Publications by authors named "Gianluca Bianchini"

22 Publications

  • Page 1 of 1

A new synthetic dual agonist of GPR120/GPR40 induces GLP-1 secretion and improves glucose homeostasis in mice.

Biomed Pharmacother 2021 Jul 22;139:111613. Epub 2021 Apr 22.

Research and Early Development, Dompé Farmaceutici S.p.A., L'Aquila, Italy. Electronic address:

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 Ca 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).
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http://dx.doi.org/10.1016/j.biopha.2021.111613DOI Listing
July 2021

Traceability and Authentication of Manila Clams from North-Western Adriatic Lagoons Using C and N Stable Isotope Analysis.

Molecules 2021 Mar 25;26(7). Epub 2021 Mar 25.

Department of Physics and Earth Sciences, University of Ferrara, 44122 Ferrara, Italy.

In the Adriatic lagoons of northern Italy, manila clam () farming provides important socio-economic returns and local clams should be registered with the Protected Designations of Origin scheme. Therefore, there is a need for the development of rapid, cost-effective tests to guarantee the origin of the product and to prevent potential fraud. In this work, an elemental analysis (EA) coupled with isotope ratio mass spectrometry (IRMS) was employed to identify the isotopic fingerprints of clams directly collected onsite in three Adriatic lagoons and bought at a local supermarket, where they exhibited certification. In particular, a multivariate analysis of C/N, δC and δN in manila clam tissues as well as δC in shells and ΔC (calculated as δC-δC) seems a promising approach for tracking the geographical origin of manila clams at the regional scale.
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http://dx.doi.org/10.3390/molecules26071859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037060PMC
March 2021

Petrographic and mineral-glass chemical dataset of igneous rock clasts from Early Oligocene Aveto-Petrignacola Formation (Northern Italy).

Data Brief 2020 Aug 12;31:106015. Epub 2020 Jul 12.

Dipartimento di Fisica e Scienze della Terra, Università degli Studi di Ferrara, Via Saragat, 1, 44100 Ferrara, Italy.

This dataset article contains petrographic and mineral-glass chemical data of igneous rock clasts from Early Oligocene Aveto-Petrignacola Formation (APF; Northern Italy). Methods for obtaining the dataset include optical microscopy, scanning electron microscopy and electron probe microanalysis. The APF volcanic rocks are basalts, basaltic andesites, andesites, dacites and rhyolites. Rare gabbroic cumulate nodules complete the dataset. Basalts are porphyritic, with calcic plagioclase (AnAbOr), ferroan enstatite (EnFsWo) and augite (EnFsWo) phenocrysts, in a hypocrystalline groundmass made up of bytownite (AnAbOr), augite (EnFsWo), ferroan enstatite (EnFsWo) and rare pigeonite (EnFsWo). The basaltic andesites are porphyritic to glomeroporphyritic with phenocrysts of zoned plagioclase (AnAbOr), orthopyroxene, Mg-rich augite (EnFsWo), rare pargasite to edenite amphibole (Mg# 69-59) and very rare biotite in a hypocrystalline to holohyaline groundmass. Andesites are highly porphyritic with phenocrysts of plagioclase (AnAbOr), pargasite to magnesio-hornblende (Mg# 72-67), Mg-rich augite (EnFsWo), subordinate ferroan enstatite (EnFsWo), biotite (Mg# 53) and Ti-magnetite (Usp). Dacites (massive lavas and ignimbrites) are porphyritic, with phenocrysts and phenoclasts of plagioclase (AnAbOr), calcic amphibole (Ti-pargasite, Mg-hornblende and edenite; Mg# 81-46), biotite (Mg# 67-56), very rare Mg-rich augite (EnFsWo) and resorbed quartz in hypohyaline to holohyaline groundmass with a dense mat of anhedral quartz, labradorite-andesine (AnAbOr) and rare anorthoclase (AnAbOr). Rhyolitic compositions have been found both as volcanic clasts (massive lava and ignimbrites) with andesine to oligoclase phenoclasts (AnAbOr), quartz, biotite (Mg# 55-53) and Ti-magnetite (Usp), and as interstitial glasses (residual melt drops) in other APF volcanic rocks. The cumulate nodules are olivine-gabbro and amphibole-gabbro/gabbronorite with a mineral paragenesis dominated by plagioclase (AnAbOr), olivine (Fo), Mg-rich augite to ferroan diopside (EnFsWo; Mg# 79-74), ferroan enstatite (EnFsWo; Mg# 76-68), magnetite (Usp) and titanian pargasite (Mg# 67-65). The main cumulus phases are plagioclase, olivine and pyroxene, while intercumulus/postcumulus phases are titanian pargasite and magnetite. The dataset can be used to compare petrographic features and chemical compositions of calc-alkaline rocks emplaced in other subduction-related settings. Above all, it can represent a useful contribution in solving the problem linked to the identification of a hidden Early-Oligocene source of the thick volcaniclastic APF succession in the Alpine-Apennine belt geodynamic evolution.
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http://dx.doi.org/10.1016/j.dib.2020.106015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390791PMC
August 2020

