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In the last years, bile acid receptors FXR and GPBAR1 have emerged as prominent targets for treatment of several human diseases, ranging from liver cholestatic disorders to metabolic syndrome, nonalcoholic steatohepatitis (NASH) and diabetes. Even if dual FXR/GPBAR1 agonists are considered a novel opportunity in the treatment of these diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation associates with severe side effects. Since bile acids often target both receptor families, speculation on non-steroidal ligands, although still in its infancy, represents a promising strategy to selectively target GPBAR1. Indeed, selective GPBAR1 modulators allow controlling glucose metabolism through the release of glucagon-like peptide (GLP)-1 without affecting the FXR-related pathways. The availability of the tridimensional model of the above receptors has opened new avenues for the rational design of selective modulators. Using such structural information, we are currently involved in developing novel active ligands with improved drug-like properties and a rational modulation of BA receptors activity. These studies have allowed identifying the first example of non-steroidal GPBAR1 antagonist, which might open the way to a new and promising field of research representing a tool in dissecting and in shedding light on the complex biological pathways under GPBAR1 control.

Synthesis of enantiomerically pure 7- and 8-hydroxystearic acids1 (7- and 8-HSA) has been accomplished starting from chiral non racemic 1-pentadecen-4-ol 1a and 1- tetradecen-4-ol 1b respectively, in accordance with the retrosynthetic procedure depicted in the Scheme. Access to enantiomerically pure homoallylic alcohols 1a,b was possible via kinetic resolution of the corresponding racemic acetates, catalyzed by Novozym 435 (Lipase B from Candida antarctica). Yamaguchi esterification2 of 1a,b with 4-pentenoic and 5-hexenoic acids 2a,b respectively afforded the suitable dienic esters 3a,b which were submitted to Ring- Closing Metathesis Reaction (RCM).3 Hydrogenation of the resulting complex reaction mixtures followed by hydrolysis under basic conditions afforded the expected chiral non racemic 7- and 8-HSA in about 40% total yield. Scheme

Imidazolium salts incorporating functional groups represent a class of compounds having great versatility due to their wide range of applications as task specific ionic liquids (ILs)1 or N-heterocyclic carbene precursors (NHCs)2. Recently our research in this field has been dealing with the high-purity synthesis of t-butyloxylcarbonyl (Boc)-protected and deprotected amino-functionalized imidazolium cation [NHR1CH2CH2ImR2]+ ([1]+, R1 = Boc, H; R2 = Me, Bz, Allyl) and related NHC-Ag(I) silver complexes have been obtained by reacting [1]+ with Ag2O.3 Here we report the synthesis of new NHC-Rh(I) (2) complexes that contain an axis of chirality. The enantiomerical inversion has been investigated by variable-temperature NMR spectroscopy, DFT calculation and X-ray diffraction. The catalytic behaviour of 2 in the 1,2 addition reaction of aryl aldehydes with boronic acid will be also presented and discussed.

Prostaglandin E2 (PGE2) is an inflammatory mediator that plays a pivotal role in the evolvement and progression of inflammatory and tumor diseases.1The identification of novel inhibitors of eicosanoids biosynthesis with unexplored scaffolds is of great demand to develop a next generation of anti-inflammatory or anti-cancer drugs. Following a multidisciplinary protocol that involves virtual combinatorial screening, chemical synthesis, and validation of the biological activities we afforded to the identification of 1,2,4-oxadiazole-based hits, as a novel class of anti-inflammatory agents able to inhibit several enzymes involved in the progression of inflammation. 1,2,4-oxadiazoles represent a versatile “privileged scaffold” in drug discovery, due to the possibility of modifying and opportunely decorating the nucleus,2 and are never explored for their inhibitory activity on eicosanoid biosynthesis. This multidisciplinary scientific approach led to the identification of a multi-target inhibitor of cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, in vivo studies on the disclosed hit demonstrate that it attenuates leukocytes migration in a model of zymosan-induced peritonitis and modulates the production of IL-1β and TNF-α. These promising outcomes pave the way toward a medicinal chemistry optimization campaign of the disclosed hit characterized by a promising and safer pharmacological profile.

