Search

Transient receptor potential melastatin 8 (TRPM8) is crucially involved in pain modulation and perception, and TRPM8 antagonists have been proposed as potential therapeutic approaches for pain treatment. Previously, we developed two TRPM8 antagonists and proposed them as drug candidates for topical and systemic pain treatment. Here, we describe the design and synthesis of these two TRPM8 antagonists (27 and 45) and the rational approach of modulation/replacement of bioisosteric chemical groups, which allowed us to identify a combination of narrow ranges of pKa and LogD values that were crucial to ultimately optimize their potency and metabolic stability. Following the same approach, we then pursued the development of new TRPM8 antagonists suitable for the topical treatment of ocular painful conditions and identified two new compounds (51 and 59), N-alkoxy amide derivatives, that can permeate across ocular tissue and reduce the behavioral responses induced by the topical ocular menthol challenge in vivo.

The aim of this opinion article is to highlight the trends in the development of efficient catalyst-free synthesis of the Hantzsch polysubstituted 1,3-thiazoles. They are heterocycles of particular importance in the pharmaceutical industry, and the strategy involves the cyclization reaction of acyclic precursors with minimum auxiliary substances, toxic reagents, organic solvents, and disposal problems.

Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt/cocrystal polymorphism of the ketoprofen (KET)–lysine (LYS) system, with the cocrystal, KET–LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET–LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a different sensorial kinetics compared to the cocrystal, suggesting that different coating/flavoring processes should be envisioned for the new compound. Thus, the new KLS polymorphic form with its different physicochemical and pharmacokinetic characteristics can open the way to the development of a new KET–LYS polymorph drug that can emphasize the properties of commercial KLS for the treatment of acute inflammatory and painful conditions.

Carbon and nitrogen elemental (C-N, wt%) and isotopic ( δ 13 C- δ 15 N, ‰) investigation has been carried out on alluvial and deltaic soils from the Padanian plain (northern Italy), an area interested by intensive agricultural activities, to refine previous inferences on depositional facies, pedogenetic processes and anthropogenic influences. Soil analysis, carried out by EA-IRMS, have been focused on inorganic and organic fractions properly speciated by a thermally-based method, whereas further insights on the organic matter constituents have been obtained by sequential fractionation. The bulk EA-IRMS analyses reveal a remarkable compositional heterogeneity of the investigated soils (TC 0.89 to 11.93 wt%, TN 0.01 to 0.78 wt%, δ 13 C TC -1.2 to -28.2‰, δ 15 N -1.2 to 10.0‰) that has to be explained as an integration between inorganic and organic pools. The latter have been subdivided in Non-Extractable Organic Matter (NEOM, δ 13 C -16.3 to -28.6‰) and in extractable fractions as Fulvic (FA, δ 13 C -24.7 to -27.5‰, δ 15 N 0.6 to 5.7‰) and Humic (HA, δ 13 C -24.6 to -27.0‰, δ 15 N 1.0 to 9.7‰) Acids, which have been used to infer soil dynamics and Soil Organic Matter (SOM) stability processes. Results indicate that SOM at depth of 100 cm was generally affected by microbial reworking, with the exception of clayey and peaty deposits in which biological activity seems inhibited. Peaty and clayey soils display an organic fraction loss of ca. 20% toward the surface, suggesting deterioration possibly induced by intensive agricultural activities. These latter may be the cause of the ubiquitous losses of organic fraction throughout the investigated area over the last seventy years, evaluated by the comparison with historical data on corresponding topsoils. The obtained insights are very important because these soils are carbon (and nitrogen) sinks that are vulnerable and can be degraded, loosing agricultural productivity and potentially contributing to greenhouse gases fluxes.

The density, colour and texture, plus mineral and chemical features of 18 ceramic-like CDW samples from the Abruzzo region (Central Italy) were characterised. The concretes, natural stones, tiles, roof-tiles, bricks and perforated bricks are either aphanitic to porphyric. Concretes and natural stones are grey to white and tend to be > 2.0 g/cm3; the masonries are brown to reddish and close to 40 wt%) and LOI (volatiles, CO2 + H2O). The masonries are instead calcite-, CaO- ( The petrography of CDW concretes is similar among geographical areas with abundance of limestones used as aggregates. However, in limestone-poor areas CDW are SiO2- and Al2O3-rich, reflecting the prevalent use of masonry and/or silicate-rich construction materials, implying that each geographical area is characterised by peculiar CDW composition. Therefore, the knowledge of mesoscopic, physical and petrographic aspects has to be known for planning adequate sorting methods, promoting upcycling reusing applications. Some of the studied CDW samples are susceptible to release relative high Cr and As content.

G-protein coupled receptors 40 and 120 (GPR40 and GPR120) are increasingly emerging as potential therapeutic targets for the treatment of altered glucose homeostasis, and their agonists are under evaluation for their glucagon-like peptide-1 (GLP-1)-mediated therapeutic effects on insulin production and sensitivity. Here, we characterized a new dual GPR40 and GPR120 agonist (DFL23916) and demonstrated that it can induce GLP-1 secretion and improve glucose homeostasis. Resulting from a rational drug design approach aimed at identifying new dual GPR120/40 agonists able to delay receptor internalization, DFL23916 had a good activity and a very high selectivity towards human GPR120 (long and short isoforms) and GPR40, as well as towards their mouse orthologous, by which it induced both Gαq/11-initiated signal transduction pathways with subsequent Ca2+ intracellular spikes and G protein-independent signaling via β-arrestin with the same activity. Compared to the endogenous ligand alpha-linolenic acid (ALA), a selective GPR120 agonist (TUG-891) and a well-known dual GPR40 and GPR120 agonist (GW9508), DFL23916 was the most effective in inducing GLP-1 secretion in human and murine enteroendocrine cells, and this could be due to the delayed internalization of the receptor (up to 3 h) that we observed after treatment with DFL23916. With a good pharmacokinetic/ADME profile, DFL23916 significantly increased GLP-1 portal vein levels in healthy mice, demonstrating that it can efficiently induce GLP-1 secretion in vivo. Contrary to the selective GPR120 agonist (TUG-891), DFL23916 significantly improved also glucose homeostasis in mice undergoing an oral glucose tolerance test (OGTT).

