High temperature behaviour of Ag-exchanged Y zeolites used for PFAS sequestration from water.

Per- and polyfluorinated alkyl substances (PFAS) are anthropogenic compounds which have recently drawn great attention due to their high biological, chemical and physical stability and lipid/water repelling properties. The present work aims to provide for the first time insights on the thermal behaviour of Ag-exchanged Y zeolite loaded with perfluorooctanoic acid (PFOA, C8HF15O2) and perfluorooctane sulfonate (PFOS, C8HF17O3S) emphasizing the close link between crystal structure and desorption/dehydration processes. Elemental and isotopic abundance of carbon analysis, thermal analysis, and in situ high-temperature synchrotron X-ray powder diffraction were used to evaluate critically if the thermal regeneration affects the initial zeolites structural features. Rietveld refinements revealed that PFAS sites are emptied in the 550-650 °C temperature range, when the thermal degradation of PFOA and PFOS are reached. The crystallinity of the samples is not affected by the adsorption/desorption processes. Upon heating, the removal of both PFAS and coadsorbed water molecules induced a cation migration of the silver ions and changes of initial geometry of the framework. The dimensions of the channels remain comparable to those of the pristine materials thus suggesting the potential re-use of the samples in other adsorption PFAS cycles. Additionally, once regenerated and reloaded Ag-exchanged Y can re-adsorb PFAS in amounts comparable to that adsorbed in the first cycle with clear benefits on the costs of the whole water treatment process.

BCAAs and Di-Alanine supplementation in the prevention of skeletal muscle atrophy: preclinical evaluation in a murine model of hind limb unloading.

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.

Design, synthesis and biological evaluation of new thiazole scaffolds as potential TRPM8 antagonists.

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.

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

In the Adriatic lagoons of northern Italy, manila clam (Ruditapes philippinarum) 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, δ13C and δ15N in manila clam tissues as well as δ13C in shells and Δ13C (calculated as δ13Cshell-δ13Ctissues) seems a promising approach for tracking the geographical origin of manila clams at the regional scale.

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

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.

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

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.

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

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.

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

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-1ß 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.

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

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.

Soil organic carbon data comparison after 85 years and new 13 C/12 C compositions: The case study of the Ferrara province (Northeastern Italy).

The main causes of soil organic matter (SOM) loss are land use (e.g., conventional agriculture) and land-use change (e.g., conversion of wetlands into croplands). Before World War II and until 1960s, the Ferrara province in the Emilia-Romagna region (Northeast Italy) enlarged its agricultural production area through drainage of wetlands. After that, the newly drained area was put into intensive agricultural production with practices that proved to be unsustainable, and whose negative effects (depletion of soil organic carbon [SOC] and emissions of greenhouse gases [GHGs], e.g., CO2 ) have never been quantified. In this work, we estimated the changes in SOC 85 years after the drainage of the palustrine environment, by comparing 1937 SOC measurements with those made in 2022. Comparison of SOC maps from 1937 and 2022 indicates that most of the area suffered a significant SOC loss (∆OC85 years from 0.05 to 18.57 wt%), except for northern areas in which the peat nature of the soil has been preserved. We also measured the 13 C/12 C on the 2022 soil samples and generated a present-day map of the SOC isotopic ratios, which could be used in future as a benchmark to evaluate changes in soil carbon stocks and fluxes.

Branched-chain amino acids and L-alanine supplementation ameliorate calcium dyshomeostasis in sarcopenia: New insights for nutritional interventions.

Introduction: During aging, sarcopenia and decline in physiological processes lead to partial loss of muscle strength, atrophy, and increased fatigability. Muscle changes may be related to a reduced intake of essential amino acids playing a role in proteostasis. We have recently shown that branched-chain amino acid (BCAA) supplements improve atrophy and weakness in models of muscle disuse and aging. Considering the key roles that the alteration of Ca2+-related homeostasis and store-operated calcium entry (SOCE) play in several muscle dysfunctions, this study has been aimed at gaining insight into the potential ability of BCAA-based dietary formulations in aged mice on various players of Ca2+ dyshomeostasis. Methods: Seventeen-month-old male C57BL/6J mice received a 12-week supplementation with BCAAs alone or boosted with two equivalents of L-alanine (2-Ala) or with dipeptide L-alanyl-L-alanine (Di-Ala) in drinking water. Outcomes were evaluated on ex vivo skeletal muscles indices vs. adult 3-month-old male C57BL/6J mice. Results: Ca2+ imaging confirmed a decrease in SOCE and an increase of resting Ca2+ concentration in aged vs. adult mice without alteration in the canonical components of SOCE. Aged muscles vs. adult muscles were characterized by a decrease in the expression of ryanodine receptor 1 (RyR1), the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) pump, and sarcalumenin together with an alteration of the expression of mitsugumin 29 and mitsugumin 53, two recently recognized players in the SOCE mechanism. BCAAs, particularly the formulation BCAAs+2-Ala, were able to ameliorate all these alterations. Discussion: These results provide evidence that Ca2+ homeostasis dysfunction plays a role in the functional deficit observed in aged muscle and supports the interest of dietary BCAA supplementation in counteracting sarcopenia-related SOCE dysregulation.