Human skin forms a unique interface between the body and the external environment. Its main role is to protect the internal organs from external factors. Notably, the outermost skin layer, stratum corneum, forms a remarkable barrier for permeation of xenobiotics in general, but unfortunately it may become an entry route of hazardous substances. Metals can penetrate and permeate the skin inducing local effects such as skin sensitization with allergic contact dermatitis and potential metals diffusion into the bloodstream with systemic intoxication[1] [2]. Metals in nano dimensions penetrate and permeate the skin in higher amount[3] [4] compared to bulk materials due to their smaller dimensions[5].Therefore, if the stratum corneum is damaged to various factors such as inflammation, desquamation, defects in lipid distribution or epidermal thickening, the transcutaneous passage of a molecule is expected to be drastically enhanced[6] [7]. In this study, we investigate the percutaneous penetration of metals from the road dust powder in intact as well damaged skin to mimic the effect of skin lesions. In addition, porcine and human skin were compared as skin models. The certified reference material BCR®-723 provided by the European Institute for Reference Materials and Measurements was used as road dust formulation. To evaluate the extent of ionization of metals from BCR®-723, the dissolution of powder in synthetic sweat solutions at two different pH (pH 4.5, 6.5) was carried out. Periodic quantification of metals concentration was monitored and analyzed via inductively coupled plasma - optical emission spectroscopy (ICP-OES). The choice of synthetic sweat solution at pH 4.5 was dictated to reproduce the workplace conditions. Dermal absorption from donor compartment containing metals was monitored for 24 hours. The amounts of metals retained in skin were quantified post-exposure by inductively coupled plasma - mass spectrometer (ICP-MS). Percutaneous absorption of lead (Pb) was higher in both intact skin models (549 ng/cm2 in porcine skin vs 68.80 ng/cm2 in human model). Moreover, cobalt (Co) accumulation was higher in porcine skin reaching a value of 518 ng/cm2 than those found in human skin (1.85 ng/cm2). In contrast with the observations reported in human skin model, chromium (Cr) achieved the lowest skin absorption in porcine model (183 ng/cm2). As expected, metals permeation on damaged skin was enhanced due to the removal of the barrier function. These consequence differences may be due to the skin tissues, but pig skin appeared as the most suitable replacement for human skin.

Sediments often act as reservoirs of contaminants, but they can also be considered a secondary source of contamination due to remobilisation processes at the sediment-water interface (SWI) which may affect the quality of the overlying water and aquatic biota [1,2]. The estuarine system of the Timavo/Reka River is located in the Gulf of Trieste (northern Adriatic Sea) and the innermost sector of the estuary was recognised as the most critical area. There, elevated concentrations of potentially toxic trace elements (PTEs) were detected in surface sediments and the scarce water circulation led to a permanent oxic-hypoxic interface along the water column [3]. This research aims at understanding if and how biogeochemical processes may affect PTE (As, Cr, Hg, Fe, Mn, Ni, Pb, V) mobility and related fluxes at the SWI. Sampling activities were performed before (June) and after September) the forced aeration by means of a system of porous pipes laid on the bottom with the aim to re-oxygenate the water column in summer. Water aliquots were sampled along the water column, short sediment cores were collected to investigate the solid (sediments) and dissolved (porewater) phases and in situ benthic chamber experiments were conducted at the SWI. Results showed that the water column was oxygen stratified and hypoxic conditions were observed in the bottom water layer, mostly in June (2.29 mg/L of dissolved oxygen) when reductive conditions also occurred (-58 mV). Consequently, dissolved PTE concentrations increased with increasing depth and were maximum at the bottom due to dissolution/desorption processes involving Fe and Mn oxy-hydroxides [4]. A gradual oxygen depletion was also observed inside the chamber during the benthic chamber experiments testifying to organic matter remineralisation processes and subsequent increase of dissolved PTEs. Regarding PTE profiles in porewater, the highest PTE concentrations were observed in June, especially at the top of the sedimentary sequence implying that hypoxic conditions may promote the release of PTEs at the SWI.