The preliminary results on the development of a viable methodology for the further functionalization of 4-hydroxythiazole derivatives to afford target TRPM8 antagonists are reported. The combined Sonogashira coupling/annulation reactions of the ethyl 2-(3-fluorophenyl)-4-tifluoromethylsulfonyloxy-1,3-thiazole-5-carboxylate have been applied to the synthesis of analogues of the selective blocker of TRPM8 DFL23448. Among all the synthetised derivatives, the most promising compound resulted to be active as TRPM8 blocker (IC50 = 4.06 µM), showing an excellent metabolic stability and no cytotoxic effects. Finally, in silico characterisation of the derivatives showed no violation of the drug-likeness rules.

The exploitation of soils due to farming has produced a progressive loss of soil organic matter (SOM) over the years. At the same time, the degradation of SOM has led to a decline of several ecosystem services provided by soil, especially in mountain. Against this background, the partnership between Department of Physics and Earth Sciences of University of Ferrara and Department of Agricultural and Food Sciences of University of Bologna led to the creation of the SaveSOC2 project (Save Soil Organic Carbon), funded by Rural Development Programme of Emilia-Romagna Region. This project primarily seeks to investigate and promote carbon storage processes in agricultural soils of Emilia-Romagna Region (NE Italy). The present study outlines an overview about the SOM dynamics of “I Rodi” organic farm, located in the Modena Apennine. “I Rodi” produces and processes small organic fruits, especially raspberries. Three different sites (grassland -G, very low productive raspberries -LR, and good productive raspberries -GR) have been selected and the topsoils (0-15 cm and 15-30 cm) have been investigated. Elemental and isotopic analyses of soil C were performed using an EA-IRMS. In particular, the application of the Thermally Based Separation protocol [1] allowed the determination of both inorganic (IC) and organic (OC) carbon contents in each soil sample. OC accounted for 93.50% of the total carbon (1.72-4.84 wt.%). The negative δ13C values of the total carbon (from -27.8 to -19.7 ‰) confirmed the predominance of OC over IC in the investigated soils. The average values of OC isotopic C signature showed a decreasing trend among the three sites (-28.2, -27.2 and -25.8‰ for GR, G and LR, respectively), with the low productivity site having the highest δ13C value. The isotopic C signature of separated organic C fractions (0-15 cm topsoils) showed that humin (832-879 g/kg), which is the SOM fraction mostly interacting with the soil mineral phase and the largest pool, confirmed the observed trend (-27.5, -27.0, -26.4‰, GR, G and LR). The humic acids (6-17 g/kg) showed similar trend but lower δ13C values in all sites (-28.5, -28.0, -26.8 ‰, GR, G and LR). Finally, fulvic acids (5-10 g/kg) differed, having dissimilar trend and values of δ13C (-27.1, -26.8, -26.0 ‰ for G, GR and LR). Comparing to G, the GR data suggested that organic management i) did not decrease quantity and quality of organic matter, and ii) it was more efficient in OC stabilisation, increasing the amount of less transformed OC in both humin and humic acids (more negative δ13C values). In the LR site, instead, the observed trend can be due to low suitability of this soil to raspberries production, negatively affecting both crop yields and organic C dynamics. In our opinion, in order to combine agricultural productivity and its sustainability, more attention should be paid both to soil management and suitability in the area.[1] Natali C., Bianchini G., Vittori Antisari L. 2018. Thermal separation coupled with elemental and isotopic analysis: A method for soil carbon characterisation. Catena 164, 150-157.

Sustainable agricultural management is needed to promote carbon (C) sequestration in soil, prevent loss of soil fertility, and reduce the release of greenhouse gases. However, the influence of agronomic practices on soil C sequestration depends on the existing pedoclimatic features. We characterized the soils of three farms far away each other in the Emilia-Romagna region (Northern Italy): an organic farm in the Northern Apennines, a biodynamic farm, and a conventional farm on the Po Plain. The total, inorganic, and organic carbon in soil, as well as the distinct humic fractions were investigated, analyzing both the elemental and isotopic (13C/12C) composition. In soils, organic matter appears to be variously affected by mineralization processes induced by microorganisms that consume organic carbon. In particular, organic carbon declined in farms located in the plain (e.g., organic carbon down to 0.75 wt%, carbon stock0-30 cm down to 33 Mg/ha), because of the warmer climate and moderately alkaline environment that enhance soil microbial activity. On the other hand, at the mountain farm, the minimum soil disturbance, the cold climate, and the neutral conditions favored soil C sequestration (organic carbon up to 4.42 wt%, carbon stock0-30 cm up to 160 Mg/ha) in humified organic compounds with long turnover, which can limit greenhouse gas emissions into the atmosphere. This work shows the need for thorough soil investigations, to propose tailored best-practices that can reconcile productivity and soil sustainability.

