Search

The qualification of the Nb3Sn conductors for ITER coils is performed by using short straight samples tested in the unique EU test facility SULTAN. The performances of the conductors in a real coil situation as the TFMC are shown to be different from the short sample.

Pliny the Elder testifies that roman workshops used volcanic glass (obsidian), but also produced and used a dark glass (obsidian-like glass) quite similar to the natural one. In the context of the study on medieval mosaics, the use of the obsidian and obsidian-like tesserae is a challenging research topic. In this paper, we present the results of a multidisciplinary study carried out on the Dedication wall mosaic, realized by a byzantine workshop in the 12th century in the Church of St. Mary of the Admiral in Palermo, and where numerous black-appearing tesserae, supposed to be composed of obsidian by naked-eyes observation, are present. Historical documents, multispectral imaging of the wall mosaic, and some analytical methods (SEM-EDS and XRPD) applied to a sample of black tesserae, concur in identifying here the presence of obsidian and different obsidian-like glass tesserae. This evidence, although related to the apparent tampering and restoration, could open a new scenario in the use of obsidian and obsidian-like glass tesserae during the Byzantine period in Sicily and in the reconstruction of multiple restoration phases carried out between 12th and 20th century AD on the mosaics of St. Mary of the Admiral.

We identified 2,4-dinitro-biphenyl-based compounds as new inhibitors of leukotriene C 4 synthase (LTC 4 S) and 5-lipoxygenase-activating protein (FLAP), both members of the "Membrane Associated Proteins in Eicosanoid and Glutathione metabolism" (MAPEG) family involved in the biosynthesis of pro-inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell-free and cell-based assays we assessed the inhibition of LTC 4 S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E 2 synthase (mPGES)-1, suggesting that the 2,4-dinitro-biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro-inflammatory mediators in inflammation and cancer treatment., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Dual inhibition of microsomal prostaglandin E 2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (∼2.0×10 4 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lipid mediators (LM) encompass pro-inflammatory prostaglandins (PG) and leukotrienes (LT) but also specialized pro-resolving mediators (SPM) which display pivotal bioactivities in health and disease. Pharmacological intervention with inflammatory disorders such as osteoarthritis and rheumatoid arthritis commonly employs anti-inflammatory drugs that can suppress PG and LT formation, which however, possess limited effectiveness and side effects. Here, we report on the discovery and characterization of the two novel benzoxanthene lignans 1 and 2 that modulate select LM biosynthetic enzymes enabling the switch from pro-inflammatory LT to SPM biosynthesis as potential pharmacological strategy to intervene with inflammation. In cell-free assays, compound 1 and 2 inhibit microsomal prostaglandin E 2 synthase-1 and leukotriene C 4 synthase (IC 50  ∼ 0.6-3.4 µM) and potently interfere with 5-lipoxygenase (5-LOX), the key enzyme in LT biosynthesis (IC 50  = 0.04 and 0.09 µM). In human neutrophils, monocytes and M1 and M2 macrophages, compound 1 and 2 efficiently suppress LT biosynthesis (IC 50  < 1 µM), accompanied by elevation of 15-LOX-derived LM including SPM. In zymosan-induced murine peritonitis, compound 1 and 2 ameliorated self-limited inflammation along with suppression of early LT formation and elevation of subsequent SPM biosynthesis in vivo. Together, these novel benzoxanthene lignans promote the LM class switch from pro-inflammatory towards pro-resolving LM to terminate inflammation, suggesting their suitability as novel leads for pharmacotherapy of arthritis and related inflammatory disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Targeting microsomal prostaglandin E 2 synthase-1 (mPGES-1) represents an efficient strategy for the development of novel drugs against inflammation and cancer with potentially reduced side effects. With this aim, a virtual screening was performed on a large library of commercially available molecules using the X-ray structure of mPGES-1 co-complexed with a potent inhibitor. Combining fast ligand-based shape alignment, molecular docking experiments, and qualitative analysis of the binding poses, a small set of molecules was selected for the subsequent steps of validation of the biological activity. Compounds 2 and 3 , bearing the 3-hydroxy-3-pyrrolin-2-one nucleus, showed mPGES-1-inhibitory activity in the low micromolar range. These data highlighted the applicability of the reported virtual screening protocol for the selection of new mPGES-1 inhibitors as promising anti-inflammatory/anti-cancer drugs.

Leukotrienes (LTs) and prostaglandin (PG)E 2 , produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E 2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC 50  = 2.3 and 0.4 μM for isolated 5-LO and 5-LO in intact cells, respectively). Compound 47 prevented the interaction of 5-LO with its activating protein (FLAP) at the nuclear envelope in transfected HEK293 cells as shown by in situ proximity ligation assay. Comprehensive assessment of the LM profile produced by human macrophages revealed the ability of 47 to selectively down-regulate pro-inflammatory LMs (i.e. LTs and PGE 2 ) in M1 but to enhance the formation of pro-resolving LMs (i.e. resolvins and maresins) in M2 macrophages. Moreover, 47 strongly inhibited LT formation and cell infiltration in two in vivo models of acute inflammation (i.e., peritonitis and air pouch sterile inflammation in mice). Together, 47 represents a novel LT biosynthesis inhibitor with an attractive pharmacological profile as anti-inflammatory drug that also promotes the biosynthesis of pro-resolving LM., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE 2 production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE 2 levels induced by inflammatory stimuli, with neither affecting PGE 2 constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE 2 related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug-like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The methanol extract of the leafy covers of Corylus avellana, source of the Italian PGI (protected geographical indication) product "Nocciola di Giffoni", afforded two new cyclic diarylheptanoids, giffonins T and U (2 and 3), along with two known cyclic diarylheptanoids, a quinic acid, flavonoid-, and citric acid derivatives. The structures of giffonins T and U were determined as highly hydroxylated cyclic diarylheptanoids by 1D and 2D NMR experiments. Their relative configurations were assigned by a combined quantum mechanical/NMR approach, comparing the experimental 13 C/ 1 H NMR chemical shift data and the related predicted values. The absolute configurations of carpinontriol B (1) and giffonins T and U (2 and 3) were assigned by comparison of their experimental electronic circular dichroism curves with the TDDFT-predicted curves. The ability of the compounds to inhibit the lipid peroxidation induced by H 2 O 2 and H 2 O 2 /Fe 2+ was determined by measuring the concentration of thiobarbituric acid reactive substances. Furthermore, the antimicrobial activity of the methanol extract of leafy covers of C. avellana and of the isolated compounds against the Gram-positive strains Bacillus cereus and Staphylococcus aureus and the Gram-negative strains Escherichia coli and Pseudomonas aeruginosa was evaluated. Carpinontriol B (1) and giffonin U (3) at 40 μg/disk caused the formation of zones of inhibition.