Airborne Particulate Matter (APM) is used by the World Health Organization (WHO) as a proxy indicator for ambient air pollution. For this reason the identification as well the quantification of the different sources influencing PM levels at a receptor are essential for the estimation and improvement of Air Quality. The Source Apportionment at receptor site is reliable using receptor modelling techniques [1, 2]. Receptor models, relying on multivariate statistical methods (such as Positive Matrix Factorization – PMF), require the inputting of a matrix composed of a relatively large number of samples to function correctly [3]. A number of publications have sought to define objective criteria aimed at establishing the minimum number of samples for use with these receptor models. However, the issue is far from settled. Results of a source apportionment exercise using positive matrix factorization (PMF) for PM10 and PM2.5 are reported. This study is based on a small dataset of 29 PM10 and 33 PM2.5 samples for a receptor in a rural setup in Apulia (Southern Italy). Running PMF on the two size fractions separately resulted in the model not functioning correctly. We therefore, augmented the size of the dataset by aggregating the PM10 and PM2.5 data. The 5 factor solution obtained for the aggregated data was fairly rotationally stable, and was further refined by the rotational tools included in USEPA PMF v5. These refinements include the application of constraints on the solution, based on our knowledge of the chemical composition of the aerosol sources affecting the receptor. Additionally, the uncertainties associated with this solution were fully characterised using the improved error estimation techniques in USEPA PMF v5. The results of the error estimation techniques in PMF (BS, DISP and BS – DISP) show reasonable uncertainties in the tracer species. Five factors in all were isolated by PMF: ammonium sulfate, sea salt, mixed carbonaceous aerosol, crustal/Saharan dust and total traffic. These results obtained by PMF were further tested inter alia, by comparing them to those obtained by two other receptor modelling techniques: constrained weighted non-negative matrix factorization (CW – NMF) and chemical mass balance (CMB). The PMF results were confirmed by CW – NMF, while the CMB estimates

In recent years we have prepared a large variety of stable supported metal nanoparticles by using supports such as silica, alumina, titania, magnetite (hereafter generally termed as Oxides Supports, OS), Indium Tin Oxide (ITO) and hydroxyapatite (HA) to be employed as catalytic systems and biomaterials. With regards to the OS, we have developed a convenient method for the anchoring of AuNPs on matrices modified with a propynylcarbamate functionality, without the need of any additional reducing and/or stabilizing agents. Among these systems, the Au/SiO2 catalyst was also the most active in the oxidation of a large variety of primary and secondary alcohols both in batch and flow settings (Fig. 1A), yielding very stable performances as a function of time without any detrimental activity degradation [1]. Figure 1. In the HA case we have reported an easy, green and low-cost method to support AgNPs onto multifunctionalized HA-R crystals (Fig. 1B, R = zoledronate, (9R)-9-hydroxystearate) obtaining materials that combine the biological properties of R with a significant long-standing antibacterial activity [2]. ___________ [1] M. Giorgetti, G. Aquilanti, B. Ballarin, M. Berrettoni, M.C. Cassani, S. Fazzini, D. Nanni, D. Tonelli, Anal. Chem. 2016, 88, 6873; M.C. Cassani, B. Ballarin, D. Barreca, E. Boanini, E. Bonansegna, G. Carraro, S. Fazzini, A. Mignani, D. Nanni, D. Pinelli, RSC Adv. 2016, 6, 25780; B. Ballarin, D. Barreca, E. Boanini, M.C. Cassani, P. Dambruoso, A. Massi, A. Mignani, D. Nanni, C. Parise, A. Zaghi, ACS Sustain. Chem. Eng. 2017, 5, 4746. [2] E. Boanini, P. Torricelli, C. Boga, G. Micheletti, M.C. Cassani, M. Fini, A. Bigi, Langmuir 2016, 32, 188; E. Boanini, P. Torricelli, F. Bonvicini, M.C. Cassani, M. Fini, G.A. Gentilomi, A. Bigi, Eur. J. Pharm. Biopharm. 2018, 127, 120; E. Boanini, M.C. Cassani, K. Rubini, C. Boga, A. Bigi, Nanomaterials 2018, 8, 390.

