Progettazione, sintesi e valutazione biologica di nuovi composti benzopiranici 4-spiro sostituiti come potenziali attivatori dei canali KATP mitocondriali cardiaci

I canali del potassio ATP-dipendenti sono coinvolti in un meccanismo cardioprotettivo noto come precondizionamento ischemico; la possibilita’ di modulare la cardioprotezione inducendo tale processo attraverso l’apertura dei canali KATP rappresenta una base razionale per lo sviluppo di nuovi potenziali farmaci antiischemici. In questa tesi e’ stata progettata e sintetizzata una serie di composti benzopiranici 4-spirosostituiti ed e’ stata valutata la loro attivita’ cardioprotettiva

Developmental excitatory-to-inhibitory GABA-polarity switch is disrupted in 22q11.2 deletion syndrome: a potential target for clinical therapeutics.

Individuals with 22q11.2 microdeletion syndrome (22q11.2 DS) show cognitive and behavioral dysfunctions, developmental delays in childhood and risk of developing schizophrenia and autism. Despite extensive previous studies in adult animal models, a possible embryonic root of this syndrome has not been determined. Here, in neurons from a 22q11.2 DS mouse model (Lgdel +/-), we found embryonic-premature alterations in the neuronal chloride cotransporters indicated by dysregulated NKCC1 and KCC2 protein expression levels. We demonstrate with large-scale spiking activity recordings a concurrent deregulation of the spontaneous network activity and homeostatic network plasticity. Additionally, Lgdel +/- networks at early development show abnormal neuritogenesis and void of synchronized spontaneous activity. Furthermore, parallel experiments on Dgcr8 +/- mouse cultures reveal a significant, yet not exclusive contribution of the dgcr8 gene to our phenotypes of Lgdel +/- networks. Finally, we show that application of bumetanide, an inhibitor of NKCC1, significantly decreases the hyper-excitable action of GABAA receptor signaling and restores network homeostatic plasticity in Lgdel +/- networks. Overall, by exploiting an on-a-chip 22q11.2 DS model, our results suggest a delayed GABA-switch in Lgdel +/- neurons, which may contribute to a delayed embryonic development. Prospectively, acting on the GABA-polarity switch offers a potential target for 22q11.2 DS therapeutic intervention

Selective detection of dopamine with an all PEDOT:PSS Organic Electrochemical Transistor

open6noAn all PEDOT:PSS Organic Electrochemical Transistor (OECT) has been developed and used for the selective detection of dopamine (DA) in the presence of interfering compounds (ascorbic acid, AA and uric acid, UA). The selective response has been implemented using a potentiodynamic approach, by varying the operating gate bias voltage and the scan rate. The trans-conductance curves allow to obtain a linear calibration plot for AA, UA and DA and to separate the redox waves associated to each compound; for this purpose, the scan rate is an important parameter to achieve a good resolution. The sensitivities and limits of detection obtained with the OECT have been compared with those obtained by potential step amperometric techniques (cyclic voltammetry and differential pulse voltammetry), employing a PEDOT:PSS working electrode: our results prove that the all-PEDOT:PSS OECT sensitivities and limits of detection are comparable or even better than those obtained by DPV, a technique that employs a sophisticate potential wave and read-out system in order to maximize the performance of electrochemical sensors and that can hardly be considered a viable readout method in practical applications.openGualandi, Isacco; Tonelli, Domenica; Mariani, Federica; Scavetta, Erika; Marzocchi, Marco; Fraboni, BeatriceGualandi, Isacco; Tonelli, Domenica; Mariani, Federica; Scavetta, Erika; Marzocchi, Marco; Fraboni, Beatric