The quantification of soil carbon pools is a pressing topic both for the agriculture productivity and to evaluate the Greenhouse Gases (GHG) sequestration potential, therefore a rapid and precise analytical protocol for carbon speciation is needed. Temperature-dependent differentiation of soil carbon in compliance with the DIN (German Institute for Standardization) 19539 standard has been applied for the first time on 24 agricultural soil samples from the Po River Plain (Italy), with the aim of investigate their thermal behavior in the 50−900 °C interval. The results invariably show the existence of three soil carbon pools having different thermal stabilities, namely, thermally labile organic carbon (TOC400), residual oxidizable carbon (ROC) and total inorganic carbon (TIC900), in the intervals of 300−400 °C, 510−600 °C and 700−900 °C, respectively. Significant relationships have been observed between the above mentioned organic and inorganic carbon pools and the associated isotopic composition: 1) inverse correlation between TOC400/ROC and δ13C links thermal stability and soil organic matter (SOM) composition; 2) direct correlation between carbonate breakdown temperature and δ13C denotes the mineralogical association of the inorganic pool. The results give clues regarding the nature and evolution of soil carbon pools.

A catalyst-free heterocyclization reaction of &alpha, chloroglycinates with thiobenzamides or thioureas leading to 2,4-disubstituted-5-acylamino-1,3-thiazoles has been developed. The methodology provides straightforward access to valuable building blocks for pharmaceutically relevant compounds.

A new analytical approach (Thermally Based Separation, TBS) for the characterisation of inorganic (IC) and organic (OC) carbon pools in alluvial soils has been tested. The method does not involve any chemical pre-treatment of samples and relies on different thermal stabilities of IC and OC pools, which can be accurately determined with an EA-IRMS analytical system. Elemental (C, g/kg) and isotopic (δ13C, ‰) carbon data were used to check the reliability of the TBS method by calculating the mass balances using the measured IC and OC fractions and total carbon (TC). TBS was applied to 7 soil samples from the Padanian alluvial plain (NE Italy) that were collected from different depths and characterised by textural/geochemical heterogeneity. The method allowed for a mean carbon elemental recovery of 99% (SD = 2%), and mean isotopic deviation (Δ13C) between theoretical (δ13COC XOC + δ13CIC XIC)/(XOC + XIC) and measured δ13CTC of 0.2‰ (SD = 0.3‰). A comparison of TBS with other conventional methods for carbon separation provided insights into the possible effects of sample acidification on the soil organic pools. The results suggest a higher robustness of TBS compared to conventional methods in the determination of organic and inorganic carbon pools in soils. This is because TBS bypasses any possible fractionation derived from the hydrolysis of soil organic matter and therefore accurately determines the carbon isotopic composition of the OC and IC fractions. TBS appears to be more robust than conventional methods and is independent from the IC/OC ratio of the samples, from the unpredictable complexity of soil organic matter and from the arbitrary application of the acidification routine. On this basis, TBS represents a very promising approach for a correct and complete characterisation of soil carbon pools.

The Sacca di Goro and Sacca di Scardovari are two coastal lagoons of the Po River delta facing the northern Adriatic Sea. They are sensitive ecosystems both from the naturalistic and socio-economic point of view, since they are included in a natural park and are high productivity shellfish sites. Bottom sediments from the two lagoons have been analysed for their textural and geochemical (major and trace elements by XRF) composition in order to identify natural backgrounds and anthropogenic inputs. OC, N and δ13COC data have been also carried out by EA-IRMS to highlight the association of heavy metals with inorganic or organic sedimentary components. Results show that abundances of siderophile (Cr, Ni, Co) heavy metals in samples from the two lagoons are generally in the range of those recorded in alluvial sediments from the neighbours and are associated with the finest (clayey) fraction. Among chalcophile heavy metals, Pb and Zn display significant enrichments relative to the local geochemical backgrounds suggesting anthropogenic sources. They appear to be preferentially associated with the sedimentary organic matter that, according to the isotopic composition, is mainly formed by the incorporation of different proportions of macroalgae and macrophytes that have a significant bioaccumulation capacity. Taking into consideration that the extent of the algal biomass is sensitive to anthropogenic pressure and climatic changes, the trace element budget of sediments from these lagoons has to be monitored in the future, also to assess the impact of heavy metals on shellfish production.

Skeletal muscle atrophy occurs in response to various pathophysiological stimuli, including disuse, aging, and neuromuscular disorders, mainly due to an imbalance of anabolic/catabolic signaling. Branched Chain Amino Acids (BCAAs: leucine, isoleucine, valine) supplements can be beneficial for counteracting muscle atrophy, in virtue of their reported anabolic properties. Here, we carried out a proof-of-concept study to assess the in vivo/ex vivo effects of a 4-week treatment with BCAAs on disuse-induced atrophy, in a murine model of hind limb unloading (HU). BCAAs were formulated in drinking water, alone, or plus two equivalents of L -Alanine (2 ALA) or the dipeptide L -Alanyl- L -Alanine (Di-ALA), to boost BCAAs bioavailability. HU mice were characterized by reduction of body mass, decrease of soleus – SOL – muscle mass and total protein, alteration of postural muscles architecture and fiber size, dysregulation of atrophy-related genes (Atrogin-1, MuRF-1, mTOR, Mstn). In parallel, we provided new robust readouts in the HU murine model, such as impaired in vivo isometric torque and ex vivo SOL muscle contractility and elasticity, as well as altered immune response. An acute pharmacokinetic study confirmed that L -ALA, also as dipeptide, enhanced plasma exposure of BCAAs. Globally, the most sensitive parameters to BCAAs action were muscle atrophy and myofiber cross-sectional area, muscle force and compliance to stress, protein synthesis via mTOR and innate immunity, with the new BCAAs + Di-ALA formulation being the most effective treatment. Our results support the working hypothesis and highlight the importance of developing innovative formulations to optimize BCAAs biodistribution.

