heterologous genes into A. oryzae is required. In this study, we demonstrated an effective method for introducing multiple genes involved in the biosynthesis of fungal metabolites by using the expression vectors pUARA2 and pUSA2, each of which contains two cloning sites. The successful introduction of all the aflatrem biosynthetic genes (seven genes in total) after two rounds of transformation enabled the total biosynthesis of aflatrem. This rapid reconstitution strategy will facilitate the functional analysis of the biosynthetic machinery of fungal metabolites.     

Precipitation recovery of boron from wastewater by hydrothermal mineralization

It is well known that boric acid exhibits various toxic effects on plant, animal and human beings even at very low concentrations. Thus, the development of boron-removal technique from wastewater has been intensively investigated. In this study, a new hydrothermal treatment technique was developed to recover boron as recyclable precipitate Ca(2)B(2)O(5).H(2)O from aqueous solutions. As a result, it was found that the hydrothermal treatment using calcium hydroxide as a mineralizer converted boron in the aqueous media effectively into calcium borate, Ca(2)B(2)O(5).H(2)O. In the optimal hydrothermal condition, more than 99% of boron was collected from the synthetic wastewater of 500 ppm. Thus, the present hydrothermal treatment in the presence of calcium hydroxide is recommended as one of the effective techniques to recover boron from aqueous media.