The trace element distribution in peat soils affected by natural burning events: A proxy of the original composition and metals mobility assessment.

This work evaluates for the first time the effects on the trace element composition of peat soils affected by natural burning events, a recurrent phenomenon in the reclaimed wetland of the Mezzano Lowland (Padanian plain, NE Italy). The trace element distribution of two neighboring soil profiles, one pristine and one deeply affected by burning events, were compared to identify the original geochemical fingerprint of saltmarsh peat environment. The pre-combustion composition of the fired profile was reconstructed to infer the physico-chemical changes occurred as a consequence of the burning event, with a special attention to the mobility of elements of environmental concern, such as potentially toxic trace metals. The increase in concentration of potentially toxic elements (PTE) was particularly evident in two layers of the fired profile. V, Cr, Cu, Zn, Pb, and As contents progressively increase toward intermediate depths (30-75 cm) together with Th, Sr, Ba, U. On the contrary, Tl, Bi and Cd show a concentration peak in a thin, shallower (14-17 cm depth) horizon. The trace element composition of the unfired profile allowed the identification of specific ratios between immobile elements that can be used as geochemical fingerprint of the soils horizons with different soil organic matter (SOM) content. On the basis of Sr/Rb, Th/U and Ba/Sr it was possible to classify three types of sedimentary deposits characterizing both the unfired and fired profile, as well as to delineate the fire severity trends occurred in the different soil horizons of the fired profile. The distribution of immobile trace element, representative of the organic (U) and mineral (silicate, Th, Ba, REE and non-silicate, Sr) soil fractions with organic matter and bulk density in the non-fired profile, allowed the reconstruction of the original physico-chemical composition of the fired/burned profile and the accurate determination of the relative CO2 lost during the burning event. Moreover, the distribution of PTE with respect to immobile trace elements, used to estimate the element redistribution and mobility after burning in the fired profile, suggested that elements such as Cr, Ni, Zn, V were mainly immobile, whereas Pb, Mo and in particular Tl and Bi suffered a significant redistribution along the burned profile. Nonetheless, results of the gain/loss calculation for the whole soil profile suggested that no significant entry or leak of these elements occurred, limiting their redistribution inside the investigated soil system.

Branched-Chain Amino Acids and Di-Alanine Supplementation in Aged Mice: A Translational Study on Sarcopenia.

In age-related sarcopenia, the gradual loss of skeletal muscle mass, function and strength is underpinned by an imbalanced rate of protein synthesis/breakdown. Hence, an adequate protein intake is considered a valuable strategy to mitigate sarcopenia. Here, we investigated the effects of a 12-week oral supplementation with branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) with recognized anabolic properties, in 17-month-old (AGED) C57BL/6J male mice. BCAAs (2:1:1) were formulated in drinking water, alone or plus two L-Alanine equivalents (2ALA) or dipeptide L-Alanyl-L-Alanine (Di-ALA) to boost BCAAs bioavailability. Outcomes were evaluated on in/ex vivo readouts vs. 6-month-old (ADULT) mice. In vivo hind limb plantar flexor torque was improved in AGED mice treated with BCAAs + Di-ALA or 2ALA (recovery score, R.S., towards ADULT: ≥20%), and all mixtures significantly increased hind limb volume. Ex vivo, myofiber cross-sectional areas were higher in gastrocnemius (GC) and soleus (SOL) muscles from treated mice (R.S. ≥ 69%). Contractile indices of isolated muscles were improved by the mixtures, especially in SOL muscle (R.S. ≥ 20%). The latter displayed higher mTOR protein levels in mice supplemented with 2ALA/Di-ALA-enriched mixtures (R.S. ≥ 65%). Overall, these findings support the usefulness of BCAAs-based supplements in sarcopenia, particularly as innovative formulations potentiating BCAAs bioavailability and effects.

Ketoprofen, lysine and gabapentin co-crystal magnifies synergistic efficacy and tolerability of the constituent drugs: Pre-clinical evidences towards an innovative therapeutic approach for neuroinflammatory pain.

Chronic pain is an enormous public health concern, and its treatment is still an unmet medical need. Starting from data highlighting the promising effects of some nonsteroidal anti-inflammatory drugs in combination with gabapentin in pain treatment, we sought to combine ketoprofen lysine salt (KLS) and gabapentin to obtain an effective multimodal therapeutic approach for chronic pain. Using relevant in vitro models, we first demonstrated that KLS and gabapentin have supra-additive effects in modulating key pathways in neuropathic pain and gastric mucosal damage. To leverage these supra-additive effects, we then chemically combined the two drugs via co-crystallization to yield a new compound, a ternary drug-drug co-crystal of ketoprofen, lysine and gabapentin (KLS-GABA co-crystal). Physicochemical, biodistribution and pharmacokinetic studies showed that within the co-crystal, ketoprofen reaches an increased gastrointestinal solubility and permeability, as well as a higher systemic exposure in vivo compared to KLS alone or in combination with gabapentin, while both the constituent drugs have increased central nervous system permeation. These unique characteristics led to striking, synergistic anti-nociceptive and anti-inflammatory effects of KLS-GABA co-crystal, as well as significantly reduced spinal neuroinflammation, in translational inflammatory and neuropathic pain rat models, suggesting that the synergistic therapeutic effects of the constituent drugs are further boosted by the co-crystallization. Notably, while strengthening the therapeutic effects of ketoprofen, KLS-GABA co-crystal showed remarkable gastrointestinal tolerability in both inflammatory and chronic neuropathic pain rat models. In conclusion, these results allow us to propose KLS-GABA co-crystal as a new drug candidate with high potential clinical benefit-to-risk ratio for chronic pain treatment.