In this paper we present an elemental and isotopic investigation of carbon and nitrogen in the soil-plant system. Plants grown in an unamended soil were compared to plants grown in a soil amended with natural and NH4+-enriched zeolitites. The aim was to verify that zeolitites at natural state increase the chemical fertilization efficiency and the nitrogen transfer from NH4+-enriched zeolitites to plants. Results showed that plants grown on plots amended with zeolitites have generally a δ15N approaching that of chemical fertilizers, suggesting an enhanced nitrogen uptake from this specific N source with respect to the unamended plot. The δ15N of plants grown on NH4+-enriched zeolitites was strongly influenced by pig-slurry δ15N (employed for the enrichment process), confirming the nitrogen transfer from zeolitites to plants. The different agricultural practices are also reflected in the plant physiology as recorded by the carbon discrimination factor, which generally increases in plots amended with natural zeolitites, indicating better water/nutrient conditions.

The presented research highlights relationships between the climatic anomalies that occurred in northern Italy in 2015 and the water system of Po river. We investigated the effect of anomalous high temperature and paucity of meteoric precipitation on the Po river discharge and water geochemistry. The new geochemical data, carried out on river water sampled at Pontelagoscuro (close to the city of Ferrara) and in the delta, have been compared with an extended dataset collected since 2009. The comparison emphasizes that water samples of 2015 were characterized by a high electrical conductivity due to high concentrations of conservative ionic species (e.g. Na, Cl, SO4) and nutrients such as nitrate. Oxygen and hydrogen isotopes, particularly sensitive to the observed climatic changes, reveal in a δ18O-δD diagram evaporative trends (highlighted by displacement from the Meteoric Water Lines) with a magnitude that was not recorded in the last years. The monitoring is currently in progress to develop functions that relate geochemical parameters to the evolving meteo-hydrological conditions.

Sulfide mineralization in the province of Trento (northeastern Italy) includes various mineral assemblages that are often silver-rich and have been exploited in different phases from the Middle Ages until the 20th century. This study investigates mineralized rocks from three historically important sites (Calisio mount, Erdemolo lake, and the locality of Cinque Valli), providing new analytical data (Inductively Coupled Plasma-Mass Spectrometry on bulk rocks, and Scanning Electron Microscopy on thin sections) that demonstrate that parageneses do not only include galena, chalcopyrite, and sphalerite but also accessory minerals, such as tetrahedrite, tennantite, acanthite, and sulfosalts (matildite/polybasite). This explains the high content of As (up to 278 ppm), Bi (up to 176 ppm), and Sb (up to 691 ppm) that are associated with Pb–Cu–Zn mineralization. Notably, trace-element ratios indicate that, although closely associated from a geographical point of view, the studied sites are not genetically related and have to be referred to in distinct mineralization events, possibly induced by three diverse magmatic and hydrothermal phases that occurred in the Variscan post-orogenic setting. Besides geological and petrogenetic reconstruction, the new data outline potential geochemical risks, as they reveal a high concentration of elements characterized by marked toxicity that can be transferred into the local soil and water. Therefore, future studies should be devoted to better investigating the metal distribution in the surroundings of ancient mining sites and their geochemical behavior during the weathering processes.

The central nervous system (CNS) constitutively expresses complement (C) membrane receptors and complement proteins, including the component C5a. This is a crucial terminal effector of the C cascade, mostly involved in pain and neuroinflammatory conditions. Aberrant activation of C5a protein and its receptor C5aR has been reported to play a critical role in neurodegenerative diseases, with important clinical consequences. Here we have investigated the effects of DF3016A, a novel selective C5aR antagonist, able to penetrate the blood-brain barrier (BBB), on cortical neurons exposed to oxygen-glucose deprivation-reoxygenation (OGD/R), a neuroinflammation-related process. We demonstrated that a mild ischemic insult induces an early upregulation of C5aR associated with the over-production of pro-inflammatory cytokines and the over-expression of the transcriptional regulatory factor miR-181. Furthermore, we report the first experimental evidence of the effect of DF3016A, modulating complement component C5a, on neurons in a model of injury. Interestingly, DF3016A protects neuronal viability by restoring intracellular calcium levels, thus opposing the increase in pro-inflammatory cytokine levels and miR-181 expression. Based on our results, we suggest that DF3016A is a novel C5aR antagonist promoting protective effects against OGD/R-induced damage that could be a new therapeutic approach to controlling CNS neuroinflammatory conditions.

Background: Branched-chain amino acids (BCAAs: leucine, isoleucine, valine) account for 35% of skeletal muscle essential amino acids (AAs). As such, they must be provided in the diet to support peptide synthesis and inhibit protein breakdown. Although substantial evidence has been collected about the potential usefulness of BCAAs in supporting muscle function and structure, dietary supplements containing BCAAs alone may not be effective in controlling muscle protein turnover, due to the rate-limiting bioavailability of other AAs involved in BCAAs metabolism. Methods: We aimed to evaluate the in vivo/ex vivo effects of a 4-week treatment with an oral formulation containing BCAAs alone (2:1:1) on muscle function, structure, and metabolism in a murine model of physiological exercise, which was compared to three modified formulations combining BCAAs with increasing concentrations of L-Alanine (ALA), an AA controlling BCAAs catabolism. Results: A preliminary pharmacokinetic study confirmed the ability of ALA to boost up BCAAs bioavailability. After 4 weeks, mix 2 (BCAAs + 2ALA) had the best protective effect on mice force and fatigability, as well as on muscle morphology and metabolic indices. Conclusion: Our study corroborates the use of BCAAs + ALA to support muscle health during physiological exercise, underlining how the relative BCAAs/ALA ratio is important to control BCAAs distribution.

