Notch Signaling Regulation in Autoinflammatory Diseases

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.     

Design,Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents

Fenretinide (4-HPR) is a synthetic derivative of all-trans-retinoic acid (ATRA) characterised by improved therapeutic properties and toxicological profile relative to ATRA. 4-HPR has been mostly investigated as an anti-cancer agent, but recent studies showed its promising therapeutic potential for preventing metabolic syndrome. Several biological targets are involved in 4-HPR's activity, leading to the potential use of this molecule for treating different pathologies. However, although 4-HPR displays quite well-understood multitarget promiscuity with regards to pharmacology, interpreting its precise physiological role remains challenging. In addition, despite promising results in vitro, the clinical efficacy of 4-HPR as a chemotherapeutic agent has not been satisfactory so far. Herein, we describe the preparation of a library of 4-HPR analogues, followed by the biological evaluation of their anti-cancer and anti-obesity/diabetic properties. The click-type analogue 3 b showed good capacity to reduce the amount of lipid accumulation in 3T3-L1 adipocytes during differentiation. Furthermore, it showed an IC₅₀ of 0.53±0.8 μM in cell viability tests on breast cancer cell line MCF-7, together with a good selectivity (SI=121) over noncancerous HEK293 cells. Thus, 3 b was selected as a potential PET tracer to study retinoids in vivo, and the radiosynthesis of [¹⁸F] 3b was successfully developed. Unfortunately, the stability of [¹⁸F] 3b turned out to be insufficient to pursue imaging studies.     

Frontal cationic curing of epoxy resins in the presence of defoaming or expanding compounds

Thermal frontal polymerization was carried out with trimethylol propane triglycidyl ether using two different BF₃‐amine complexes, B‐950 and B‐110 from Leepoxy, as initiators for cationic polymerization. The amounts of filler (kaolin or fumed silica), defoaming, or expansion agents were varied to study how the compositions affected the front velocity, expansion, and flexural modulus of the resulting epoxy resins. The polymer produced with B‐950 initiator showed higher modulus than the polymers produced with B‐110. Moreover, fumed silica created stronger materials than kaolin. The presence of BYK as a defoamer or an expansion agent such as the Expancel #80 was also able to affect significantly the mechanical properties. differential scanning calorimetry studies indicated that the conversion was complete and that kaolin and silica increased the rate of reaction. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40339.     

Performance Evaluation of Two High‐Shear Impellers in an Unbaffled Stirred Tank

High‐shear impellers (HSIs) are mixers used in industrial stirred tanks to incorporate powders into liquids and break down particle agglomerates. A detailed numerical study of two commercial ring‐style HSIs of laboratory scale was carried out and their performance was compared with the Rushton turbine (RT). It was found that power and pumping numbers or their ratio cannot be simply connected for properly selecting an impeller in applications where highly localized viscous dissipation is desirable. The ratio of the average viscous dissipation in the impeller swept volume to the mean in the entire volume at two constant values of power input turned out to be lower for HSIs compared to that evaluated for RT. However, at higher power input, the dimensionless average viscous dissipation in the blade swept volume was found to be similar for the HSI of two rings and the RT, corroborating the high local viscous dissipation of this HSI when operated at higher speeds.     

Extensive N‐methylation of chitosan: evaluating the effects of the reaction conditions by using response surface methodology