Multi stable isotope ratio analysis for the traceability of northern Italian apples.

Isotope ratio mass spectrometry is a well-known technique used to trace the origin of agri-food products from different countries. Here this method was tested to trace the exact orchard of provenance of Italian apples harvested at sites close to each other. We measured the δ13C, δ15N, and δ34S values of apple subfractions (peel, petiole, pulp, seed) from two orchards in Ferrara and one orchard in Trento. Sulfur represents the best marker for tracing the regions of provenance of samples because it is linked to the presence of sulfate (Ferrara1: +9.0 ‰; Ferrara 2: +7.3 ‰) and sulfide (Trento: -1.3 ‰) minerals in soils. However, the δ13C of apple subfractions combined with the δ34S of seed in a linear discrimination analysis better discriminated the three orchards. The isotopic fingerprint of apples is thus significantly affected by the relative terroir, and it can be used as "isotopic identity card" to certify "protected designations of origin".

Quartz-bearing rhyolitic melts in the Earth's mantle.

The occurrence of rhyolite melts in the mantle has been predicted by high pressure-high temperature experiments but never observed in nature. Here we report natural quartz-bearing rhyolitic melt inclusions and interstitial glass within peridotite xenoliths. The oxygen isotope composition of quartz crystals shows the unequivocal continental crustal derivation of these melts, which approximate the minimum composition in the quartz-albite-orthoclase system. Thermodynamic modelling suggests rhyolite was originated from partial melting of near-anhydrous garnet-bearing metapelites at temperatures ~1000 °C and interacted with peridotite at pressure ~1 GPa. Reaction of rhyolite with olivine converted lherzolite rocks into orthopyroxene-domains and orthopyroxene + plagioclase veins. The recognition of rhyolitic melts in the mantle provides direct evidence for element cycling through earth's reservoirs, accommodated by dehydration and melting of crustal material, brought into the mantle by subduction, chemically modifying the mantle source, and ultimately returning to surface by arc magmatism.

Isotope Geochemistry for Seafood Traceability and Authentication: The Northern Adriatic Manila Clams Case Study.

In Italy, the production of manila clams (Ruditapes philippinarum, Adams and Reeve, 1850) is mainly localized in northern Adriatic lagoons in the Po River delta, where shellfish farming provides important socio-economic revenue. However, in our globalized world, the seafood market is threated by fraudulent activities, in which agri-food products whose provenance is not certified are sold, posing a risk to consumer health. Multi-isotope ratio analysis is commonly used to trace the provenance of goods produced in different countries with different climatic and environmental conditions. Here, we investigated the reliability of this approach in terms of tracing the exact provenance of manila clams harvested in three Adriatic northern lagoons that are close to each other. We also verified the origin of samples bought at a local supermarket with a certificate of provenance. We carried out elemental analyses of carbon (C), nitrogen (N), and sulfur (S) and the respective isotopic ratios (13C/12C; 15N/14N; 34S/32S) on manila clam tissues, plus isotopic analyses of carbon (13C/12C), oxygen (18O/16O), and strontium (87Sr/86Sr) on manila clam shells. Each isotopic parameter can be used to identify the marine and continental contributions of water and/or nutrient supplies occurring in the lagoons. Therefore, the combination of isotopic parameters in a linear discriminant analysis (LDA) allowed for the identification of the lagoons in which the manila clams were produced.

Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. Ex vivo and in vitro studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS.

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

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 ß-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).

Peat Soil Burning in the Mezzano Lowland (Po Plain, Italy): Triggering Mechanisms and Environmental Consequences.

The effects of peat burning on organic-rich agricultural soils of the Mezzano Lowland (NE Italy) were evaluated on soil profiles variously affected by smoldering. Profiles were investigated for pH, electrical conductivity, bulk density, elemental and isotopic composition of distinct carbon (and nitrogen) fractions. The results suggest that the horizons affected by carbon loss lie at depths 10-70 cm, where the highest temperatures are developed. We suggest that the exothermal oxidation of methane (mediated by biological activity) plays a significant role in the triggering mechanism. In the interested soils we estimated a potential loss of Soil Organic Carbon of approximately 110 kg m -2 within the first meter, corresponding to 580 kg CO2 m -3. The released greenhouse gas is coupled with a loss of soil structure and nutrients. Moreover, the process plausibly triggers mobility of metals bound in organometallic complexes. All these consequences negatively affect the environment, the agricultural activities and possibly also health of the local people.