Strontium isotopic composition (Sr-87/Sr-86) of river water provides insight on the nature of rocks involved in the weathering processes and important constraints for reconstructing silicate versus carbonate weathering in large scale basins. New data, presented in the context of a geochemical map of the Po river basin, highlight that the Po river water evolves from the upper part of the catchment, where Sr-87/Sr-86 approaching 0.7097 relates to the weathering of igneous and metamorphic silicate rocks, to the middle part, where less radiogenic compositions (Sr-87/Sr-86 similar to 0.7089) are driven by the confluence of the tributaries draining Mesozoic carbonate rocks of the South Alpine domain and from inflow of Apennine streams characterized by less radiogenic Sr signatures due to weathering of marly sediments and mafic magmatic rocks. Down flow, the Sr isotopic compositions of Po river water rises at 0.7091 either by the confluence of the last Apennine tributary (Panaro, Sr-87/Sr-86 similar to 0.7095) and/or by the possible contribution from hyporheic exchanges. Po river isotopic signatures reveal slightly more radiogenic Sr-87/Sr-86 in comparison to other important Alpine river systems (e.g. Danube, Rhine and Rhone), likely suggesting that silicate rocks are comparatively contributing more weathering byproducts in the Po basin.

A comprehensive study including new field, petrological and geochemical data is reported on the Jacupiranga alkaline-carbonatite complex (133–131 Ma) which, together with other alkaline complexes, occurs in southern Brazil and is coeval with the Parana CFB province. It consists of a shallow intrusion (ca. 65 km2) in the Precambrian crystalline basement, and can be subdivided in two main diachronous plutonic bodies: an older dunite-gabbro-syenite in the NW and a younger clinopyroxenite-ijolite (s.l.) in the SE, later injected by a carbonatitic core (ca. 1 km2). An integrated petrogenetic model, based on bulk rock major and trace element analyses, mineral chemistry and Sr-Nd-Pb-C isotopic data, suggests that the two silicate intrusions generated from different mantle-derived magmas that evolved at shallow level (2–3 km depth) in two zoned cup-shaped plutonic bodies growing incrementally from independent feeding systems. The first intrusion was generated by OIB-like alkaline to mildly alkaline parental basalts that initially led to the formation of a dunitic adcumulate core, discontinuously surrounded by gabbroic cumulates, in turn injected by subanular syenite intrusive and phonolite dykes. Nephelinitic (± melilite) melts – likely generated deep in the lithosphere at ≥ 3 GPa – were the parental magmas of the second intrusion and gave rise to large coarse-grained clinopyroxenite ad- to meso-cumulates, in turn surrounded, and partially cut, by semi-annular fine-layered melteigite-ijolite-urtite ortho-cumulates. The available isotopic data do not evidence genetic links between carbonatites and the associated silicate intrusions, thus favouring an independent source from the mantle. Moreover, it may be suggested that, unlike gabbro-syenites and carbonatites, mostly generated from lithospheric mantle sources, the parental magmas of the ijolite-clinopyroxenite intrusion also record the influence of sublithospheric (plume-related?) geochemical components.

Chiral substituted phenylethyl-1 H -tetrazoles were built-up from the corresponding carboxylic acid derivatives by a useful three-step synthesis. The procedure, that preserves the chiral center from racemization, was successfully applied to a selection of several hit compounds by conversion of the carboxylic acid moiety to the nitrile derivatives and subsequent reaction with trimethylstannyl azide, under microwave conditions. A useful application to the corresponding tetrazole analogue has been found also in the conversion of the aminoacidic moiety like ( R )- N -Cbz-phenylglycine showing a wide potential synthetic application.

Heavy metals having both natural and anthropogenic origin are common contaminants in soils and sediments, and can be transferred and bioaccumulated at all levels of the food chain, posing serious environmental concern to the local population. In this paper, agricultural soils from the Province of Ferrara (easternmost part of the Padanian Plain, northern Italy) were investigated to assess the levels of potentially toxic metals in relation to their phytoavailability. Agricultural soils have been sampled in order to identify the origin, mobility and bioavailability of heavy metals, collecting superficial and deeper (depths of 20–30 and 100–120 cm, respectively) horizons. The “total” XRF analyses properly elaborated with a statistical approach reveal that soils evolved from two distinct types of alluvial sediments, in turn related to the Po and Reno rivers; the former type is distinctively enriched in heavy metals (particularly Cr and Ni), reflecting the presence of femic and ultrafemic rocks in the hydrological basin of River Po. The absence of Top Enrichment Factors for Ni, Co, Cr, V, and Pb suggests that the content of these elements is natural and unaffected by contamination, whereas superficial enrichments of Cu (and Zn) is ascribed to anthropogenic inputs related to agricultural activities. Multiple extraction tests using variously aggressive reactants (aqua regia, DTPA, EDTA, NH4NO3, and H2O) analyzed by ICP gave insights on the specific mobility of the distinct elements, which decreases in the following order: Pb > Cu > Cd > Co > >Ni > Cr. Taking into consideration the elements that are inducing the main concerns, Cr appears scarcely mobile, whereas Ni could be more phytoavailable and has to be monitored in the local agricultural products. Cd although scarcely abundant has to be monitored for its mobility and toxicity, whereas Cu although abundant and extremely mobile doesn’t induce concerns as it is not hazardous for the living receptors.

Po is the main Italian river and the δ18O and δ2H of its water reveal a similarity between the current meteoric fingerprint and that of the past represented by groundwater. As concerns the hydrochemisty, the Ca–HCO3 facies remained constant over the last 50 year, and only nitrate significantly increased from less than 1 mg/L to more than 10 mg/L in the 1980s, and then attenuated to a value of 9 mg/L. Coherently, δ13CDIC and δ34SSO4 are compatible with the weathering of the lithologies outcropping in the basin, while extremely variable δ15NNO3 indicates contribution from pollutants released by urban, agricultural and zootechnical activities. This suggests that although the origin of the main constituents of the Po river water is geogenic, anthropogenic contributions are locally significant. Noteworthy, the associated aquifers have the same nitrogen isotopic signature of the Po river, but are characterized by significantly higher NO– 3 concentration. This implies that aquifers’ pollution is not ascribed to inflow of current river water, and that the attenuation of the nitrogen load recorded in the river is not occurring in the aquifers, due to their longer water residence time and delayed recovery from anthropogenic contamination.