Ergogenic Effect of BCAAs and L-Alanine Supplementation: Proof-of-Concept Study in a Murine Model of Physiological Exercise.

Nutrients 2020 Jul 30;12(8). Epub 2020 Jul 30.

Section of Pharmacology, Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", Orabona 4-Campus, 70125 Bari, Italy.

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, (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.
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http://dx.doi.org/10.3390/nu12082295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468919PMC
July 2020

Catalyst-Free Synthesis of Polysubstituted 5-Acylamino-1,3-Thiazoles via Hantzsch Cyclization of α-Chloroglycinates.

Molecules 2019 Oct 25;24(21). Epub 2019 Oct 25.

School of Science and Technology, Chemistry Division, University of Camerino, Camerino 62032, Italy.

A catalyst-free heterocyclization reaction of α-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.
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http://dx.doi.org/10.3390/molecules24213846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864457PMC
October 2019

DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain.

Sci Rep 2019 08 13;9(1):11729. Epub 2019 Aug 13.

Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of several anti-neoplastics and a main cause of sensory disturbances in cancer survivors, negatively impacting patients' quality of life. Peripheral nerve degeneration or small fibre neuropathy is generally accepted as the underlying mechanism in the development of CIPN. Recent evidence has contributed to clarify the determinant role of cytokines and chemokines in the process leading to neuronal hyperexcitability. Exposure to oxaliplatin triggers alterations in peripheral neuropathic pathways previously linked to IL-8 pathway. We investigated a novel selective inhibitor of IL-8 receptors, DF2726A, and showed its effects in counteracting CINP pathways, extending the relevance of the activation of IL-8 pathway to the class of platinum chemotherapeutics. Based on our results, we suggest that DF2726A might be a promising candidate for clinical treatment of CIPN conditions due to its efficacy and optimized pharmacokinetic/pharmacodynamic profile.
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http://dx.doi.org/10.1038/s41598-019-48231-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692352PMC
August 2019

Heavy oxygen recycled into the lithospheric mantle.

Sci Rep 2019 Jun 19;9(1):8793. Epub 2019 Jun 19.

Dipartimento di Scienze della Terra, Università degli Studi di Firenze, Via G. La Pira, 4, I-50121, Firenze, Italy.

Magmas in volcanic arcs have geochemical and isotopic signatures that can be related to mantle metasomatism due to fluids and melts released by the down-going oceanic crust and overlying sediments, which modify the chemistry and mineralogy of the mantle wedge. However, the effectiveness of subduction-related metasomatic processes is difficult to evaluate because the composition of arc magmas is often overprinted by interactions with crustal lithologies occurring during magma ascent and emplacement. Here, we show unequivocal evidence for recycling of continental crust components into the mantle. Veined peridotite xenoliths sampled from Tallante monogenetic volcanoes in the Betic Cordillera (southern Spain) provide insights for mantle domains that reacted with Si-rich melts derived by partial melting of subducted crustal material. Felsic veins crosscutting peridotite and the surrounding orthopyroxene-rich metasomatic aureoles show the highest O/O ratios measured to date in upper mantle assemblages worldwide. The anomalously high oxygen isotope compositions, coupled with very high Sr/Sr values, imply the continental crust origin of the injected melts. Isotopic anomalies are progressively attenuated in peridotite away from the veins, showing O isotope variations well correlated with the amount of newly formed orthopyroxene. Diffusion may also affect the isotope ratios of mantle rocks undergoing crustal metasomatism due to the relaxation of O isotope anomalies to normal mantle values through time. Overall, the data define an O isotope "benchmark" allowing discrimination between mantle sources that attained re-equilibration after metasomatism (>5 Myr) and those affected by more recent subduction-derived enrichment processes.
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http://dx.doi.org/10.1038/s41598-019-45031-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584624PMC
June 2019

