Preparation and a novel rearrangement reaction of 1, 2, 3, 4-tetrahydro-9-hydroxy-β-carboline, and their applications for the total synthesis of (±)-coerulescine

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学部Novel 9-hydroxy-β-carboline derivatives were produced for the first time. A novel rearrangement reaction of 1, 2, 3, 4-tetrahydro-9-hydroxy-β-carbolines was discovered to give 3, 3-disubstituted oxindoles, which was successfully applied to the total synthesis of (±)-coerulescine

Expression of nephronectin is inhibited by oncostatin M via both JAK/STAT and MAPK pathways

AbstractNephronectin (Npnt), also called POEM, is an extracellular matrix protein considered to play critical roles as an adhesion molecule in the development and functions of various tissues, such as the kidneys, liver, and bones. In the present study, we examined the molecular mechanism of Npnt gene expression and found that oncostatin M (OSM) strongly inhibited Npnt mRNA expression in MC3T3-E1 cells from a mouse osteoblastic cell line. OSM also induced a decrease in Npnt expression in both time- and dose-dependent manners via both the JAK/STAT and MAPK pathways. In addition, OSM-induced inhibition of osteoblast differentiation was recovered by over-expression of Npnt. These results suggest that OSM inhibits Npnt expression via the JAK/STAT and MAPK pathways, while down-regulation of Npnt by OSM influences inhibition of osteoblast differentiation

Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity

Metformin is the first-line drug in the treatment of type 2 diabetes. In addition to its hypoglycemic effect, metformin has an anti-inflammatory function, but the precise mechanism promoting this activity remains unclear. High mobility group box 1 (HMGB1) is an alarmin that is released from necrotic cells and induces inflammatory responses by its cytokine-like activity and is, therefore, a target of anti-inflammatory therapies. Here we identified HMGB1 as a novel metformin-binding protein by affinity purification using a biotinylated metformin analogue. Metformin directly bound to the C-terminal acidic tail of HMGB1. Both in vitro and in vivo, metformin inhibited inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in which HMGB1 released from injured cells exacerbates the initial injury, metformin effectively reduced liver injury and had no additional inhibitory effects when the extracellular HMGB1 was blocked by anti-HMGB1-neutralizing antibody. In summary, we report for the first time that metformin suppresses inflammation by inhibiting the extracellular activity of HMGB1. Because HMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation

Current status of space gravitational wave antenna DECIGO and B-DECIGO

Deci-hertz Interferometer Gravitational Wave Observatory (DECIGO) is the future Japanese space mission with a frequency band of 0.1 Hz to 10 Hz. DECIGO aims at the detection of primordial gravitational waves, which could be produced during the inflationary period right after the birth of the universe. There are many other scientific objectives of DECIGO, including the direct measurement of the acceleration of the expansion of the universe, and reliable and accurate predictions of the timing and locations of neutron star/black hole binary coalescences. DECIGO consists of four clusters of observatories placed in the heliocentric orbit. Each cluster consists of three spacecraft, which form three Fabry-Perot Michelson interferometers with an arm length of 1,000 km. Three clusters of DECIGO will be placed far from each other, and the fourth cluster will be placed in the same position as one of the three clusters to obtain the correlation signals for the detection of the primordial gravitational waves. We plan to launch B-DECIGO, which is a scientific pathfinder of DECIGO, before DECIGO in the 2030s to demonstrate the technologies required for DECIGO, as well as to obtain fruitful scientific results to further expand the multi-messenger astronomy.Comment: 10 pages, 3 figure