Interleukin-8 and growth related oncogene-α-chemokines (formerly CXCL8 and CXCL1, respectively) mediate chemotaxis of neutrophils to inflammatory sites via interactions with two transmembrane receptors, the type A CXCL8 receptor (CXCR1) and the type B CXCL8 receptor (CXCR2). In a previous work, we published the molecular modeling-driven structure activity relationship (SAR) results culminated in the discovery of R-(-)-2-[(4'-trifluoromethanesulphonyloxy)phenyl]-N-methanesulfonyl propionamide (19), in which an unusual aryltriflate moiety was embedded. Although triflates are broadly used in organic synthesis, this group is scarcely used in medicinal chemistry programs. Here we detail the drug profiling-driven approach used for the selection and characterization of 19, the most potent dual CXCR1 and CXCR2 noncompetitive inhibitor described to date. Reported data suggest that the aryltriflate moiety might represent a valid choice for the selection of clinical candidates with suitable druglike properties.

A novel one-pot two-step procedure has been developed to synthesize highly substituted 2-arylpropionic and arylacetic acids, by treatment with aqueous HI, from cyanohydrins. The hydrogenolytic reduction of α-hydroxy-2-arylpropionic acids was the key step of the process and the optimization of the reaction conditions led to identify aqueous HI as an appropriate and selective reagent for the reductive deoxygenation of cyanohydrins. The synthetic route described a general and efficient strategy for the preparation of large libraries of phenylacetic and phenylpropionic acids derivatives.

The transient receptor potential melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity is available. This study characterizes a new TRPM8-selective antagonist (DFL23448 [5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol]) and evaluates it in cold-induced behavioral tests and tests on bladder function and experimental bladder overactivity in vivo in rats. DFL23448 displayed IC50 values of 10 and 21 nM in hTRPM8 human embryonic kidney 293 cells activated by Cooling Agent 10 or cold, but it had limited activity (IC50 > 10 μM) at transient receptor potential vanilloids TRPV1, TRPA1, or TRPV4 or at various G protein-coupled receptors. In rats, DFL23448 administered intravenously or orally had a half-life of 37 minutes or 4.9 hours, respectively. DLF23448 (10 mg/kg i.v.) reduced icilin-induced "wet dog-like" shakes in rats. Intravesical DFL23448 (10 mg/l), but not vehicle, increased micturition intervals, micturition volume, and bladder capacity. During bladder overactivity by intravesical prostaglandin E2 (PGE2), vehicle controls exhibited reductions in micturition intervals, micturition volumes, and bladder capacity by 37%-39%, whereas the same parameters only decreased by 12%-15% (P < 0.05-0.01 versus vehicle) in DFL23448-treated rats. In vehicle-treated rats, but not in DFL23448-treated rats, intravesical PGE2 increased bladder pressures. Intravenous DFL23448 at 10 mg/kg, but not 1 mg/kg DFL23448 or vehicle, increased micturition intervals, micturition volumes, and bladder capacity. During bladder overactivity by intravesical PGE2, micturition intervals, micturition volumes, and bladder capacity decreased in vehicle- and 1 mg/kg DFL23448-treated rats, but not in 10 mg/kg DFL23448-treated rats. Bladder pressures increased less in rats treated with DFL23448 10 mg/kg than in vehicle- or 1 mg/kg DFL23448-treated rats. DFL23448 (10 mg/kg i.v.), but not vehicle, prevented cold stress-induced bladder overactivity. Our results support a role for bladder TRPM8-mediated signals in experimental bladder overactivity.

One of the molecular factors contributing to Leishmania sp. virulence and pathogenesis is the major surface metalloprotease GP63, alternatively called leishmanolysin, MSP, and PSP (EC 3.4.24.36). Here, the molecular dynamics simulation of Leishmania major GP63 in water at pH 7 is reported. Upon solvation, GP63 undergoes a sharp structural relaxation with respect to the crystal structure. The fluctuation pattern occurs essentially in solvent-exposed nonstructured regions. By contrast, the active site turns out to be rigid. Essential dynamics and dynamic-domain analyses, both carried out on the equilibrated portion of GP63, show that the fingerprint fluctuations of GP63 are practically characterized by the motion of a large part of the N-terminal domain. These results appear to be in line with substrate recognition and (pro)enzyme activation played by the N-terminal domain of GP63. A systematic analysis among a series of 10 homologs of GP63 also shows that the residues involved in the interdomain bending result highly conserved. This finding also suggests possible relationship between the maintainance of proteolytic activity and the similarity of the dynamical properties of the related enzymes.

Elemental and isotopic analyses of carbon in environmental matrices usually highlight multiple pools of different composition and (13)C/(12)C (δ(13)C‰) isotopic ratio. Interpretation necessarily needs the characterization of the diverse end-members that usually are constituted by inorganic and organic components. In this view, we developed a routine protocol based on coupling of elemental and isotopic analyses that is able to discriminate the inorganic (IC) and organic (OC) contributions to the total carbon (TC) content. The procedure is only based on thermal destabilization of the different carbon pools and has been successfully applied on different environmental matrices (rocks, soils, and biological samples) with a mean C elemental and isotopic recoveries of 99.5% (SD = 1.3%) and 0.2‰ (SD = 0.2‰), respectively. The thermally based speciation (TBS) leads us to define precise isotopic end-members, which are unaffected by any chemical treatment of the sample, to be used for accurate mass balance calculation that represents a powerful tool to quantify the distinct carbon pools. The paper critically evaluates the method explaining the potentials and the current limits of the proposed analytical protocol.