Correction to: The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury.

Neurotox Res 2019 Aug;36(2):439

Institute of Translational Pharmacology (IFT) - National Council of Research (CNR), L'Aquila, Italy.

The article The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury, written by Laura Brandolini, Marta Grannonico, Gianluca Bianchini, Alessia Colanardi, Pierluigi Sebastiani, Antonella Paladini, Alba Piroli, Marcello Allegretti, and Giustino Varrassi.
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http://dx.doi.org/10.1007/s12640-019-00049-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828472PMC
August 2019

The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury.

Neurotox Res 2019 Jul 5;36(1):163-174. Epub 2019 Apr 5.

Institute of Translational Pharmacology (IFT) - National Council of Research (CNR), L'Aquila, Italy.

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.
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http://dx.doi.org/10.1007/s12640-019-00026-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570783PMC
July 2019

Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat.

Br J Pharmacol 2018 05 14;175(10):1691-1706. Epub 2018 Apr 14.

Dompé Farmaceutici S.p.A., L'Aquila, Italy.

Background And Purpose: Transient receptor potential (TRP) channels are a superfamily of non-selective cation permeable channels involved in peripheral sensory signalling. Animal studies have shown that several TRPs are important players in pain modulation. Among them, the TRP melastatin 8 (TRPM8) has elicited more interest for its controversial role in nociception. This channel, expressed by a subpopulation of sensory neurons in dorsal root ganglia (DRG) and trigeminal ganglia (TG), is activated by cold temperatures and cooling agents. In experimental neuropathic pain models, an up-regulation of this receptor in DRG and TG has been observed, suggesting a key role for TRPM8 in the development and maintenance of pain. Consistent with this hypothesis, TRPM8 knockout mice are less responsive to pain stimuli.

Experimental Approach: In this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested.

Key Results: Two potent and selective TRPM8 antagonists with distinct pharmacokinetic profiles, DFL23693 and DFL23448, have been fully characterized in vitro. In vivo studies in well-established models, namely, the wet-dog shaking test and changes in body temperature, confirmed their ability to block the TRPM8 channel. Finally, TRPM8 blockage resulted in a significant antinociceptive effect in formalin-induced orofacial pain and in chronic constriction injury-induced neuropathic pain, confirming an important role for this channel in pain perception.

Conclusion And Implications: Our findings, in agreement with previous literature, encourage further studies for a better comprehension of the therapeutic potential of TRPM8 blockers as novel agents for pain management.
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http://dx.doi.org/10.1111/bph.14177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913409PMC
May 2018

Natural vs anthropogenic components in sediments from the Po River delta coastal lagoons (NE Italy).

Environ Sci Pollut Res Int 2018 Jan 19;25(3):2981-2991. Epub 2017 Dec 19.

Department of Physics and Earth Sciences, University of Ferrara, Saragat 1, 44123, Ferrara, Italy.

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 δC 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.
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http://dx.doi.org/10.1007/s11356-017-0986-yDOI Listing
January 2018

Natural and anthropogenic variations in the Po river waters (northern Italy): insights from a multi-isotope approach.

Isotopes Environ Health Stud 2016 Dec 16;52(6):649-72. Epub 2016 Mar 16.

e Department of Earth Sciences , Sapienza University of Rome , Rome , Italy.

