Role of Vitamin D3 and Alginates in Prevention of NSAID-Dependent Cellular Injury

About 30 million people use nonsteroidal anti-inflammatory drugs. Therefore, they have a high risk of developing gastropathic and enteropathic damages. These patients receive anti-acid treatment, but a number of clinical studies provided evidence of the ineffectiveness of proton-pump inhibitors. Vitamin D, on the other hand, appears to have high preventive and therapeutic potential. Recently, it has been introduced a product that, in addition to anti-acid properties of alginates, claims to possess gastroprotective properties deriving from vitamin D3 and from plant extractsThis study was planned to verify the effectiveness of vitamin D3 combined with alginates to prevent the damage induced in cul-tured gastric cells by diclofenac during acidic or hyperacidic exposition measuring cell viability, radical oxygen species production along with apoptotic and survival pathways.Around 30 million people consume nonsteroidal anti-inflammatory drugs (NSAID) globally every day [1] since they are widely pre-scribed because of their efficacy in the management of pain, inflammation, and fever [2]. Generally, the action mechanism of these drugs consists in the inhibition of the biosynthesis of prostaglandins, the inactivation of cyclooxygenase, and an increase in leukotrienes produc-tion [3]. Adverse events associated with NSAID, such as alterations in renal function, effects on blood pressure, hepatic injury, and plate-let inhibition, are a challenge in clinical treatment optimization [4]. However, severe gastrointestinal disorder accompanied by gastric mucosal perforation and bleeding is a major concern as well as the worst outcome of prolonged NSAID-therapy [5]: indeed, they induce gastric mucosal lesions because of their acidic properties [3]. Gastric mucosal erosions, ulceration, bleeding, and perforation, as well as an increased risk of bleeding from pre-existing peptic ulcers are major causes of gastrointestinal iatrogenic diseases [6]. The mechanism behind gastric damage involves a highly acidic gastric environment that favours the migration of nonionized lipophilic NSAID into the Findings show that this combination is more potent to counteract the negative effects of diclofenac and hyperacidic conditions than some other gastroprotective agents on epithelial gastric cells. This was confirmed by the maintenance of p53 expression at physiological level. In addition, when added before diclofenac, it can exert beneficial effects counteracting the negative effect of diclof-enac alone. These data were similar to the sample treated with pantoprazole, supporting the hypothesis that the combination could act as a gastroprotector to prevent cell loss. These results have pointed out the gastroprotective effect of the combination when compared to other commercial natural ex-tracts, this effect is obtained via antioxidant pathway, inhibiting apoptosis, enhancing cell viability and activating survival kinase

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander's Disease

Alexander's disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a "threshold hypothesis" has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization

Fenomeni di crollo delle falesie salentine: le preferenze della collettività a supporto degli interventi di recupero e gestione

In recent years, the cliffs along the coastal stretch of Melendugno are being interested by coastal erosion. For its environmental, landscape and tourist value, the local authorities are planning several actions to be implemented in the short, medium and long term as part of one of the five regional projects included in the new Territorial Landscape Plan of Apulia. The paper aims to verify the effective interest of residents and tourists in the province of Lecce towards the renovation and upgrading projects for the cliffs of Melendugno through the choice experiment (CE). Such an approach could also define economic and fiscal incentives, as well as improve measures in order to promote bottom-up initiatives, with positive effects on the governance of the shores of Salento

Euclid preparation -XIX. Impact of magnification on photometric galaxy clustering

Aims. We investigate the importance of lensing magnification for estimates of galaxy clustering and its cross-correlation with shear for the photometric sample of Euclid. Using updated specifications, we study the impact of lensing magnification on the constraints and the shift in the estimation of the best fitting cosmological parameters that we expect if this effect is neglected. Methods. We follow the prescriptions of the official Euclid Fisher matrix forecast for the photometric galaxy clustering analysis and the combination of photometric clustering and cosmic shear. The slope of the luminosity function (local count slope), which regulates the amplitude of the lensing magnification, and the galaxy bias have been estimated from the Euclid Flagship simulation. Results. We find that magnification significantly affects both the best-fit estimation of cosmological parameters and the constraints in the galaxy clustering analysis of the photometric sample. In particular, including magnification in the analysis reduces the 1σ errors on Ωm, 0, w0, wa at the level of 20–35%, depending on how well we will be able to independently measure the local count slope. In addition, we find that neglecting magnification in the clustering analysis leads to shifts of up to 1.6σ in the best-fit parameters. In the joint analysis of galaxy clustering, cosmic shear, and galaxy–galaxy lensing, magnification does not improve precision, but it leads to an up to 6σ bias if neglected. Therefore, for all models considered in this work, magnification has to be included in the analysis of galaxy clustering and its cross-correlation with the shear signal (3 × 2pt analysis) for an accurate parameter estimation. Key words: large-scale structure of Universe / cosmological parameters / cosmology: theor

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental Astronomy with minor editin

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033