Motivation: Traditional pulp and paper processes as well as emerging biorefineries generating cellulosic ethanol from lignocellulosic agricultural waste material lead to large amounts of kraft lignin and side-stream straw lignin.1 Both types of technical lignins, i.e., organosolv lignins and kraft lignins, offer various amounts of different functional groups, mainly aliphatic and phenolic hydroxyl groups and double bonds.2,3 Whereas the hydroxyl groups are normally used for lignin functionalisation, a more versatile type of functionalisation is obtained when leaving the hydroxyl groups intact and creating carbon-carbon bonds. Design of experiment: Lignin modification was thus performed using nascent hydrogen, as well as carbenes of varying reactivity. Exploiting the possibilities for in situ production of the reactive species, various technical lignins were subjected to standardised reactions conditions. Re-isolated modified lignin samples were subjected to GPC analysis,4 FTIR analysis, quantitative 31P NMR after phosphitylation,5 as well as quantitative {13C-1H}-HSQC analyses.6,7 Results: Molar mass distribution effects were noted in the modified lignins. In case of carbenes, detection of new, unexpected cross-peaks in the HSQC spectra area specific for newly emerging C=C bonds were observed, while other ‘typical’ lignin signals in the aromatic region underwent drastic changes. Together with unexpectedly decreased amounts of the respective free phenolic OH groups in the modified lignins, quinone-formation involving G- and H-type aromatic rings of lignins through a Reimer-Tiemann mechanism8 is postulated, among other reactions and rearrangements. In case of treatment of lignins with nascent hydrogen, structural changes lead to yet different, ‘atypical’ lignins.

Potentially harmful elements (PHEs) are supplied to estuarine environments in association with freshwater inputs affected by several anthropogenic sources [1]. The present work aims to understand the PHE (Pb, Hg, Cs, As, Zn, Cu, Ni, Co, Fe, Mn, Cr) partitioning between particulate (> 0.45 μm), colloidal (0.45 μm - 10 kDa) and dissolved (< 10 kDa) fractions in river mouths of the Gulf of Trieste (northern Adriatic Sea). In order to achieve these objectives, CTD (Hydrolab H2O Multiprobe) vertical profiles of salinity, temperature and turbidity were recorded before sampling to identify the water masses. The surface samples were collected at variable depth, according to the salinity trend and along the salinity gradient, whereas the bottom water samples were representative of salt water intrusion. In addition, the main physico-chemical parameters (T, pH, Eh, DO and EC) were measured in situ (pH-meter PH25, Conductivity-meter CM35+ by Crison Instruments). Samples were filtered through 0.45 μm filters (Millipore HA, Ø 47 mm) to isolate the particulate fraction which was aciddigested through a total dissolution in a closed microwave system (Multiwave PRO, Anton Paar). The filtrate samples were ultrafiltered through 10 kDa membranes (Vivaflow 200, Sartorius). All sample aliquots were analysed for PHE determination by means of Inductively Coupled Plasma Mass Spectrometry (Nexion 350x Perkin Elmer), whereas Hg was analysed via Cold Vapor Atomic Fluorescence Spectrometry (Mercur Analytic Jena). Hydrodynamic conditions at the river mouths showed the presence of two distinct layers due to the freshwater input and salinity vertical profiles displayed a sharp halocline or mixing layer depending on the river discharge. Elevated PHE contents were detected in the particulate and dissolved fractions and in some parts, PHEs seem to be associated with the colloidal fraction. As expected, Hg reaches elevated values in the particulate fraction of the Isonzo River [2]. The Timavo River samples showed elevated concentrations of PHEs, most likely due to wastewater discharge from a paper mill located near the river mouth. Information on PHE mobility can be provided by the correlations observed between PHE content and salinity, which appear to have an important role in PHE phase partitioning.