Design of an electrochemically gated organic semiconductor for pH sensing

Since the development of potentiometric ion-selective electrodes, remarkable steps have been taken towards progressive simplification and improved robustness of pH sensing probes. In particular, the design of compact sensing architectures using solid-state components holds great potential for portable and wearable applications. Here we report the development of an electrochemically gated device for pH detection, combining the robustness of potentiometric-like transduction with an extremely simple and integrated geometry requiring no reference. The sensor is a two-point probe device comprising two thin polymeric films, i.e. a charge transport layer and a pH-sensitive layer, and exhibits a sensitivity of (8.3 ± 0.2) × 10−3 pH unit−1 in the pH range from 2 to 7. Thanks to the versatility and robustness of the optimised design, a textile pH sensor was fabricated whose performance is comparable with that of glass sensors

Benzimidazole-based derivatives as privileged scaffold developed for the treatment of the RSV infection: a computational study exploring the potency and cytotoxicity profiles

Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI1/4CC50/EC50) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents

Smart Bandaid Integrated with Fully Textile OECT for Uric Acid Real-Time Monitoring in Wound Exudate

: Hard-to-heal wounds (i.e., severe and/or chronic) are typically associated with particular pathologies or afflictions such as diabetes, immunodeficiencies, compression traumas in bedridden people, skin grafts, or third-degree burns. In this situation, it is critical to constantly monitor the healing stages and the overall wound conditions to allow for better-targeted therapies and faster patient recovery. At the moment, this operation is performed by removing the bandages and visually inspecting the wound, putting the patient at risk of infection and disturbing the healing stages. Recently, new devices have been developed to address these issues by monitoring important biomarkers related to the wound health status, such as pH, moisture, etc. In this contribution, we present a novel textile chemical sensor exploiting an organic electrochemical transistor (OECT) configuration based on poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) for uric acid (UA)-selective monitoring in wound exudate. The combination of special medical-grade textile materials provides a passive sampling system that enables the real-time and non-invasive analysis of wound fluid: UA was detected as a benchmark analyte to monitor the health status of wounds since it represents a relevant biomarker associated with infections or necrotization processes in human tissues. The sensors proved to reliably and reversibly detect UA concentration in synthetic wound exudate in the biologically relevant range of 220-750 μM, operating in flow conditions for better mimicking the real wound bed. This forerunner device paves the way for smart bandages integrated with real-time monitoring OECT-based sensors for wound-healing evaluation

Linking coastal and seafloor morphological features along the eastern side of the Maltese archipelago

The integration of detailed geomorphological information from the present subaerial exposures of the Maltese archipelago, with morphobathymetric data obtained from the adjacent continental margin may serve in understanding processes active in shaping the archipelago since the Last Glacial Maximum. In perspective, this appears also to be of fundamental importance to better define the kinematics of active gravitational processes occurring along the coastlines. Preliminary results reveal the existence of submerged morphologies comparable to subaerial analogous. A case in point is circular depressions at shallow depth interpreted as inundated former karst features like sinkholes on-land. This is probably the case also of fractured plateaus surrounded by detached blocks identified offshore, which are comparable to terrestrial landforms formed by lateral spreading. Other relevant features identified on the continental margin and easily correlatable with morphologies on land include meandering river valleys.peer-reviewe

Inhibition of chloride intracellular channel 1 (CLIC1) as biguanide class-effect to impair human glioblastoma stem cell viability

The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50values significantly lower than metformin, (range 0.054-0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanidestructured molecules, characterized by high antitumor efficacy and safe toxicological profile

Images from a drowned prehistoric landscape : the eastern side of the maltese archipelago

Offshore research carried out to map the seafloor on the north-eastern Maltese margin resulted in the first acquisition of multibeam bathymetric data imaging with detail the seascape. The surveys were conducted during cruises MEDCOR and DECORS in December 2009 and August 2011 respectively onboard R/V Urania. These missions mapped the north-eastern Maltese continental margin from off north Gozo to the southern tip of Malta. These data have been integrated by further high-resolution multibeam records acquired during cruise RICS 2010 onboard R/V Hercules on the shallow eastern margin between southern Gozo and north Malta.peer-reviewe