A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Tumor Necrosis Factor α and Interleukin-1β Acutely Inhibit AgRP Neurons in the Arcuate Nucleus of the Hypothalamus

Obesity-associated low-grade inflammation favors weight gain, whereas systemic infection frequently leads to anorexia. Thus, inflammatory signals can either induce positive or negative energy balance. In this study, we used whole-cell patch-clamp to investigate the acute effects of three important proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin-6, and interleukin-1β (IL-1β) on the membrane excitability of agouti-related peptide (AgRP)- or proopiomelanocortin (POMC)-producing neurons. We found that both TNF-α and IL-1β acutely inhibited the activity of 35–42% of AgRP-producing neurons, whereas very few POMC neurons were depolarized by TNF-α. Interleukin-6 induced no acute changes in the activity of AgRP or POMC neurons. Our findings indicate that the effect of TNF-α and IL-1β, especially on the activity of AgRP-producing neurons, may contribute to inflammation-induced anorexia observed during acute inflammatory conditions.     

Characterization of (1'R,4S,4aR,7S,7aR)-dihydronepetalactol as a semiochemical for lacewings,including Chrysopa spp. and Peyerimhoffina gracilis

The enantiomerically pure diastereoisomers (1R,4S,4aR,7S,7aR)- (1) and (1R,4R,4aR,7S,7aR)-dihydronepetalactol (2) were synthesized diastereoselectively from a renewable resource, (4aS,7S,7aR)-nepetalactone (3), isolated as the main constituent of the essential oil of the catmint plant Nepeta cataria. The stereochemistry of the compounds was determined by NMR spectroscopy and X-ray crystallography, and the compounds were identified, respectively, as neomatatabiol and isoneomatatabiol, natural products from Actinidia polygama, for which the lactol stereochemistry was previously incompletely defined. Compound 1 was found to catch significant numbers of three species of lacewing in the field: in Korea, Chrysopa cognata, and in the United Kingdom, Nineta vittata and most notably Peyerimhoffina gracilis. All species caught in significant numbers were found more frequently in traps releasing 1 than 2, while more C. cognata, C. formosa, and C. phyllochroma were found in traps releasing (1R,4aS,7S,7aR)-nepetalactol (4). The catch of P. gracilis with 1 is of particular interest as this lacewing has only recently been recorded in the United Kingdom. Where sexed, the lacewings of all species trapped were found to be male, implying a possible pheromonal role for these or structurally related compounds.     

K- and Cs-FeV/Al2O3soot combustion catalysts for diesel exhaust treatment

Alkali-doped FeV oxide catalysts supported on -alumina were prepared and their catalytic activity in the combustion of diesel soot is reported. The catalysts were characterized by XRD, TPR and SEM–EDX analysis. The influence of the nature of the alkali metal (K and Cs), the temperature of treatment of the catalysts and the stability to sulfur poisoning have been investigated.

Catalysts doped with Cs were the most active and stable also after several combustion cycles and in the presence of sulfur in the stream. The activity measurements and microstructural results suggest that the combustion of soot is favored on catalysts where amorphous phases and/or mixed Fe---V---O phases, ensuring an intimate contact between iron and vanadium, are present. A reaction mechanism involving the participation of the redox couple Fe(II)–Fe(III) in the activation of the vanadium combustion sites, is proposed.     

Graft copolymers of lignin from straw with 1‐ethenylbenzene: Synthesis and characterization

The synthesis of copolymers between lignin from steam‐exploded straw and 1‐ethenylbenzene is described. Beforehand, lignin from steam‐exploded straw was fully characterized by using elemental analysis, ultraviolet spectroscopy, gel permeation chromatography (GPC), Fourier transform infrared (FTIR), and both ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy. Using a previously described procedure utilizing calcium chloride and hydrogen peroxide as reagents the synthesis of the copolymers was performed. FTIR of the copolymers showed the presence of both lignin and polystyrene. GPC analysis showed the presence of a fraction with high molecular weights. These results were confirmed from both viscosity data and differential calorimetry. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 79: 72–79, 2001     

Development of phase morphology in immiscible poly(styrene‐co‐acrylonitrile)/poly(butylene terephthalate) nanoblends: Mechanical properties and effect of the compatibilizer

Nanoblends were obtained from poly(styrene‐co‐acrylonitrile) (SAN) as a matrix, and poly(butylene terephthalate) (PBT) was used as a nanodispersed phase. Compatibilized SAN/PBT blends were prepared by reactive extrusion, and the PBT concentrations ranged between 3 and 30 wt %. Nanoblends were obtained for up to 10 wt % PBT concentrations in the presence of the compatibilizer. With 20 and 30 wt % PBT, the extruded material presented a droplet dispersed phase. The same blends were subjected to an injection‐molding process, which provided a cocontinuous phase morphology. The influence of the concentration of the dispersed phase and the type of morphology on the mechanical behavior of tensile test, flexural test, impact test, and deflection temperature of the blends was analyzed. The results show an important reduction in the particle size of the dispersed phase, which was due to the presence of the compatibilizer. Furthermore, the type of morphology and an excess of compatibilizer exerted a stronger influence on the mechanical properties than the particle size of the dispersed phase. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45030.     

The state of Tin on Pt–Sn/Nb2O5 catalysts

The effect of tin addition on niobia supported catalysts was studied and compared to the properties of alumina supported bimetallic Pt–Sn catalysts. The catalyst surfaces were probed by methylcyclopentane conversion, showing that both the presence of Sn and the reduction of the support caused a decrease in hydrogenolysis activity, favoring the ring enlargement reaction. The thermodynamics of reduction of these systems, evaluated by following the reduction step (temperature programmed reduction — TPR) with a differential scanning calorimeter (DSC), and irreversible H₂ and CO uptakes, allowed to conclude that a Pt–Sn alloy is formed on niobia supported catalysts.     

Cis–trans isomerization of olefinic alcohols promoted by Rh(I) complexes

Homogeneous hydrogenation and isomerization reaction of cis-2-butene-1,4-diol has been investigated in ethanol by using tris(triphenylphosphine)chlororhodium(I), RhCl(PPh₃)₃, and triethylamine at 303 K and 0.01–0.1 MPa partial hydrogen pressure. Under reduced H₂ pressure, the geometric isomerization reaction occurs, to a high extent, leading to trans-2-butene-1,4-diol up to 93% selectivity at 90% conversion of the cis analogous. Effects of H₂ partial pressure as well as triethylamine, added phosphine and olefin concentrations on the rate of reaction and on the products distribution were also investigated. The results obtained can be interpreted on the basis of a proposed mechanism in which RhH(PPh₃)₃ is the active species. The high selectivity towards cis-trans isomerization of cis-2-butene-1,4-diol is attributed to steric factors of the Rh(I) coordinated triphenylphosphine groups.     

Oxidation of Benzene Catalyzed by 2,2′-Bipyridine and 1,10-Phenantroline Cu(II) Complexes

The use of mononuclear Cu(II) 2,2′-bipyridine and 1,10-phenantroline complexes as catalysts in the oxidation of benzene, using hydrogen peroxide and tert-butyl hydroperoxide as oxidant in CH₃CN/H₂O solution is presented. The reactions were carried out at 25 and at 50 °C. The complexes [Cu(bipy)₃]Cl₂ · 6H₂O (1), [Cu(bipy)₂Cl]Cl · 5H₂O (2), [Cu(bipy)Cl₂] (3), [Cu(phen)₃]Cl₂ · 7H₂O (4), [Cu(phen)₂Cl]Cl · 5H₂O (5), [Cu(phen)Cl₂] (6) were able to oxidize benzene into phenol, hydroquinone and p-benzoquinone. Highest conversion (22%) was obtained using [Cu(Phen)Cl₂] (6) as catalyst.     

Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation

Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using Human MicroRNA Card A followed by real-time PCR validations. In addition, to assess the discriminative power of selected miRNAs, we implemented a machine learning analysis. MiRNA profiling and validations revealed that miR-140-3p, 150-5p, 210-3p, 451a, and 487a-3p were significantly upregulated in MVP, while miR-223-3p, 323a-3p, 340-5p, and 361-5p were significantly downregulated in MVP compared to CTRL (p ≤ 0.01). Functional analysis identified several biological processes possible linked to MVP. In addition, machine learning analysis correctly classified MVP patients from CTRL with high accuracy (0.93) and an area under the receiving operator characteristic curve (AUC) of 0.97. To the best of our knowledge, this is the first study performed on human plasma, showing a strong association between miRNAs and MVP. Thus, a circulating molecular signature could be used as a first-line, fast, and cheap screening tool for MVP identification.