The effects of reaction time, concentration of aqueous sodium hydroxide and molar ratio iodomethane/chitosan on the yield of the reaction of chitosan with iodomethane in N‐methyl‐2‐pyrrolidone (NMP) at 25.0 ± 0.1 °C, as well as on the characteristics of the resulting N,N,N‐trimethylchitosan (TMCh), were evaluated by using full‐factorial 2³ design analysis and response surface methodology. This study also aimed to determine the reaction conditions allowing the production of water‐soluble TMCh presenting a high average degree of quaternization and intrinsic viscosity at high reaction yield. ¹H NMR spectroscopy was employed for structural characterization, including the determination of average degrees of acetylation () and quaternization (), while capillary viscometry was used to determine intrinsic viscosity [η]. The results show that when the extensive N‐methylation is carried out for 24 h in NMP/15% NaOH (w/v) employing a lower excess of iodomethane (CH₃I/Ch = 9), water‐soluble highly substituted ( = 46.0%) TMCh ([η] = 213.0 mL g^?1) can be produced in high yield (81.8%). The highly significant mathematical models resulting from this study describe the dependence of the experimental responses on the reaction conditions and allow the characteristics and properties of the resulting TMCh to be defined by properly choosing the reaction conditions. © 2015 Society of Chemical Industry     

Scanning microelectrochemical characterization of the anti-corrosion performance of inhibitor films formed by 2-mercaptobenzimidazole on copper

The aim of this work is to explore the applicability of the scanning electrochemical microscope (SECM) to characterize the inhibiting effect of 2-mercaptobenzimidazole against the corrosion of copper. SECM was operated in the feedback mode by using ferrocene-methanol as redox mediator, and the sample was left unbiased at all times. The kinetic changes in the corrosion processes were monitored over time from the Z-approach curves. Furthermore, inhibitor-modified copper samples presenting various surface finishes were imaged by SECM and the scanning vibrating electrode technique (SVET), allowing changes both in the surface activity of metal-inhibitor films and in the extent of corrosion attack to be spatially resolved. Differences in the local electrochemical activity between inhibitor-free and inhibitor-covered areas of the sample were successfully monitored.     

The Proteomics Big Challenge for Biomarkers and New Drug-Targets Discovery

In the modern process of drug discovery, clinical, functional and chemical proteomics can converge and integrate synergies. Functional proteomics explores and elucidates the components of pathways and their interactions which, when deregulated, lead to a disease condition. This knowledge allows the design of strategies to target multiple pathways with combinations of pathway-specific drugs, which might increase chances of success and reduce the occurrence of drug resistance. Chemical proteomics, by analyzing the drug interactome, strongly contributes to accelerate the process of new druggable targets discovery. In the research area of clinical proteomics, proteome and peptidome mass spectrometry-profiling of human bodily fluid (plasma, serum, urine and so on), as well as of tissue and of cells, represents a promising tool for novel biomarker and eventually new druggable targets discovery. In the present review we provide a survey of current strategies of functional, chemical and clinical proteomics. Major issues will be presented for proteomic technologies used for the discovery of biomarkers for early disease diagnosis and identification of new drug targets.     

Synthesis and characterization of nanocomposites of thermoplastic polyurethane with both graphene and graphene nanoribbon fillers

Thermoplastic polyurethane (TPU) nanocomposites containing graphene and graphene nanoribbons were obtained by polymerizing 1,4-butanediol with two diisocyanates (namely, 1,6-hexane diisocyanate or isophorone diisocyanate), in which the nanofillers were previously dispersed. Raman spectroscopy and Transmission Electron Microscopy demonstrated the formation of few-layer graphene and graphene nanoribbons dispersed in the monomers. At variance to the methods commonly reported in literature, that used in this work consists of the direct exfoliation of graphite without any chemical manipulation. Apart from the obvious cost and ease advantages, the so-obtained graphene does not contain any carboxy or alkoxy groups formed during the exfoliation process, which, at variance, are typically present in the most commonly reported methods. This finding paves the way toward the large-scale production of graphene and its nanoribbons, which are considered even more interesting than graphene itself for many potential applications. The obtained nanocomposites show a peculiar thermal and rheological behavior due to the presence of the nanofillers and to their reinforcing or plasticizing effect exerted on the TPU matrices.     

Synthesis,characterization and rheological properties of multiblock associative copolymers by RAFT technique

Polymer Bulletin - Preparation of associating multiblock copolymer electrolytes mediated by radical addition–fragmentation chain transfer (RAFT) technique has been evaluated and reported in...