Gases and seabed fluid fluxes at the Panarea shallow hydrothermal vents (Aeolian Islands)

CO2 leaking into the shallow sediments and overlying seawater is partitioned in different forms, each migrating at its own rate and having potentially different impacts. To begin with the CO2 gas will migrate through the shallow subsurface either alone as a free gas or together with associated deep fluids (e.g. brines), with the free-phase CO2 equilibrating with the surrounding pore waters/associated brines. Migrating upward these fluids will enter the base of the water column, with the release of gas bubbles (and possibly associated waters) from the sediments into the overlying seawater. The bubbles will rise in the water column creating what is known as a bubble “flare” with the CO2 in the bubbles dissolving in the surrounding surface water as they rise. Depending on the depth and the chemical/physical characteristics of the water column, these bubbles may or may not reach the water surface. Any co-migrating water/brine will also be released into the water column, creating a plume having a chemical composition that is distinct from the surrounding seawater, consisting of dissolved gases (mainly CO2), elements in the original brine, and elements liberated via CO2-induced water-rock interaction. The height that this dissolved plume will reach in the water column will depend on the original flow rate across the sediment-water interface and the density contrast between the plume and surrounding seawater. Both the gas-induced and water plumes will then migrate laterally and vertically as a result of the local currents, water column stratification, and density effects, meaning that there is the potential for impact both in the near and far field for pelagic organisms, both in terms of a lower pH and the possibility of elevated concentrations of toxic elements. This study was carried out in the framework of two EC funded projects, RISCS and ECO2 related to research on sub-seabed CO2 storage as climate change mitigation strategy, and potential impact on marine ecosystems. Here, we investigated how CO2-leakage, a risk associated with subseafloor CO2-storage, can affect physical and chemical characteristics of the surrounding ecosystem. We studied the Panarea natural laboratory site (Aeolian Islands), where natural CO2 is leaking from the seafloor into the overlying water column, as an analogue for a leakage scenario

Geochemical signatures of intense episodic anaerobic oxidation of methane in near-surface sediments of a recently discovered cold seep (Kveithola trough, NW Barents Sea)

At cold seep environments, the detection of large 34S enrichments within bulk sulphide minerals has been frequently used as a proxy to infer the vertical migrations of the sulphate-methane transition zone (SMTZ). Processes related to the oxidative part of the sulphur cycle can alter the original stable sulphur isotope composition (\u3b434S) of the solid sulphur phases, in particular at the sediment-water interface. Identification of paleo and present positions of methane fronts in the sedimentary records requires the use of multiple geochemical proxies. Authigenic enrichment of Mo has been demonstrated to represent a valid and durable tracer of the past SMTZ depth fluctuations and of the intensities of the related methane seepages. This study is based on two closely-spaced short cores collected from the Main Drift of the Kveithola trough, a glacially-carved depression located in northwestern Barents Sea. Active fluid seepage has been recently reported in this area and a gas flare was specifically observed in proximity of the sampling sites where the cores object of our study were retrieved. In order to collect evidences of the possible occurrence of anaerobic oxidation of methane (AOM) at the sedimentwater interface of the investigated area and infer the entity of the associated methane flux, we combined the analyses of reduced sulphur species \u3b434S, total organic carbon and redox-sensitive elements. The negative \u3b434S values within the extracted solid sulphur phases (up to 1249.1\u2030 for pyritic sulphur) show that organoclastic sulphate reduction (OSR) coupled with disproportionation of sulphur intermediates are the only active processes in the near-surface sediments. However, moderate to strong enrichments of Mo detected in the relatively organic carbon poor intervals of both cores and the lack of concurrent enrichments of Co, Cu, Ni, V and Zn, usually associated to OSR-dominated environment, suggested that the sulphidic conditions favouring the Mo enrichments were produced by AOM. Therefore, we infer that high methane flux events characterized the drift area of the Kveithola, occasionally moving upward the SMTZ and thus inducing intense AOM in proximity of the sediment- water interface of this part of the trough. Our results confirmed the validity of sedimentary Mo as an indicator of the occurrence and intensity of past methane seepages

(+)-(R)- and (−)-(S)-Perhexiline maleate: Enantioselective synthesis and functional studies on Schistosoma mansoni larval and adult stages

Schistosomiasis is a neglected tropical disease mainly affecting the poorest tropical and subtropical areas of the world with the impressive number of roughly 200 million infections per year. Schistosomes are blood trematode flukes of the genus Schistosoma causing symptoms in humans and animals. Organ morbidity is caused by the accumulation of parasite eggs and subsequent development of fibrosis. If left untreated, schistosomiasis can result in substantial morbidity and even mortality. Praziquantel (PZQ) is the most effective and widely used compound for the treatment of the disease, in prevention and control programs in the last 30 years. Unfortunately, it has no effect on juvenile immature schistosomes and cannot prevent reinfection or interfere with the schistosome life cycle; moreover drug-resistance represents a serious threat. The search for an alternative or complementary treatment is urgent and drug repurposing could accelerate a solution. The anti-anginal drug perhexiline maleate (PHX) has been previously shown to be effective on larval, juvenile, and adult stages of S. mansoni and to impact egg production in vitro. Since PHX is a racemic mixture of R-(+)- and S-(−)-enantiomers, we designed and realized a stereoselective synthesis of both PHX enantiomers and developed an analytical procedure for the direct quantification of the enantiomeric excess also suitable for semipreparative separation of PHX enantiomers. We next investigated the impact of each enantiomer on viability of newly transformed schistosomula (NTS) and worm pairs of S. mansoni as well as on egg production and vitellarium morphology by in vitro studies. Our results indicate that the R-(+)-PHX is mainly driving the anti-schistosomal activity but that also the S-(−)-PHX possesses a significant activity towards S. mansoni in vitro

Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation

In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile

Screening and Phenotypical Characterization of Schistosoma mansoni Histone Deacetylase 8 (SmHDAC8) Inhibitors as Multistage Antischistosomal Agents

Schistosomiasis (also known as bilharzia) is a neglected tropical disease caused by platyhelminths of the genus Schistosoma. The disease is endemic in tropical and subtropical areas of the world where water is infested by the intermediate parasite host, the snail. More than 800 million people live in endemic areas and more than 200 million are infected and require treatment. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment and transmission control being safe and very effective against adult worms of all the clinically relevant Schistosoma species. Unfortunately, it is ineffective on immature, juvenile worms; therefore, it does not prevent reinfection. Moreover, the risk of development and spread of drug resistance because of the widespread use of a single drug in such a large population represents a serious threat. Therefore, research aimed at identifying novel drugs to be used alone or in combination with PZQ are needed. Schistosoma mansoni histone deacetylase 8 (SmHDAC8) is a class I zinc-dependent HDAC, which is abundantly expressed in all stages of its life cycle, thus representing an interesting target for drug discovery. Through virtual screening and phenotypical characterization of selected hits, we discovered two main chemical classes of compounds characterized by the presence of a hydroxamate-based metal binding group coupled to a spiroindoline or a tricyclic thieno[3,2-b]indole core as capping groups. Some of the compounds of both classes were deeply investigated and showed to impair viability of larval, juvenile, and adult schistosomes, to impact egg production in vitro and/or to induce morphological alterations of the adult schistosome reproductive systems. Noteworthy, all of them inhibit the recombinant form of SmHDAC8 enzyme in vitro. Overall, we identified very interesting scaffolds, paving the way to the development of effective antischistosomal agents

Dense water plumes SW off Spitsbergen Archipelago (Arctic) in 2014-2017

In the last decades, the Arctic region has gained a large interest because of climate changes and relevant effects on ice melting and global warming. Abrupt changes in the atmosphere are responsible for significant changes in ocean water masses and large-scale circulation patterns, which in turn affect the global climate. Studying ocean circulation and related processes along the west Svalbard slope and within the Storfjorden (south Svalbard Archipelago) is essential to describe the thermohaline circulation and the dense water formation (DWF) in the Arctic, and the way they contribute to the global thermohaline circulation. DWF processes in this region depend on the rate of cooling and homogenisation of the Atlantic water along its northwards pathway, brine rejection phenomena, boundary convection on the Arctic Ocean shelves and slopes, and deep open-ocean convection in the central gyres of the Greenland and Iceland Seas. This study focuses on brine rejection, shelf convection and entrainment processes, which occur on the west Svalbard margin and in the Storfjorden during the winter season. Two short (~140m) moorings (named S1 and ID2, figure 1) were deployed ~1000m deep along the slope in 2014, to collect multiannual time-series in an area of potential interaction between the West Spitsbergen Current and the descending dense shelf plumes. Four oceanographic cruises were carried out between 2014 and 2017 to integrate time-series with CTD (conductivity-temperature-depth) casts in the area. One purpose of this research activity was to study the role played by bottom currents in the formation of two sediment drifts (Isfjorden and Bellsund). At S1 and ID2, time-series revealed a large thermohaline and current variability during the winter period, from October to April. Our data highlight the presence of a stable signal of Norwegian Sea Deep Water (θ = -0.90°C, S = 34.90, σθ = 28.07 kg m-3) at 1000m depth, influenced by occasional intrusions of warmer (up to +2°C), saltier (up to ~35), and less dense (down to 27.98 kg m-3) water during fall-winter periods. Interestingly, such intrusions occur simultaneously at both sites, despite their distance (~170km), suggesting also that winter meteorological perturbations play an important role in triggering dense shelf plumes. In this paper, the origin, timing, and role of shelf turbidity plumes (denser than TS plumes), which descend along the slope and undergo a strong entrainment process that modify their properties will be discussed. The role of possible mesoscale processes and land-sea atmosphere interactions will also be investigated

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line

Shelf and slope dynamics offshore the west Svalbard continental margin

The large-scale circulation and dense water formation (DWF) in the Svalbard archipelago influence the thermohaline circulation in the whole Arctic. In particular, DWF depends on the rate of cooling and homogenisation of the Atlantic water along its northward pathway, brine rejection, boundary convection on shelves and slopes, and open-ocean convection. This study focuses on brine rejection, shelf convection and entrainment processes, which occur in the SW Spitsbergen area. Two short (~140m) moorings (named S1 and ID2), deployed at a depth of ~1040 m over the slope, collected multiannual (2014-2017) time-series in an area of interaction between the West Spitsbergen Current and the descending dense shelf plumes. Time-series revealed a large thermohaline and current variability between October and April. Data highlight the presence of Norwegian Sea Deep Water (θ = -0.90°C, S = 34.90, σθ = 28.07 kg m-3) influenced by occasional intrusions of warmer (up to +2°C), saltier (up to ~35), and less dense (down to 27.98 kg m-3) water during fall-winter periods. Interestingly, such intrusions occur simultaneously at both sites, despite their distance (~170 km), suggesting that winter meteorological perturbations play an important role in triggering dense shelf plumes, which collect particulate matter during their descent. Here we discuss the origin, timing, and role of such turbidity plumes in a period characterized by a general warming and ice reduction of the Arctic

Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor 2a. When tested in two rodent models of epilepsy, 2a reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, 2a did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (3a-m). Biological studies highlighted 3h and 3m as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, 3h and 3m could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for 3h (Langendorff perfused rat heart). Finally, the new analogue 3h reduced the severity of the pilocarpine-induced status epilepticus as observed for 2a