Synthesis and cycloxygenase inhibitory properties of new naphthalene-methylsulfonamido, naphthalene-methylsulfonyl and tetrahydronaphthalen-methylsulfonamido compounds

We synthesized a series of new naphthalene derivatives: naproxen- and 6-methoxy naphthalene acetic acid-like 1–5. In these compounds the carboxylic function, typical of the classical NSAIDs, was replaced by a methylsulfonamido (1, 2 and 6a–c) or methylsulfonyl (3–5) group present in some selective COX-2 inhibitors. We also synthesized compounds 7 and 8 in which the naphthalene portion was substituted by tetrahydronaphthalene ring. Some of the new compounds were assayed for their enzymatic inhibitory activity towards cycloxygenase enzymes. Compounds 4 and 6b, at a concentration of 10 µM exhibit percentage inhibition values of 65%, 50% and 29%, 87% towards COX-2 and COX-1, respectively. The substitution of carboxylic group with a mehylsulfonamido or a methylsulfonyl groups does not allow to direct the selectivity versus to cycloxygenase enzymes

N-(aroyl)-N-(arylmethyloxy)-α-alanines: selective inhibitors of aldose reductase

Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50 in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications

Analoghi sintetici dello xantumolo

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Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models

Activated Leukocyte Cell Adhesion Mol. (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a sol. form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addn., ADAM-17 plays a key role in EGFR signalling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previous mol. 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biol. activity of the newly synthesized compds. was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compd. 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compd. maintained good inhibitory properties on sALCAM shedding in several in vitro assays

HTRA1 and TGF-β1 concentrations in the aqueous humor of patients with neovascular age-related macular degeneration

PURPOSE: To evaluate the expression of high-temperature requirement A serine peptidase 1 (HTRA1), transforming growth factor beta 1 (TGF-β1), bone morphogenetic protein 4 (BMP4), growth differentiation factor 6 (GDF6), and vascular endothelial growth factor A (VEGFA) proteins in the aqueous humor of patients with naïve choroidal neovascularization (nCNV) secondary to age-related macular degeneration. METHODS: We measured by ELISA the concentrations of HTRA1, TGF-β1, BMP4, GDF6 and VEGFA in the aqueous humor of 23 patients affected by nCNV who received 3 consecutive monthly intravitreal injections of 0.5 mg ranibizumab. Samples were collected at baseline (before the first injection), month 1 (before the second injection), and month 2 (before the third injection). 23 age-matched cataract patients served as controls. RESULTS: BMP4 and GDF6 were not detectable in any samples. Baseline HTRA1 was higher than controls (P<0.0001), and higher than both the month 1 (P<0.0001) and the month 2 (P<0.0001) values. Baseline VEGFA was higher than controls (P<0.0001), not different from month 1 value (P=0.0821), but higher than month 2 value (P<0.0001). Baseline TGF-β1 was higher than controls (P=0.0015) and not different from month 1 (P=0.129) and month 2 values (P=0.5529). No correlation was found in naïve patients between concentrations of HTRA1 and TGF-β1, HTRA 1 and VEGFA, or TGF-β1 and VEGFA. CONCLUSIONS: In nCNV patients, HTRA1 and TGF-β1 were significantly higher compared to controls. After treatment, TGF-β1 was persistently elevated, while HTRA1 returned to control levels, suggesting the involvement of TGF-β1 and HTRA1 in nAMD and a VEGFA-independent role for TGF-β1

SABRE and the Stawell Underground Physics Laboratory: Dark Matter Research at the Australian National University

The direct detection of dark matter is a key problem in astroparticle physics that generally requires the use of deep-underground laboratories for a low-background environment where the rare signals from dark matter interactions can be observed. This work reports on the Stawell Underground Physics Laboratory – currently under construction and the first such laboratory in the Southern Hemisphere – and the associated research program. A particular focus will be given to ANU’s contribution to SABRE, a NaI:Tl dark matter, direct detection experiment that aims to confirm or refute the long-standing DAMA result. Preliminary measurements of the NaI:Tl quenching factor and characterisation of the SABRE liquid scintillator veto are reported.I.M. and F.N acknowledge travel support from AINSE for their attendance at the ANU quenching factor measurements. This research was supported by the Australian Research Council, grant numbers DP170101675, LE160100080, LE170100162 and LE190100196

TGF-β concentrations and activity are down-regulated in the aqueous humor of patients with neovascular age-related macular degeneration

Controversy still exists regarding the role of the TGF-β in neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Here, we measured the concentrations of active TGF-β1, TGF-β2, and TGF-β3 by ELISA in the aqueous humor of 20 patients affected by nAMD, who received 3 consecutive monthly intravitreal injections of anti-VEGF-A antibody. Samples were collected at baseline (before the first injection), month 1 (before the second injection), and month 2 (before the third injection). The same samples were used in a luciferase-based reporter assay to test the TGF-β pathway activation. Active TGF-β1 concentrations in the aqueous humor were below the minimum detectable dose. Active TGF-β2 concentrations were significantly lower at baseline and at month 1, compared to controls. No significant differences in active TGF-β3 concentration were found among the sample groups. Moreover, TGF-β pathway activation was significantly lower at baseline compared to controls. Our data corroborate an anti-angiogenic role for TGF-β2 in nAMD. This should be considered from the perspective of a therapy using TGF-β inhibitors

Integrating Health Technology Assessment and Multi-Criteria Decision Analysis in Optimizing Diabetic Macular Edema Management: Results from an Italian Multi-Regional Study

Health Technology Assessment (HTA) is a widely implemented technical tool used to inform the decision-making process..

The large area detector onboard the eXTP mission

The Large Area Detector (LAD) is the high-throughput, spectral-timing instrument onboard the eXTP mission, a flagship mission of the Chinese Academy of Sciences and the China National Space Administration, with a large European participation coordinated by Italy and Spain. The eXTP mission is currently performing its phase B study, with a target launch at the end-2027. The eXTP scientific payload includes four instruments (SFA, PFA, LAD and WFM) offering unprecedented simultaneous wide-band X-ray timing and polarimetry sensitivity. The LAD instrument is based on the design originally proposed for the LOFT mission. It envisages a deployed 3.2 m2 effective area in the 2-30 keV energy range, achieved through the technology of the large-area Silicon Drift Detectors - offering a spectral resolution of up to 200 eV FWHM at 6 keV - and of capillary plate collimators - limiting the field of view to about 1 degree. In this paper we will provide an overview of the LAD instrument design, its current status of development and anticipated performance

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P &lt; 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria