Growth and dissection of a fold and thrust belt: the geological record of the High Agri Valley, Italy

We present a 130 km2 wide geological map for the NE side of the fault-bounded High Agri Valley Southern Italy, that formed in the Quaternary in response to extensional tectonics dissecting the folds and thrusts of the Lucanian Apennine. To prepare the map, at 1:25,000 scale, we integrated information obtained through field surveys and the review of pre-existing geological data. Our work describes a number of significant map-scale structures, which can be related to well-constrained tectonic episodes. The new geological map provides important constraints that can be used to distinguish ancient structures from those that were active during the Quaternary, allowing a more detailed reconstruction of the processes that operate during the development of a post-orogenic trough. We expect that the new map will be used for different types of geological investigations, including studies of inversion tectonics, active tectonics, geosite mapping, 3D modelling of geological structures. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Journal of Maps

Exploiting the indole scaffold to design compounds binding to different pharmacological targets

Several indole derivatives have been disclosed by our research groups that have been collaborating for nearly 25 years. The results of our investigations led to a variety of molecules binding selectively to different pharmacological targets, specifically the type A γ-aminobutyric acid (GABAA) chloride channel, the translocator protein (TSPO), the murine double minute 2 (MDM2) protein, the A2B adenosine receptor (A2B AR) and the Kelch-like ECH-associated protein 1 (Keap1). Herein, we describe how these works were conceived and carried out thanks to the versatility of indole nucleus to be exploited in the design and synthesis of drug-like molecules

Design and pharmacological evaluation of Ibuprofen amides derivatives as dual FAAH/COX inhibitors

Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme responsible of the hydrolytic degradation of N-acylethanolamine endocannabinoids, such as the Arachidonoylethanolamide (anandamide, AEA), which it has been shown to alleviate pain and inflammation (1). In particular, the anti-nociceptive and anti-inflammatory effects of AEA could be enhanced by the simultaneous block of FAAH and COX enzymes (2). For this reason, several studies have been carried out in order to develop new FAAH/COX inhibitors (2). In 1997 it was reported that the NSAID ibuprofen inhibited FAAH, although with a modest potency (3), and successively the first dual inibhitor, the amide derivative of ibuprofen with a 2-amino-3-methylpyridine side chain (Ibu-AM5) was reported (4). -5). Benzylamides and piperazinoamides analogs of Ibuprofen have been also designed as less potent FAAH inhibitors than Ibu-AM5 (5). Here, I discuss the computational studies and the structure–activity relationships leading to the design, of novel Ibuprofen amide derivatives with a higher inhibition potency of FAAH and COX, which represent novel powerful anti-nociceptive agents

Biophysical and biochemical characterization of a liposarcoma-derived recombinant MnSOD protein acting as an anticancer agent

A recombinant MnSOD (rMnSOD) synthesized by specific cDNA clones derived from a liposarcoma cell line was shown to have the same sequence as the wild-type MnSOD expressed in the human myeloid leukaemia cell line U937, except for the presence of the leader peptide at the N-terminus. These results were fully confirmed by the molecular mass of rMnSOD as evaluated by ES/MS analysis (26662.7 Da) and the nucleotide sequence of the MnSOD cDNA. The role of the leader peptide in rMnSOD was investigated using a fluorescent and/or 68Gallium-labelled synthetic peptide. The labelled peptide permeated MCF-7 cells and uptake could be inhibited in the presence of an excess of oestrogen. In vivo it was taken up by the tumour, suggesting that the molecule can be used for both therapy and diagnosis. The in vitro and in vivo pharmacology tests confirmed that rMnSOD is only oncotoxic for tumour cells expressing oestrogen receptors. Pharmacokinetic studies in animals performed with 125I- and 131I-labelled proteins confirmed that, when administered systemically, rMnSOD selectively reached the tumour, where its presence was unambiguously demonstrated by scintigraphic and PET scans. PCR analysis revealed that Bax gene expression was increased and the Bcl2 gene was down regulated in MCF7 cells treated with rMnSOD, which suggests that the protein induces a pro-apoptotic mechanism

Sampling protein motion and solvent effect during ligand binding.

An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one

N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides. A new class of Potent and Selective Ligands at the Peripheral Benzodiazepine Receptor.

We report the synthesis and the affinity data at both the peripheral (PBR) and the central benzodiazepine receptors of a series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamide derivatives III, designed as conformationally constrained analogues of 2-phenylindole-3-acetamides II such as FGIN-1-27. Most of the new compounds showed a high specificity and affinity for PBR, with Ki in the nanomolar to subnanomolar range. The most potent ligands (4−7, 9, 13−27) stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classical ligands. The SARs of this new class of compounds are discussed

Nanopharmaceutics: Part II - Production scales and clinically compliant production methods