Current status of space gravitational wave antenna DECIGO and B-DECIGO

The Deci-hertz Interferometer Gravitational Wave Observatory (DECIGO) is a future Japanese space mission with a frequency band of 0.1 Hz to 10 Hz. DECIGO aims at the detection of primordial gravitational waves, which could have been produced during the inflationary period right after the birth of the Universe. There are many other scientific objectives of DECIGO, including the direct measurement of the acceleration of the expansion of the Universe, and reliable and accurate predictions of the timing and locations of neutron star/black hole binary coalescences. DECIGO consists of four clusters of observatories placed in heliocentric orbit. Each cluster consists of three spacecraft, which form three Fabry–Pérot Michelson interferometers with an arm length of 1000 km. Three DECIGO clusters will be placed far from each other, and the fourth will be placed in the same position as one of the other three to obtain correlation signals for the detection of primordial gravitational waves. We plan to launch B-DECIGO, which is a scientific pathfinder for DECIGO, before DECIGO in the 2030s to demonstrate the technologies required for DECIGO, as well as to obtain fruitful scientific results to further expand multi-messenger astronomy

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Differentiation of acute fatty liver of pregnancy from syndrome of hemolysis, elevated liver enzymes and low platelet counts

As proposed criteria (Swansea criteria) for the diagnosis of acute fatty liver of pregnancy (AFLP) do not include antithrombin (AT) activity, diagnosis of AFLP may be delayed. The aim of this review is to underscore problems in the differential diagnosis of AFLP and the syndrome of hemolysis, elevated liver enzymes and low platelet counts (HELLP syndrome) and to facilitate prompt diagnosis of AFLP. Published works dealing with liver dysfunction in pregnancy, HELLP syndrome and AFLP were reviewed. AFLP and HELLP syndrome shared common clinical, laboratory, histological and genetic features, and differential diagnosis between them was often difficult. However, HELLP syndrome was likely to occur in patients with hypertension, but AFLP occurred often in the absence of hypertension. In addition, AFLP was exclusively associated with pregnancy-induced antithrombin deficiency (PIATD). Approximately 50% of patients with AFLP did not have thrombocytopenia at presentation. As the Swansea criteria for AFLP did not include PIATD, diagnosis of AFLP was delayed until manifestation of life-threatening complications; 60% of women were admitted to intensive care and 15% to a specialist liver unit. In conclusion, incorporation of AT activity of less than 65% into the diagnostic criteria for AFLP may facilitate suspicion and prompt diagnosis of AFLP, decrease uncertainty regarding the diagnosis of AFLP, and contribute to better investigation and understanding of the process leading to the development of liver dysfunction

Clinical features of isolated gestational proteinuria progressing to pre-eclampsia: retrospective observational study

Objectives Some women with isolated gestational proteinuria (IGP) later develop hypertension and are diagnosed with pre-eclampsia (PE). This study was performed to determine whether clinical features of such proteinuria preceding PE (P-PE) differ from those of other PE (O-PE). Design Retrospective observational study after approval of the institutional review board of ethics. Setting A single university hospital. Proteinuria was defined as a protein-to-creatinine ratio (mg/mg; P/Cr) of 0.27 in the spot urine specimen. IGP was defined as proteinuria in the absence of hypertension. P-PE was defined as PE in which proteinuria preceded hypertension by more than 2days. Participants All of 10 and 18 consecutive women with P-PE and O-PE, respectively, who gave birth between January 2008 and August 2013. Results Proteinuria appeared earlier (at 30.23.0 vs 35.3 +/- 4.3weeks, p=0.001), the P/Cr level was greater at birth (7.28 +/- 2.14 vs 3.19 +/- 2.49, p<0.001), net maternal weight gain during the last antenatal 1week was greater (3.1 +/- 1.8 vs 1.3 +/- 1.7kg, p=0.023) and length of pregnancy was shorter (32.5 +/- 1.9 vs 36.1 +/- 3.6weeks, p=0.001) in women with P-PE than in O-PE. The duration of IGP was 10.0 +/- 5.9days (range 3-20), and the time interval until delivery after diagnosis of PE was 6.1 +/- 8.2days (range 0-23) in 10 women with P-PE. The P/Cr levels at birth were significantly inversely correlated with the antenatal lowest antithrombin activity and fibrinogen levels among the 28 women with PE. Conclusions Women with P-PE were likely to exhibit greater proteinuria in the urine, greater water retention in the interstitial space and more enhanced coagulation-fibrinolysis, thus suggesting that they may constitute a more severe form of PE than women with O-PE do