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.     

Apoptosis occurs in granulosa cells but not cumulus cells in the atretic antral follicles in pig ovaries

The porcine antral follicles, 3-6 mm in diameter, were dissected from the ovaries of mature pigs, and then granulosa and cumulus cells were isolated from each follicle. In atretic follicles, high activity of neutral Ca2+/Mg2+-dependent endonuclease and DNA ladder formation, estimated by electrophoresis, were noted in granulosa cells but not in cumulus cells. Extremely low activity of the endonuclease and no DNA ladder formation were observed in both types of cells obtained from healthy follicles. Moreover, apoptotic cells were observed histochemically among granulosa cells only. A good correlation (r = 0.987) between the endonuclease activity of granulosa cells and the progesterone/estradiol ratio of follicular fluid in each follicle was found. These results suggest that apoptosis occurs in granulosa cells but not cumulus cells in the atretic antral follicles in pigs.     

Evaluation of inelastic constitutive models under plasticity-creep interaction for steel at 600°C

Uniaxial tests to identify plasticity-creep interaction in steel at 600°C were carried out as the Benchmark Project by the Subcommittee on Inelastic Analysis and Life Prediction, JSMS. The purpose of this paper is to present recent experimental data and predictions of constitutive models obtained in the project. Ten types of constitutive models were utilized to compare analytical predictions to sixteen benchmark experiments which are grouped into four categories: (I) tensile and creep tests under monotonic loading, (II) mixed mode tests under plastic and creep loading, (III) ratcheting deformation tests under program loads, and (IV) cyclic deformation tests under the combination of different strain rates. The benchmark tests in Group IV are used to estimate the creep-fatigue life of steel; the results will be published in a separate paper.     

Biotransformation of three aromadendrane‐type sesquiterpenoids by Aspergillus wentii

BACKGROUND: The biotransformation of sesquiterpenoids, which are a large class of naturally occurring compounds, using microorganisms as a biocatalyst to produce useful novel organic compounds was investigated. The biotransformation of sesquiterpenoids, (+)‐aromadendrene ( 1 ), (−)‐alloaromadendrene ( 2 ) and (+)‐ledene ( 3 ) has been investigated using Aspergillus wentii as a biocatalyst. Results: Compound 1 was converted to (−)‐(10S,11S)‐10,13,14‐trihydroxyaromadendrane ( 4 ). Compound 2 was converted to (+)‐(1S,11S)‐1,13‐dihydroxyaromadendrene ( 5 ) and (−)‐5,11‐epoxycadin‐1(10)‐en‐14‐ol ( 6 ). Compound 3 was converted to compound 6 , (+)‐(10R,11S)‐10,13‐dihydroxyaromadendr‐1‐ene ( 7 ) and (+)‐(10S,11S)‐10,13‐dihydroxyaromadendr‐1‐ene ( 8 ). The structure of the metabolic products has been elucidated on the basis of their spectral data. CONCLUSION: Compound 1 gave only one product that was hydroxylated at C‐10, C‐13 and C‐14. By contrast, compounds 2 and 3 gave a number of products, one of which was common. The differences in oxidation of 1–3 are due to the configuration of the C‐1 position. Compounds 4–8 were new compounds. Copyright © 2008 Society of Chemical Industry     

Characterization of a cartilage-derived 66-kDa protein (RGD-CAP/beta ig-h3) that binds to collagen

Malignant human gliomas are the most common forms of primary tumors in the central nerve system. Due to their location and invasive nature, treatment so far has been mainly palliative. Thus, understanding the molecular detail of tumor transformation and progression is crucial for developing effective therapeutic strategy for this fetal tumor. Among the genetic alternations found in these tumors, p53 inactivation and PDGF/PDGFR activation represent the early events, and the loss of chromosome 10 and gene amplification and rearrangement of EGFR represent the late events. Studies with both glioma cell lines and primary tumor tissues have strongly suggested that TGF-alpha and EGFR function as an important autocrine loop in supporting proliferation of human glioma, especially in high grade glioma, since elevated TGF-alpha expression is also found in these high grade tumors. Furthermore, down regulation of the expression of TGF-alpha by antisense constructs has been shown to inhibit several types of human tumor cell growth including glioma. Other means of therapeutic approaches using this autocrine loop as a target also include the use of monoclonal antibodies and their cytotoxic conjugated. Considerable understanding of the EGFR-mediated signal transduction pathways has become available recently, which including GRB2/mSOS1 mediated MAP kinase activation; JAK/STATs pathway; PLC-gamma pathway. However, much work still needs to be done before a specific component of these pathways can be applied for effective control of tumor growth in the clinic.     

Pressureless sintering and characterization of cordierite/ZrO2 composites

Cordierite/ZrO₂ composites with 5 to 25 wt% ZrO₂ were fabricated by conventional powder mixing and pressureless sintering method. Their densification behavior, microstructure, mechanical and thermal properties were studied. By dispersing 25 wt% (9.57 vol%) ZrO₂, densified cordierite/ZrO₂ composite with a relative density of 98.5% was obtained at an optimum sintering condition of 1440 °C and 2 h. ZrO₂ particles were homogenously dispersed within matrix grains and at the grain boundaries. The intragranular particles were finer than 100 nm and the intergranular particles were coarser. Both fracture strength and toughness could be enhanced more than two times higher, compare to those of monolithic cordierite, by dispersing 25 wt% ZrO₂ into the cordierite matrix. The toughening mechanism in the present composites was mainly attributed to martensitic transformation due to ZrO₂ dispersion. Electronic Publication     

An analysis of slow phase velocity on congenital nystagmus-asymmetrical responses of optokinetic stimulation

Persistence of the hypoglossal artery is an unusual congenital abnormality of the carotid arterial system, and the simultaneous occurrence of atheromatous disease in the internal carotid artery and persistent hypoglossal artery is even more uncommon. Carotid surgery in this situation is challenging, and the surgeon must be aware of potential inherent pitfalls. A 74-year-old woman with asymptomatic stenosis of both internal carotid and hypoglossal arteries associated with occlusion of the contralateral internal carotid artery underwent successful revascularization. The anatomy of this unusual lesion and the surgical strategies, which included cranial nerve dissection and mandibular subluxation, are reviewed.     

Hot-carrier-injected oxide region in front and back interfaces inultra-thin (50 nm), fully depleted, deep-submicron NMOS andPMOSFET's/SIMOX and their hot-carrier immunity

The hot-carrier-injected oxide region in the front and back interfaces is systematically clarified for fully depleted surface-channel nMOSFET's and surface-channel and buried-channel pMOSFET's fabricated on an ultra-thin (50 nm)-film SIMOX wafer. Based on these results, the influence of these injected carriers on front-channel properties is investigated. NMOSFET degradation is shown to be caused by hot-carriers injected into the drain side of the front oxide and pMOSFET degradation by hot-electrons injected into the drain side of both the front oxide and the back oxide. Additionally, it is shown experimentally that these fully depleted devices with effective channel lengths between 0.1-0.2 μm have fairly high hot-carrier immunity, even for single-drain structures