Due the implementation of nanotechnologies in the pharmaceutical industry over the last few decades, new type of cutting-edge formulationsnanopharmaceuticshave been proposed. These comprise pharmaceutical products at the nanoscale, developed from different types of materials with the purpose to, e.g., overcome solubility problems of poorly water-soluble drugs, the pharmacokinetic and pharmacodynamic profiles of known drugs but also of new biomolecules, to modify the release profile of loaded compounds, or to decrease the risk of toxicity by providing site-specific delivery reducing the systemic distribution and thus adverse side effects. To succeed with the development of a nanopharmaceutical formulation, it is first necessary to analyze the type of drug which is to be encapsulated, select the type matrix to load it (e.g., polymers, lipids, polysaccharides, proteins, metals), followed by the production procedure. Together these elements have to be compatible with the administration route. To be launched onto the market, the selected production method has to be scaled-up, and quality assurance implemented for the product to reach clinical trials, during which in vivo performance is evaluated. Regulatory issues concerning nanopharmaceutics still require expertise for harmonizing legislation and a clear understanding of clinically compliant production methods. The first part of this study addressing Nanopharmaceutics: Part IClinical trials legislation and Good Manufacturing Practices (GMP) of nanotherapeutics in the EU has been published in Pharmaceutics. This second part complements the study with the discussion about the production scales and clinically compliant production methods of nanopharmaceutics.The financial support was received from Portuguese Science and Technology Foundation (FCT/MCT) and from European Funds (PRODER/COMPETE) for the projects M‐ERA‐NET‐0004/2015‐PAIRED and UIDB/04469/2020 (strategic fund), co‐financed by FEDER, under the Partnership Agreement PT2020. Authors thank the support of the project: Nutraceutica come supporto nutrizionale nel paziente oncologico; CUP: B83D18000140007.info:eu-repo/semantics/publishedVersio

Antiviral activity of Taurisolo® during bovine alphaherpesvirus 1 infection

: Bovine alphaherpesvirus 1 (BoAHV-1), the pathogen causing Infectious Bovine Rhinotracheitis (IBR) and predisposing to polymicrobial infections in cattle, provokes farm economic losses and trading restrictions in the world. However, nontoxic antiviral agents for BoAHV-1 infection are still unavailable, but plant extracts, such as flavonoid derivatives possess activity against BoAHV-1. Taurisolo®, a nutraceutical produced by Aglianico grape pomace, has recently shown promising antiviral activity. Herein, the potential activity of Taurisolo® during BoAHV-1 infection in Madin Darby bovine kidney (MDBK) cells was tested. Taurisolo® enhanced cell viability and reduced morphological death signs in BoAHV-1-infected cells. Moreover, Taurisolo® influenced the expression of bICP0, the key regulatory protein of BoAHV-1, and it strongly diminished virus yield. These effects were associated with an up-regulation of aryl hydrocarbon receptor (AhR), a transcription factor involved in microbial metabolism and immune response. In conclusion, our findings indicate that Taurisolo® may represent a potential antiviral agent against BoAHV-1 infection. Noteworthy, AhR could be involved in the observed effects and become a new target in antiviral therapy

Nanopharmaceutics: Part IClinical trials legislation and Good Manufacturing Practices (GMP) of nanotherapeutics in the EU

The latest advances in pharmaceutical technology are leading to the development of cutting edged approaches to produce what is now known as the “Holy Grail” of medicine—nanopharmaceutics. Over the latest decade, the pharmaceutical industry has made important contributions to the scale up of these new products. To ensure their quality, efficacy, and safety for human use, clinical trials are mandatory. Yet, regulation regarding nanopharmaceuticals is still limited with a set of guidelines being recently released with respect to compliance with quality and safety. For the coming years, updates on regulatory issues about nanopharmaceuticals and their use in clinical settings are expected. The use of nanopharmaceuticals in clinical trials depends on the approval of the production methods and assurance of the quality of the final product by implementation and verification of the good manufacturing practices (GMP). This review addresses the available legislation on nanopharmaceuticals within the European Union (EU), the GMP that should be followed for their production, and the current challenges encountered in clinical trials of these new formulations. The singular properties of nanopharmaceuticals over their bulk counterparts are associated with their size, matrix composition, and surface properties. To understand their relevance, four main clinical trial guidelines, namely, for intravenous iron-based nanopharmaceuticals, liposomal-based nanopharmaceuticals, block copolymer micelle-based nanopharmaceuticals, and related to surface coating requirements, are described here.The financial support was received from Portuguese Science and Technology Foundation (FCT/MCT) and from European Funds (PRODER/COMPETE) for the projects M‐ERA‐NET‐0004/2015‐PAIRED and UIDB/04469/2020 (strategic fund), co‐financed by FEDER, under the Partnership Agreement PT2020. Authors thank the support of the project: Nutraceutica come supporto nutrizionale nel paziente oncologico; CUP: B83D18000140007.info:eu-repo/semantics/publishedVersio

Multiscenario flood hazard assessment using probabilistic runoff hydrograph estimation and 2D hydrodynamic modelling

In this paper, we aim to define a procedure of flood hazard assessment applicable to large river basins in which flood events can be induced/sustained by the full basin area or by fractions of the total area as functions of the extent of the triggering precipitation event. The proposed procedure is based on a combined approach accounting for (1) the reconstruction of intensity–duration–frequency curves expressing the magnitude in terms of intensity for multiple return periods; (2) the application of the soil conservation service method for runoff estimation from a selected rainfall scenario considering some characteristics of the basin (i.e. soil type, land use/treatment, surface condition, and antecedent moisture conditions); (3) 2D hydrodynamic modelling conducted by the HEC-RAS model using runoff hydrographs as hydrological input data; (4) the reconstruction of flood hazard maps by overlaying multiple inundation maps depicting flood extent for different return periods. To account for the variability in the extent of the triggering precipitation event and the resulting input hydrograph, multiple contributing areas are considered. The procedure is tested at the archaeological site of Sybaris in southern Italy, which is periodically involved in flood events of variable magnitude. The obtained results highlight that the variable extent of the floodable area is strongly conditioned by the extent of the contributing area and return period, as expected. The archaeological site is always involved in the simulated flooding process, except for the smallest contributing area for which only a 300-year event involves this part of the site. Our findings may be useful for developing and supporting flood risk management plans in the area. The developed procedure might be easily exported and tested in other fluvial contexts in which evaluations of multiple flood hazard scenarios, due to the basin geometry and extent, are needed