In questo studio viene riportata la sintesi e la valutazione farmacologica di una nuova famiglia di derivati degli acidi biliari caratterizzati dalla presenza di una funzione epossidica in catena laterale. I risultati farmacologici hanno mostrato che tali composti sono in grado di attivare il recettore GPBAR1.

Potentially harmful elements (PHEs) are supplied to estuarine environments by freshwater inputs affected by anthropogenic sources. This work aims at the evaluation of PHEs (Pb, Hg, Cs, As, Zn, Cu, Ni, Co, Fe, Mn) partitioning among suspended particulate matter, retentate and permeate fractions in the river mouths of the Gulf of Trieste (Isonzo, Timavo and Dragonja rivers). Significative concentrations of PHEs were detected in the particulate and dissolved fractions and to a certain extent PHEs were associated to the retentate fraction. PHEs showed a non-conservative behavior and salinity gradient appear to have an important role in their mobility and partitioning.

PM10 and PM2.5 samples simultaneously collected at a suburban site of south eastern Italy have been analysed with the main aim of determining the atmospheric dust contribution and investigating the dust source impact. Low volume samplers were used to collect 24-h PM10 and PM2.5. Organic and elemental carbon, inorganic ions, and selected metals were measured in the collected samples. EC and OC were determined by thermal optical transmittance technique (Sunset Carbon Analyzer), soluble ions (SO42-, NO3-, NH4+, Cl-, Na+, K+, Mg2+ and Ca2+) were analysed via High Performance Ion Chromatography (HPIC, Dionex DX-500 System); eight trace elements (Ni, Cu, V, Mn, As, Pb, Cr, Sb) were analyzed via Graphite Furnace Atomic Absorption Spectroscopy (GF-AAS, Perkin Elmer Analyst 600 System); four trace elements (Fe, Al, Zn and Ti) were analysed by Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES, Varian Liberty 110 spectrometer). Moreover, ATR-FTIR analysis were performed on samples of Saharan Dust event and samples characterized by mass air transported from NE Europe. ATR-FTIR analysis let identify organic functional groups including non-acid organic hydroxyl C-OH group (eg sugars, anhydrosugars, and polyols) and carbonyl C=O group, carboxylic acid COOH group, aromatic and aliphatic unsaturated C=C-H group, aliphatic saturated C-C-H group, and amine NH2 group. Some inorganic ions have also been identified: carbonates, sulfate, silicate and ammonium. In this work, the X-ray photoelectron spectroscopy (XPS) has been used to investigate surface chemical composition of particulate matter. The mass closure analysis have been applied to the chemically speciated PM10 and PM2.5 samples to identify main natural and anthropogenic sources and determine the atmospheric dust contribution. Analytical back trajectories combined with statistical analyses and satellite true colour images were used to know about the location of potential source regions and to determine the contribution of long range transported air masses. In particular the effect of Sahara dust outbreak on PM composition was evaluated.