Background and Purpose: The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets., Experimental Approach: The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E 2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) was confirmed by CS and CA, and we determined the consequence on the eicosanoid network in activated human primary monocytes and neutrophils. Molecular interactions and binding modes of CS and CA to target enzymes were analyzed by docking studies., Key Results: CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan-induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors., Conclusion and Implications: In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti-inflammatory remedy, in the continuous expanding context of nutraceuticals., Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc., (© 2016 The British Pharmacological Society.)

Identification of new microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitors is currently sought for the treatment of cancer and inflammation. Here we show the results of a Fragment Virtual Screening campaign using the X-ray crystal structure of human mPGES-1 (PDB code: 4AL0). Among the fragments selected and biologically tested, 6 (9H-indeno [1,2-b] [1,2,5]oxadiazolo [3,4-e]pyrazin-9-one) showed the most promising mPGES-1 inhibitory activity (∼30% inhibition at 10 μM). A minimal structure-based optimization of 6 led to compounds 15, 20 and 21, with a promising enhancement of the inhibitory activity (IC 50  = 4.6 ± 0.2 μM for 15; IC 50  = 2.4 ± 1.0 μM for 20; IC 50  = 2.4 ± 0.8 μM for 21). The unprecedented chemical core and the possibility of synthesizing novel derivatives reveal a new and attractive field of action for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Two new diaryl ether heptanoids, giffonins J and K (1 and 2), along with five new diarylheptanoids, giffonins L-P (3-7), were isolated from a methanol extract of the leaves of Corylus avellana cultivar "Tonda di Giffoni". These compounds were identified as highly hydroxylated cyclized diarylheptanoids by 1D- and 2D-NMR experiments. The relative configurations of giffonins J-P (1-7) were established by a combined QM (quantum mechanical)/NMR approach, comparing the experimental (13)C/(1)H NMR chemical shift data and the related predicted values. The cytotoxic activities of giffonins J-P (1-7) were evaluated against the human osteosarcoma U2Os and SAOs cell lines.

Tanshinone IIA and cryptotanshinone are two pharmacologically active diterpenoids extracted from the roots of Salvia milthiorriza Bunge, a plant used in Chinese traditional medicine for the treatment of some cardiovascular and cerebrovascular disease. Until now, the molecular mechanisms of action of these two diterpenoids on platelets are partially known. To clarify this aspect, here we utilized an integrated study of pharmacology and computational analysis. Our results demonstrate that cryptotanshinone is able to inhibit in a concentration dependent manner the rat platelet aggregation and also is endowed of Gi-coupled P2Y12 receptor antagonist as demonstrated by docking studies. This computational method was also performed for tanshinone IIA demonstrating even for this diterpenoid an interaction with the same receptor. The findings from our study enable a better understanding of tanshinone IIA and cryptotanshinone biological properties, which could ultimately lead to the development of novel pharmaceutical strategies for the treatment and/or prevention of some cardiovascular disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The objective of this study was to compare the clinical and bacteriologic efficacy and safety of cefodizime 1 g intramuscularly (IM) once daily (group A) versus cefodizime 1 g IM twice daily (group B) and versus ceftriaxone 1 g IM once daily (group C) in patients with community-acquired pneumonia. A total of 298 patients, affected by bronchopneumonia or pneumonia with known or suspected bacterial cause, new focal signs on examination of chest, and radiographic evidence of a recent infiltrate, were randomized in three comparable groups. The infection was rated as mild, moderate, or severe. A total of 283 patients were assessable for efficacy: 95 in group A, 94 in group B, and 94 in group C. Mean (+/- SD) duration of treatment was 5.96 +/- 1.39 days in group A, 6.24 +/- 1.57 days in group B, and 6.66 +/- 1.95 days in group C. Symptoms such as purulent sputum, cough, and dyspnea improved significantly after treatment in all groups; temperature normalized by about day 3. Clinical efficacy was rated good in 94.74% of patients in group A, in 92.55% in group B, and in 87.23% in group C. Positive bacteriologic cultures were obtained before treatment from 144 patients: bacteriologic responses were rated good in 98.11%, 98.08%, and 92.80% in groups A, B, and C, respectively. No significant differences were found between the three treatment groups for any measures of clinical efficacy. No serious adverse event occurred in any of the groups. We conclude that cefodizime 1 g IM once daily is an effective dosing regimen in the treatment of patients with community-acquired pneumonia.