Po is the main Italian river and the δ(18)O and δ(2)H 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, δ(13)CDIC and δ(34)SSO4 are compatible with the weathering of the lithologies outcropping in the basin, while extremely variable δ(15)NNO3 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.
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http://dx.doi.org/10.1080/10256016.2016.1152965DOI Listing
December 2016

DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain.

Pharmacol Res 2016 Jan 28;103:69-79. Epub 2015 Nov 28.

Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil; Departamento de Bioquímica e Immunologia, Instituto Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, 31270901 Belo Horizonte, Minas Gerais, Brazil. Electronic address:

The activation of CXCR1/2 has been implicated in the genesis of inflammatory and postoperative pain. Here, we investigated a novel orally acting allosteric inhibitor of CXCR1/2 (DF2755A) and evaluated its antinociceptive effect in several models of inflammatory and post-operatory pain. DF2755A was tested in vitro for efficacy in the chemotaxis assay, selectivity and toxicity. In vivo, C57Bl/6 mice were treated orally with DF2755A and the following experiments were performed: pharmacokinetic profile; inflammatory hyperalgesia models using electronic pressure meter test; neutrophil migration assay assessed by myeloperoxidase assay. DF2755A selectively inhibited neutrophil chemotaxis induced by CXCR1/2 ligands without effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF2755A on CXCL8-induced chemotaxis. DF2755A given orally was well absorbed (88.2%), and it was able to reduce, in a dose (3-30mg/kg)-dependent manner, inflammatory hyperalgesia induced by carrageenan, LPS and CXCL1/KC as well as neutrophil recruitment and IL-1β production. In addition, DF2755A was able to reduce post-incisional nociception. Therapeutic treatment with DF2755A reduced CFA-induced inflammatory hyperalgesia even when injected intrathecally. The present results indicate that DF2755A is a novel selective allosteric inhibitor of CXCR1/2 with a favorable oral pharmacokinetic profile. Furthermore, the results might suggest that DF2755A might be a candidate of a novel therapeutic option to control inflammatory and post-operative pain.
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http://dx.doi.org/10.1016/j.phrs.2015.11.005DOI Listing
January 2016

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats.

J Pharmacol Exp Ther 2016 Jan 6;356(1):200-11. Epub 2015 Nov 6.

Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L'Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)

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.
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http://dx.doi.org/10.1124/jpet.115.228684DOI Listing
January 2016

Thermally based isotopic speciation of carbon in complex matrices: a tool for environmental investigation.

Environ Sci Pollut Res Int 2015 Aug 18;22(16):12162-73. Epub 2015 Apr 18.

Dipartimento di Fisica e Scienze della Terra, Università di Ferrara, Ferrara, Italy.

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.
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http://dx.doi.org/10.1007/s11356-015-4503-xDOI Listing
August 2015

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief.

Proc Natl Acad Sci U S A 2014 Nov 10;111(47):16937-42. Epub 2014 Nov 10.

Department of Discovery, Dompé SpA Research Center, 67100 L'Aquila, Italy;

Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the "minor pocket," previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR(-/-) mice compared with WT mice. Furthermore, treatment of C5aR(-/-) mice with DF2593A did not produce any further antinociceptive effect compared with C5aR(-/-) mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain.
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http://dx.doi.org/10.1073/pnas.1417365111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250151PMC
November 2014

The Po river water from the Alps to the Adriatic Sea (Italy): new insights from geochemical and isotopic (δ(18)O-δD) data.

Environ Sci Pollut Res Int 2015 Apr 28;22(7):5184-203. Epub 2014 Oct 28.

Dipartimento di Fisica e Scienze della Terra, Università di Ferrara, Ferrara, Italy.