Both academic and industrial laboratories currently use constraint - based reconstruction methods to predict optimal genetic modifications aiming at improving the yield of chemical production. Streptomyces ambofaciens, a prolific producer of bioactive compounds has been studied with different modeling tools . The interest is linked to its ability to produce a wide range of secondary metabolites such as spiramycin, kinamycin, antimycin and stambomycins, and novel polyketides with antibacterial and antiproliferative activities. In this study, the metabolic pattern of Streptomyces ambofaciens has been globally explored: a set of candidate overexpression gene targets supposed to lead to spiramycin overproduction have been evidenced through metabolic modeling. Model predictions were experimentally validated by genetic manipulation of the ethylmalonyl-CoA metabolic node, providing evidence that spiramycin productivity may be increased by enhancing the carbon flow through this pathway. The goal was achieved by over - expressing the ccr paralog srm4 in an ad hoc engineered plasmid. The first metabolic reconstruction of S. ambofaciens and the successful experimental validation of model predictions have been described and the validity and the importance of in silico modeling tools for the overproduction of molecules with a biotechnological interest demonstrated. As a result, the proposed metabolic reconstruction represents a solid platform for the future exploitation of S. ambofaciens biotechnological potential.

One of the main environmental issues affecting the coastal marine environments is the accumulation of contaminants in sediments and their potential mobility. The sediment acts as a sink for many chemical species (metal(oid)s, PAHs, PCBs etc.). However, this situation can be only temporary since early diagenesis biogeochemical processes can recycle these contaminants which may subsequently accumulate along the aquatic trophic chain. In this work, in situ experiments were conducted at two tourist ports (marinas) located in the Gulf of Trieste (northern Adriatic Sea), one in Slovenia and one in Italy. The latter is well known to be a site contaminated by long-term shipbuilding activities. The main aim was to understand if and where recycling at the sediment-water interface (SWI) may affect trace metal(oid)s. A benthic chamber, successfully used in other works in the same Gulf 1,2, was employed. Water sampling was performed during a 8-hour period to measure trace metal(oid) concentrations with time. Short sediment cores were collected near the chamber to investigate the solid (sediments) and dissolved phases (porewaters). Both diffusive and benthic fluxes were estimated to elucidate the release of trace metal(oid)s at the SWI. Total trace element concentrations were determined following a complete mineralization of the sediment (aqua regia + HF), whereas a weak extraction with diluted HCl (0.5 M) was carried out to quantify their potential “bioavailable fraction”. Quantitative analyses were performed by ICP–OES on sediment mineralized solutions and by ICP–MS on porewater and benthic water samples. Total element contents in sediments, resulted up to two orders of magnitude higher in the Italian marina (0.4 %Pb, 0.15% As and Cu, 0.25% Zn) than in the Slovenian one, confirming the high contamination level of this site. Despite this heavy contamination, the “bioavailable fraction” of metal(oid)s extracted was scarce or null. Conversely, sediments from the Slovenian site showed high percentages of the extractable fraction from 4% (Cr) to 82% (Cu) of the total content. Trace metal vertical profiles in porewaters showed a clear diagenetic sequence. The suboxic/anoxic conditions of sediments allowed the dissolution of Fe and Mn oxy-hydroxides, thus enhancing the concentrations in porewaters of Fe, Mn and other associated trace metal(oid)s. However, the diagenetic sequence and the suboxic/anoxic transition were highly dependent on the characteristics of each site. Maximum concentrations of dissolved Fe, Mn, Pb and Zn were found in the first centimeters of one site of the Italian marina where sediments became quickly anoxic with depth. Conversely, in the Slovenian marina and in the second Italian site, the highest concentrations were recovered from the deepest porewater layers, especially for Fe (up to 2.5 and 7.7 mg L-1, respectively). Positive effluxes were observed for Mn, Pb, Zn and V in the Italian marina whereas for Cu and Ni were most notably in the Slovenian marina and for as at both sites. Hg fluxes were low in spite of its high concentrations (up to 1000 mg kg-1) in sediments of the Italian site. In general, benthic fluxes of metal(oid)s at the SWI can be partially explained by considering the dissolution of Fe/Mn oxy-hydroxides and metal speciation in bottom sediments. The results suggest that although the bottom sediments of the Italian marina exhibit the highest trace metal(oid) concentrations, they are scarcely remobilizable. On the contrary, in the Slovenian marina, sediments seem to be comparatively a significant source of trace elements (except for Fe, Pb and V) in the water column as consequence of diagenetic processes at the related interface.