New synthetic routes to the stereoselective assembly and the elaboration of bioactive compounds

This thesis is focused on the study of the central role of chirality in different kind of molecular structures; in particular, new synthetic pathways have been developed to improve the synthesis of already existing drugs, exploring at the same time the relationship between the chirality and the pharmacological properties of these compounds. Moreover, new enantiomeric systems have been synthetized and their pharmacological properties will be tested to verify the potential bioactivity and use as drugs. The thesis is organized in three major sections focusing on the different molecule typology investigated (nucleosides, iminosugars, alkaloids). The studies on nucleosides and iminosugars have been carried out at the department of Chemical Sciences of University of Naples “Federico II”, while the synthesis of alkaloids has been accomplished at the department of Organic Chemistry of the Faculty of Pharmacy of the University of Barcelona

Interleukin-17A (IL-17A): A silent amplifier of COVID-19

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this "unique" cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy

Clinical and psychosocial constructs for breast, cervical, and colorectal cancer screening participation: A systematic review.

Research has identified a wide range of psychosocial factors associated to choosing to engage in ongoing cancer screenings. Nevertheless, a systematic review of the theoretical frameworks and constructs underpinning studies on breast, cervical, and colorectal cancer screening participation has yet to be conducted. As part of the action-research project “Miriade,” the present study aims to identifying the main theoretical frameworks and constructs adopted in the literature over the past five years to explain cancer screening participation. According to the PRISMA guidelines, a search of the MEDLINE/PubMed and PsycINFO databases was made. Empirical studies conducted from 2017 to 2021 were included. The following keywords were used: breast OR cervical OR colorectal screening AND adhesion OR participation OR engagement AND theoretical framework OR conceptual framework OR theory. Overall, 24 articles met the inclusion criteria. Each theoretical framework highlighted clinical and psychosocial constructs of cancer screening participation, focusing on the individuals (psycho-emotional functioning and skills plan) and/or the health services perspectives. Findings from the present study acknowledge the plurality of the theoretical frameworks and constructs adopted to predict or promote breast, cervical, and colorectal cancer screening adhesion and the need for new research efforts to improve the effectiveness of cancer screening promotion interventions

Colonization of electrospun polycaprolactone fibers by relevant pathogenic bacterial strains

Electrospun biodegradable polymers have emerged as promising materials for their applications in several fields, including biomedicine and food industry. For this reason, the susceptibility of these materials to be colonized by different pathogens is a critical issue for public health, and their study can provide future knowledge to develop new strategies against bacterial infections. In this work, the ability of three pathogenic bacterial species (Pseudomonas aeruginosa, Acinetobacter baumannii, and Listeria monocytogenes) to adhere and form biofilm in electrospun polycaprolactone (PCL) microfibrous meshes was investigated. Bacterial attachment was analyzed in meshes with different microstructure, and comparisons with other materials (borosilicate glass and electrospun polylactic acid (PLA)) fibers were assessed. Analysis included colony forming unit (CFU) counts, scanning electron microscopy (SEM), and crystal violet (CV) staining. All the obtained data suggest that PCL meshes, regardless of their microstructure, are highly susceptible to be colonized by the pathogenic relevant bacteria used in this study, so a pretreatment or a functionalization with compounds that present some antimicrobial activity or antibiofilm properties is highly recommended before their application. Moreover, an experiment designed to simulate a chronic wound environment was used to demonstrate the ability of these meshes to detach biofilms from the substratum where they have developed, thus making them promising candidates to be used in wound cleaning and disinfection.European Union’s H2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 691095 and Junta de Castilla y Leon-FEDER (projects BU079U16 and BU092U16)

Chiral selectivity of porphyrin-ZnO nanoparticle conjugates

Recognition of enantiomers is one of the most arduous challenges in chemical sensor development. Although several chiral systems exist, their effective exploitation as the sensitive layer in chemical sensors is hampered by several practical implications that hinder stereoselective recognition in solid state. In this paper, we report a new methodology to efficiently prepare chiral solid films, by using a hybrid material approach where chiral porphyrin derivatives are grafted onto zinc oxide nanoparticles. Circular dichroism (CD) evidences that the solid-state film of the material retains supramolecular chirality due to porphyrin interactions, besides an additional CD feature in correspondence of the absorbance of ZnO (375 nm), suggesting the induction of chirality in the underlying zinc oxide nanoparticles. The capability of hybrid material to detect and recognize vapors of enantiomer pairs was evaluated by fabricating gas sensors based on quartz microbalances. Chiral films of porphyrin on its own were used for comparison. The sensor based on functionalized nanostructures presented a remarkable stereoselectivity in the recognition of limonene enantiomers, whose ability to intercalate in the porphyrin layers makes this terpene an optimal chiral probe. The chiroptical and stereoselective properties of the hybrid material confirm that the use of porphyrin-capped ZnO nanostructures is a viable route for the formation of chiral selective surfaces. © 2019 American Chemical Society

Tunable supramolecular chirogenesis in the self-assembling of amphiphilic porphyrin triggered by chiral amines

Supramolecular chirality is one of the most important issues in different branches of science and technology, as stereoselective molecular recognition, catalysis, and sensors. In this paper, we report on the self-assembly of amphiphilic porphyrin derivatives possessing a chiral information on the periphery of the macrocycle (i.e., D- or L-proline moieties), in the presence of chiral amines as co-solute, such as chiral benzylamine derivatives. The aggregation process, steered by hydrophobic effect, has been studied in aqueous solvent mixtures by combined spectroscopic and topographic techniques. The results obtained pointed out a dramatic effect of these ligands on the morphology and on the supramolecular chirality of the final self-assembled structures. Scanning electron microscopy topography, as well as fluorescence microscopy studies revealed the formation of rod-like structures of micrometric size, different from the fractal structures formerly observed when the self-assembly process is carried out in the absence of chiral amine co-solutes. On the other hand, comparative experiments with an achiral porphyrin analogue strongly suggested that the presence of the prolinate moiety is mandatory for the achievement of the observed highly organized suprastructures. The results obtained would be of importance for unraveling the intimate mechanisms operating in the selection of the homochirality, and for the preparation of sensitive materials for the detection of chiral analytes, with tunable stereoselectivity and morphology

IL-17A neutralizing antibody regulates monosodium urate crystal-induced gouty inflammation

Gout is a paradigm of acute, self-limiting inflammation caused by the deposition of monosodium urate (MSU) crystals within intra-and/or peri-articular areas, leading to excruciating pain, joint swelling and stiffness. The infiltration of leukocytes drives the inflammatory response and remains an attractive target for therapeutic intervention. In this context, emerging evidence supports the view that systemic differentiation of Th17 cells and their in situ infiltration as one of the potential mechanisms by which these cells, and their main product IL-17, causes damage to target tissues. To test if IL-17 was having a detrimental role in gouty onset and progression we targeted this cytokine, using a neutralizing antibody strategy, in an experimental model of gout. Joint inflammation was induced in CD-1 mice by the intra-articular (i.a.) administration of MSU crystals (200 μg/20 μl). Animals from IL-17Ab-treated groups received 1, 3 and 10 μg (i.a.) in 20 μl of neutralizing antibody after MSU crystals administration. Thereafter, joints were scored macroscopically, and knee joint oedema determined with a caliper. Histological analysis, myeloperoxidase assay and western blots analysis for COX-2/mPGEs-1/IL-17R pathway were conducted at 18 h (peak of inflammation) to evaluate leukocytes infiltration and activation, followed by the analysis, in situ, of pro/anti-inflammatory cytokines and chemokines. Flow cytometry was also used to evaluate the modulation of infiltrated inflammatory monocytes and systemic Th17 and Treg profile. Treatment with IL-17Ab revealed a dose-dependent reduction of joint inflammation scores with maximal inhibition at 10 μg. The neutralizing antibody was also able to significantly reduce leukocytes infiltration and MPO activity as well the expression of JE, IL-1α, IL-1β, IL-16, IL-17, C5a, BLC and, with a less extent IP-10, Rantes, KC, TIMP-1, SDF-1 and metalloproteinases in inflamed tissues. Biochemical analysis also revealed that IL-17Ab treatment modulated COX-2/mPGEs-1 pathway (and related PGE2 production) without interfering with IL-17R expression. Furthermore, flow cytometry analysis highlighted a selective modulation of infiltrating inflammatory monocytes (B220-/GR1hi-F480hi/CD115+) and circulating Th17, but not Treg, cells after IL-17Ab treatment. Collectively the results of this study report for the first time, that i.a. injection of MSU crystals stimulates in vivo production of Th17 cells and Th17-related inflammatory cyto-chemokines. In addition, we have demonstrated that the administration of a neutralizing antibody against IL-17 attenuates joint symptoms, swelling and leukocytes infiltration to the inflamed tissue, possibly providing a new strategy for the treatment of gouty inflammation and/or arthritis

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease—study protocol and preliminary results

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy

Intellectual Property, Open Science and Research Biobanks

In biomedical research and translational medicine, the ancient war between exclusivity (private control over information) and access to information is proposing again on a new battlefield: research biobanks. The latter are becoming increasingly important (one of the ten ideas changing the world, according to Time magazine) since they allow to collect, store and distribute in a secure and professional way a critical mass of human biological samples for research purposes. Tissues and related data are fundamental for the development of the biomedical research and the emerging field of translational medicine: they represent the “raw material” for every kind of biomedical study. For this reason, it is crucial to understand the boundaries of Intellectual Property (IP) in this prickly context. In fact, both data sharing and collaborative research have become an imperative in contemporary open science, whose development depends inextricably on: the opportunities to access and use data, the possibility of sharing practices between communities, the cross-checking of information and results and, chiefly, interactions with experts in different fields of knowledge. Data sharing allows both to spread the costs of analytical results that researchers cannot achieve working individually and, if properly managed, to avoid the duplication of research. These advantages are crucial: access to a common pool of pre-competitive data and the possibility to endorse follow-on research projects are fundamental for the progress of biomedicine. This is why the "open movement" is also spreading in the biobank's field. After an overview of the complex interactions among the different stakeholders involved in the process of information and data production, as well as of the main obstacles to the promotion of data sharing (i.e., the appropriability of biological samples and information, the privacy of participants, the lack of interoperability), we will firstly clarify some blurring in language, in particular concerning concepts often mixed up, such as “open source” and “open access”. The aim is to understand whether and to what extent we can apply these concepts to the biomedical field. Afterwards, adopting a comparative perspective, we will analyze the main features of the open models – in particular, the Open Research Data model – which have been proposed in literature for the promotion of data sharing in the field of research biobanks. After such an analysis, we will suggest some recommendations in order to rebalance the clash between exclusivity - the paradigm characterizing the evolution of intellectual property over the last three centuries - and the actual needs for access to knowledge. We argue that the key factor in this balance may come from the right interaction between IP, social norms and contracts. In particular, we need to combine the incentives and the reward mechanisms characterizing scientific communities with data sharing imperative