Although the Po river is the most important fluvial system of Northern Italy, the systematic geochemical and isotopic investigations of its water are rare and were never reported for the whole basin. The present contribution aims to fill this knowledge gap, reporting a comprehensive data set including oxygen and hydrogen stable isotopes as well as major and trace element concentration of dissolved species for 54 Po river water samples, mainly collected in different hydrological conditions (peak discharge in April, drought in August) at increasing distance from the source, i.e., from the upper part of the catchment to the terminal (deltaic) part of the river at the confluence with the Adriatic Sea. The isotopic compositions demonstrate that the predominant part of the runoff derives from the Alpine sector of the catchment through important tributaries such as the Dora Baltea, Ticino, Adda, and Tanaro rivers, whereas the contribution from the Apennines tributaries is less important. The geochemical and isotopic compositions show that the Po river water attains a homogeneous composition at ca. 100 km from the source. The average composition is characterized by δ(18)O -9.8‰, δD -66.2‰, total dissolved solid (TDS) 268 mg/L, and chloride 17 mg/L and by a general Ca-HCO3 hydrochemical facies, which is maintained for most of the river stream, only varying in the terminal part where the river is diverted in a complex deltaic system affected by more significant evaporation and mixing with saline water evidenced by higher TDS and chloride content (up to 8198 and 4197 mg/L, respectively). Geochemical and isotopic maps have been drawn to visualize spatial gradients, which reflect the evolution of the river water composition at progressive distance from the source; more detailed maps were focused on the deltaic part in order to visualize the processes occurring in the transitional zone toward the Adriatic Sea. The data also highlight anthropogenic contributions, mainly represented by significant concentrations of nitrate (average 8 mg/L) and possibly arsenic (average 12 μg/L). These data allow the calculation of geochemical fluxes transferred from the river to the sea, and generally, they contribute to the definition of a "hydro-archive" which is useful to highlight ongoing variations in the related ecosystems.
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http://dx.doi.org/10.1007/s11356-014-3750-6DOI Listing
April 2015

Geochemical characterization and biomonitoring of reclaimed soils in the Po River Delta (Northern Italy): implications for the agricultural activities.

Environ Monit Assess 2014 May 29;186(5):2925-40. Epub 2013 Dec 29.

Dipartimento di Fisica e Scienze della Terra, Università di Ferrara, Via Saragat 1, 44100, Ferrara, Italy.

This geochemical study is focused on the easternmost part of the Po River alluvial plain in Northern Italy, which is interested by widespread agricultural activities, investigating a reclaimed sector of the Province of Ferrara, known as "Valle del Mezzano" (Mezzano Low Land, hereafter reported as MLL) characterized by peat-rich soils. The chemical-mineralogical characterization of these reclaimed soils is important to compare the local geochemical backgrounds with those recorded in other sectors of the River Po plain and to monitor if the observed concentration exceeds critical thresholds. The reported analyses include (a) measurement of the soil salinity, (b) nutrient evaluation, (c) major and trace element concentrations carried out on bulk soils, (d) tests of metal extraction with both aqua regia and EDTA to highlight the distinct elemental mobility and (e) phyto-toxicological measurement of heavy metal concentrations in plants (Lactuca sativa acephala) grown on the studied soils. The results indicate (1) high soil salinity, often with drastic increase of sodium and chloride along the soil profiles, (2) high nitrogen content (in part related to anthropogenic activities) on superficial horizons and nitrate decrease along the soil profiles and (3) comparative enrichments in heavy metals with respect to other soils of the province, which indicate that peat deposits are effective in trapping metals from anthropogenic sources. This, in turn, implies potential geochemical risks for the agricultural activities. In this regard, specific concerns are related to the high nickel and arsenic content of MLL soils due to the mobility of these elements and their attitude to be taken up by plants.
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http://dx.doi.org/10.1007/s10661-013-3590-8DOI Listing
May 2014

Mobilization of arsenic and other naturally occurring contaminants in groundwater of the Main Ethiopian Rift aquifers.

Water Res 2013 Oct 11;47(15):5801-18. Epub 2013 Jul 11.