The content of heavy metals in water and soil is a key parameter for evaluating the geochemical vulnerability of an ecosystem. These elements display a limited solubility and are easily trapped and adsorbed by phyllosilicate minerals; they are thus preferentially partitioned in the fine fraction of sediments. In this light, an analysis of recent river sediments gives information on possible water pollution, and more in general on the related ecosystem. We therefore investigated the chemical–mineralogical features of clay sediments outcropping around the town of Ferrara, paying particular attention to their fine fraction (grain size X-ray fluorescence (XRF) analyses indicate that the abundance of transition trace elements, such as Cr and Ni, is positively correlated with MgO wt.%, and discriminates two well-delineated populations of samples, respectively characterised by high (Cr>180 ppm; Ni>100 ppm) and low (Cr 1); on the other hand, the high-Cr samples have a coarser grain size, and a lower abundance of clay minerals in which chlorite (Mg-rich chlorite in this group of samples) predominates over smectite+mixed layers (Sm+ML/Chl An integration of similar scientific contributions would be useful to set up a geochemical–mineralogical database as a first step toward the preparation of more complete thematic maps. These would provide information relative to the behaviour (e.g. distribution and abundance) of chemical elements within the different geochemical spheres, and would be useful for recognising and interpreting possible geochemical anomalies induced by pollution processes.

Complexes [Rh(1,5-COD)(Q)] have been prepared by the reaction between [Rh(1,5-COD)Cl] 2 (1,5-COD=1,5-cyclooctadiene) and HQ (where HQ=1-phenyl-3-methyl-4-R-pyrazol-5-one: R=2-thenoyl ( HQ s ), 2-furanoyl ( HQ o ) or tert -butylacetyl ( HQ T ). [Rh(1,5-COD)(Q)] react with N 2 -donor ligands such as 1,10-phenanthroline (phen) or 2,2-bipyridyl (bipy) yielding ionic compounds [Rh(1,5-COD)(N 2 -donor)]Q. The substitutional lability of 1,5-COD in [Rh(1,5-COD)(Q)] versus mono- and di-organophosphine ligands was also investigated. In all cases 1,5-COD has been displaced. Reaction with two equivalents of PPh 3 gave, upon oxidation of the Rh(I) centre, [Rh(PPh 3 ) 2 (O 2 )(Q)] species containing a η 2 -peroxo-group. Reaction of [Rh(1,5-COD)(Q)] with the chelating P 2 -donor 1,2-bis(diphenylphosphino)ethane (dppe) or 4,4′-bis(diphenylphosphino)ferrocene (dppf) yields the peroxo Rh(III) compounds [Rh(dppe) 2 O 2 ]Q T and [Rh(dppf)O 2 (Q s )] or Rh(I) species [Rh(dppf-O 2 )(Q T )] containing the diphosphine in the oxidised form. Finally the reaction between [Rh(1,5-COD)(Q)] and allylbromide yields the well-known [Rh(1,5-COD)Br] 2 . All complexes have been characterised by analytical and spectral data (IR, 1 H and 31 P{ 1 H}-NMR spectra). The crystal structures of [Rh(1,5-COD)(Q s )], [Rh(1,5-COD)(phen)]Q s and [Rh(1,5-COD)Br] 2 , all containing a Rh(I) atom in a square coordinate environment, are also reported.

Column laboratory experiments were employed to assess the leaching behaviour of pyroclastic glassy ash deposits collected in the central Main Ethiopian Rift, where surface and groundwater resources are affected by fluoride (F−) pollution, which is the cause of an endemic disease (fluorosis) in the local community. To elucidate the source of F− and simulate the water-rock interaction processes, as well as quantify its distribution within different grain sizes, the pyroclastic ash was analysed by XRF, XRD and SEM and separated into coarse and fine fractions. Three columns were filled with raw (unsieved), coarse (63 μm-2 mm) and fine (63 μm) fraction, respectively, and flushed with synthetic rain water in saturated conditions. Very fast F− leaching was observed in the fine fraction column at the start of the experiment, while in the other two columns, F− was slowly released; in addition, a strong accumulation of F− was found in the fine fraction. The effect was more pronounced in the fine fraction column due to the available effective adsorbing surface area. Subsequent to elution experiments, the columns were characterised via moment analysis of tracer test. Finally, flow and transport modelling (MODFLOW-2000 and MT3DMS) was employed to compute the amount of F− adsorbed onto the solid phase, comparing the calculated conservative transport of F− and the observed concentrations. The results of this study suggest that fluoride is a fundamental constituent of the glass phase (about 0.3 wt.%) and that it is released during the incongruent dissolution of glassy particles. Dissolution of coatings on glass particles could provide an additional contribution to the geochemistry of the interacting fluids. These processes are more effective in the fine fraction due to a much higher reactive (specific) surface area.

Drinking water supply for the Main Ethiopian Rift (MER) area principally relies on groundwater wells and springs and is characterized by natural source of elevated fluoride concentration. New analyses reveal that the F − geochemical anomaly is associated with other potentially toxic elements such as As, U, Mo and B. Particularly, 35% of the 23 investigated groundwater wells and 70% of the 14 hot springs (and geothermal wells) show arsenic concentrations above the recommended limit of 10 μg/L ( WHO, 2006 ). Arsenic in groundwater wells has a positive correlation with Na + ( R 2 = 0.63) and alkalinity ( HCO 3 - ; R 2 = 0.70) as well as with trace elements such as U ( R 2 = 0.70), Mo ( R 2 = 0.79) and V ( R 2 = 0.68). PHREEQC speciation modelling indicates that Fe oxides and hydroxides are stable in water systems, suggesting their role as potential adsorbents that could influence the mobility of arsenic. Chemical analyses of leachates from MER rhyolitic rocks and their weathered and re-worked fluvio-lacustrine sediments were performed to evaluate their contribution as a source of the mentioned geochemical anomalies. These leachates were obtained from a 1-year leaching experiment on powdered rocks and sediments mixed with distilled water (10 g:50 ml). They contain as much as 220 μg/L of As, 7.6 mg/L of F − , 181 μg/L of Mo, 64 μg/L of U and 254 μg/L of V suggesting that the local sediments represent the main source and reservoir of toxic elements. These elements, originally present in the glassy portion of the MER rhyolitic rocks were progressively concentrated in weathered and re-deposited products. Therefore, together with the renowned F − problem, the possible presence of further geochemical anomalies have to be considered in water quality issues and future work has to investigate their possible health impact on the population of MER and other sectors of the East African Rift.

