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.     

Partial purification of <Emphasis Type="Italic">nigella sativa</Emphasis> L. Seed lipase and its application in hydrolytic reactions. Enrichment of γ-linolenic acid from borage oil

Selective hydrolysis of borage (Borago officinalis L.) oil was catalyzed by two lipase preparations of Nigella sativa L. seeds at 40°C in a mixture of borage oil, water, and hexane. Ammonium sulfate-precipitated lipase (Nigella PL) and lipase partially purified by DEAE-ion exchange chromatography (Nigella CPL) exhibited a negative specificity toward γ-linolenic acid (GLA). Best results were obtained in the experiments conducted with 330 U/g oil of Nigella PL and 200 U/g oil of nigella CPL. When 330 U/g oil of Nigella PL was used, after 8 h the GLA level rose from 21.9% in the starting oil to 29.6 and 41.8% in TAG and DAG fractions of the product mixtures, respectively (1.5-fold enrichment of GLA in the total unhydrolyzed acylglycerol fraction). At 200 U/g oil enzyme concentration of Nigella CPL, after 77 h maximum GLA enrichment was observed in the DAG fraction. The GLA content of the DAG increased to 34.6%, corresponding to almost 1.6-fold enrichment. The relative inability of Nigella sativa lipase(s) to hydrolyze γ-linolenoyl moieties of TAG can be used for the enrichment of this acid in the unhydrolyzed acylglycerol fractions of GLA-containing oils.     

Advances in the Chemical Ecology of the Spotted Wing Drosophila (<Emphasis Type="Italic">Drosophila suzukii</Emphasis>) and its Applications

Significant progress has been made in understanding the cues involved in the host and mate seeking behaviors of spotted wing drosophila, Drosophila suzukii (Matsumura). This insect pest has been discovered in many fruit growing regions around the world since 2008. Unlike closely related Drosophila species, D. suzukii attacks fresh fruit and has become a severe pest of soft fruits including strawberry, cherry, blackberry, blueberry, raspberry, and may pose a threat to grapes. Prior to 2008, little was known about the courtship and host-seeking behaviors or chemical ecology of this pest. Since then, researchers have gained a better understanding of D. suzukii attraction to specific odors from fermentation, yeast, fruit, and leaf sources, and the visual cues that elicit long-range attraction. Several compounds have also been identified that elicit aversive behaviors in adult D. suzukii flies. Progress has been made in identifying the constituent compounds from these odor sources that elicit D. suzukii antennal responses in electrophysiological assays. Commercial lures based on food volatiles have been developed to attract D. suzukii using these components and efforts have been made to improve trap designs for monitoring this pest under field conditions. However, current food-based lures and trap technologies are not expected to be specific to D. suzukii and thus capture large numbers of non-target drosophilids. Attractive and aversive compounds are being evaluated for monitoring, mass trapping, and for the development of attract-and-kill and push-pull techniques to manage D. suzukii populations. This review outlines presently available research on the chemical ecology of D. suzukii and discusses areas for future research.     

Post Zygotic,Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer,Producing a Monolateral Palmar Epidermolytic Nevus

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion {"type":"entrez-nucleotide","attrs":{"text":"NM_006121.4","term_id":"1519311739"}}NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation {"type":"entrez-protein","attrs":{"text":"NP_006112.3","term_id":"119395750"}}NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.     

A review on electrospun polymer nanostructures as advanced bioactive platforms

This review article deals with latest literature studies on the potential use of polymer ultrathin and nanosized structures obtained by electrospinning to design novel engineered materials with bioactive properties. The electrofluidodynamic process offers the option to form high‐performance bioactive systems based on polymer yarns of nanofibers or coatings of nanobeads with high surface‐to‐volume ratios. The electrospun and electrosprayed nanostructures can be further functionalized by encapsulation with bioactive fillers and substances. For both scenarios, the resultant polymer nanostructures present unique bioactive properties capable of providing a beneficial impact over human's health and with improved and advanced performance for biomedicine, pharmaceutics, nutrition, bioengineering, and healthcare applications. These novel functional materials attained by the electrospinning technology can be of interest for many bioactive applications such as functional food design, food packaging, functional coatings, controlled delivery of drug solutions and, mainly, tissue engineering. This article is purposely designed to gather, for the first time, most recent and promising multi‐ and inter‐disciplinary developments based on electrospun systems for bioactive applications, which are either bioactive material concepts or can be advantageously applied to become such. POLYM. ENG. SCI., 56:500–527, 2016. © 2016 Society of Plastics Engineers     

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     

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.     

Discovery and Pharmacophore Mapping of a Low-Nanomolar Inhibitor of P. falciparum Growth

The treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is currently compromised by the dramatic increase and diffusion of drug resistance among the various species of Plasmodium, especially P. falciparum (Pf). In this view, the development of new antiplasmodial agents that are able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments. In one of our previous communications, we described a novel class of compounds endowed with high antiplasmodial activity, characterized by a pharmacophore never described before as antiplasmodial and identified by their 4,4’-oxybisbenzoyl amide cores. Here, through a detailed structure-activity relationship (SAR) study, we thoroughly investigated the chemical features of the reported scaffolds and successfully built a novel antiplasmodial agent active on both chloroquine (CQ)-sensitive and CQ-resistant Pf strains in the low nanomolar range, without displaying cross-resistance. Moreover, we conducted an in silico pharmacophore mapping.