Division of Earth and Ocean Sciences, Box 90227, Nicholas School of the Environment, Duke University, Durham, NC 27708, United States. Electronic address:

This study investigates the mechanisms of arsenic (As) and other naturally occurring contaminants (F(-), U, V, B, and Mo) mobilization from Quaternary sedimentary aquifers of the Main Ethiopian Rift (MER) and their enrichment in the local groundwater. The study is based on systematic measurements of major and trace elements as well as stable oxygen and hydrogen isotopes in groundwater, coupled with geochemical and mineralogical analyses of the aquifer rocks. The Rift Valley aquifer is composed of rhyolitic volcanics and Quaternary lacustrine sediments. X-ray fluorescence (XRF) results revealed that MER rhyolites (ash, tuff, pumice and ignimbrite) and sediments contain on average 72 wt. % and 65 wt. % SiO2, respectively. Petrographic studies of the rhyolites indicate predominance of volcanic glass, sanidine, pyroxene, Fe-oxides and plagioclase. The As content in the lacustrine sediments (mean = 6.6 mg/kg) was higher than that of the rhyolites (mean: 2.5 mg/kg). The lacustrine aquifers of the Ziway-Shala basin in the northern part of MER were identified as high As risk zones, where mean As concentration in groundwater was 22.4 ± 33.5 (range of 0.60-190 μg/L) and 54% of samples had As above the WHO drinking water guideline value of 10 μg/L. Field As speciation measurements showed that most of the groundwater samples contain predominantly (~80%) arsenate-As(V) over arsenite-As(III) species. The As speciation together with field data of redox potential (mean Eh = +73 ± 65 mV) and dissolved-O2 (6.6 ± 2.2 mg/L) suggest that the aquifer is predominantly oxidative. Water-rock interactions, including the dissolution of volcanic glass produces groundwater with near-neutral to alkaline pH (range 6.9-8.9), predominance of Na-HCO3 ions, and high concentration of SiO2 (mean: 85.8 ± 11.3 mg/L). The groundwater data show high positive correlation of As with Na, HCO3, U, B, V, and Mo (R(2) > 0.5; p < 0.001). Chemical modeling of the groundwater indicates that Fe-oxides and oxyhydroxides minerals were saturated in the groundwater, suggesting that the As reactivity is controlled by adsorption/desorption processes with these minerals. The data show that As and other oxyanion-forming elements such as U, B, Mo, and V had typically higher concentrations at pH > ~8, reflecting the pH-dependence of their mobilization. Based on the geochemical and stable isotope variations we have established a conceptual model for the occurrence of naturally occurring contaminants in MER groundwater: 1) regional groundwater recharge from the Highland, along the Rift margins, followed by lateral flow and water-rock interactions with the aquifer rocks resulted in a gradual increase of the salinity and naturally occurring contaminants towards the center of the valley; and (2) local δ(18)O-rich lake water recharge into adjacent shallow aquifers, followed by additional mobilization of As and other oxyanion-forming elements from the aquifer rocks. We posit that the combined physical-chemical conditions of the aquifers such as oxidizing state, Na-HCO3 composition, and pH>~8 lead to enhanced mobilization of oxyanion-forming elements from Fe-oxides and consequently contamination of local groundwater. These geochemical conditions characterize groundwater resources along the Eastern African Rift and thus constitute a potential threat to the quality of groundwater in larger areas of Eastern Africa.
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http://dx.doi.org/10.1016/j.watres.2013.07.002DOI Listing
October 2013

Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors.

ACS Med Chem Lett 2011 Oct 7;2(10):768-73. Epub 2011 Aug 7.

Research Center, Dompé s.p.a., via Campo di Pile, 67100 L'Aquila, Italy.

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.
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http://dx.doi.org/10.1021/ml2001533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018143PMC
October 2011

Molecular dynamics simulation of Leishmania major surface metalloprotease GP63 (leishmanolysin).

Proteins 2006 Aug;64(2):385-90

Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universitá L'Aquila, L'Aquila, Italy.

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.
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http://dx.doi.org/10.1002/prot.21009DOI Listing
August 2006

Design, modelling, synthesis and biological evaluation of peptidomimetic phosphinates as inhibitors of matrix metalloproteinases MMP-2 and MMP-8.

Bioorg Med Chem 2005 Aug;13(15):4740-9

Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università dell'Aquila, via Vetoio, I-67010-Coppito, AQ, Italy.

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.
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http://dx.doi.org/10.1016/j.bmc.2005.04.079DOI Listing
August 2005