A novel one-pot two-step procedure has been developed to synthesize highly substituted 2-arylpropionic and arylacetic acids, by treatment with aqueous HI, from cyanohydrins. The hydrogenolytic reduction of α-hydroxy-2-arylpropionic acids was the key step of the process and the optimization of the reaction conditions led to identify aqueous HI as an appropriate and selective reagent for the reductive deoxygenation of cyanohydrins. The synthetic route described a general and efficient strategy for the preparation of large libraries of phenylacetic and phenylpropionic acids derivatives.

The central Main Ethiopian Rift suffers a severe water quality problem, characterized by an anomalously high fluoride (F) content that causes an endemic fluorosis disease. The current study, conducted in the Ziway–Shala lakes basin, indicates that the F content exceeds the permissible limit for drinking prescribed by the World Health Organization (WHO; 1.5 mg/l) in many important wells (up to 20 mg/l), with even more extreme F concentration in hot springs and alkaline lakes (up to 97 and 384 mg/l respectively). The groundwater and surface water from the highlands, typically characterized by low total dissolved solids (TDS) and Ca (Mg)–HCO3 hydrochemical facies, do not show high F content. The subsequent interaction of these waters with the various rocks of the rift valley induces a general increase of the TDS, and a variation of the chemical signature towards Na–HCO3 compositions, with a parallel enrichment of F. The interacting matrixes are mainly rhyolites consisting of volcanic glass and only rare F-bearing accessory minerals (such as alkali amphibole). Comparing the abundance and the composition of the glassy groundmass with other mineral phases, it appears that the former stores most of the total F budget. This glassy material is extremely reactive, and its weathering products (i.e. fluvio/volcano-lacustrine sediments) further concentrate the fluoride. The interaction of these “weathered/reworked” volcanic products with water and carbon dioxide at high pH causes the release of fluoride into the interacting water. This mainly occurs by a process of base-exchange softening with the neo-formed clay minerals (i.e. Ca–Mg uptake by the aquifer matrix, with release of Na into the groundwater). This is plausibly the main enrichment mechanism that explains the high F content of the local groundwater, as evidenced by positive correlation between F, pH, and Na, and inverse correlation between F and Ca (Mg). Saturation indices (SI) have been calculated (using PHREEQC-2) for the different water groups, highlighting that the studied waters are undersaturated in fluorite. In these conditions, fluoride cannot precipitate as CaF2, and so mobilizes freely without forming other complexes. These results have important implications for the development of new exploitation strategies and accurate planning of new drilling sites.

Polymer-supported methyltrioxorhenium (MTO) systems are efficient catalysts for the oxidative functionalisation of cyclohexane and cyclopentane, derivatives with H2O2 as oxygen donor. Using poly (4-vinyl)pyridine and poly(4-vinyl)pyridine-N-oxide as MTO supports, cycloalkanol, cycloalkanediol, cycloalkanone and omega-hydroxy methyl ketone derivatives were obtained in different yields depending on the experimental conditions. Interestingly, cycloalkane dimers were selectively recovered in acceptable to good yields when the oxidation was performed with polystyrene-microencapsulated MTO catalyst. The EPR investigation suggests that the homolytic cleavage of the CH3-Re bond with formation of CH3 center dot radicals occurs inside the polystyrene capsule, indicating a possible role of methyl radical in the cycloalkane dimerisation pathway. (c) 2006 Published by Elsevier Ltd.

Polymer-supported methyltrioxorhenium (MTO) compounds are shown to act as efficient and selective catalysts for the oxy-functionalization of C–H bonds in representative hydrocarbon derivatives (leading to the corresponding alcohols or ketones), using H2O2 as oxidant. The different supports used for the heterogenation of MTO, such as poly(4-vinylpyridine), poly(4-vinylpyridine)-N-oxide and polystyrene resins, all showed different catalytic behaviour in terms of substrate conversion and product yield, depending on the experimental conditions used. It is noteworthy that the novel heterogeneous catalysts were found to be stable, it being possible to effect their recover and recycle at least five times without appreciable loss of activity.

Three novel peptidomimetic phosphinate inhibitors have been synthesized and evaluated as inhibitors of matrix metalloproteinases MMP-2 and MMP-8. Their IC50 values are in the micromolar range, and one of them showed to be the most effective inhibitor of MMP-2. The differences in binding affinities for MMP-2 and MMP-8 of the three phosphinates have been rationalized by means of modelling studies and molecular dynamics simulations.

A convenient and efficient C–H insertion reaction of environment friendly H2O2 into representative hydrocarbon derivatives by homogeneous methyltrioxorhenium (MTO), heterogeneous poly(4-vinylpyridine)/methyltrioxorhenium (PVP/MTO) and microencapsulated polystyrene/methyltrioxorhenium (PS/MTO) systems in ionic liquids, is described. In some cases a higher activity was observed if compared with the same reaction in molecular solvents. The heterogeneous catalysts are stable systems under the reaction conditions and can be recycled for more transformations.

Novel poly(4-vinylpyridine) supported MTO compounds were effective heterogeneous catalysts for the C–H insertion reactions of H 2 O 2 into some representative hydrocarbon derivatives. The most relevant outcomes of these oxidations are described.