Protective Properties of Novel S‐Acyl‐Glutathione Thioesters Against Ultraviolet‐induced Oxidative Stress

UV‐induced toxicity is characterized by marked oxidative stress, accompanied by the depletion of key cellular antioxidants, particularly glutathione (GSH). Replenishing cellular GSH may represent a means of counteracting UV‐induced toxicity: however, treatment with free GSH is not therapeutically effective due to its unfavorable pharmacokinetic properties. In this study, we show that S‐acyl‐glutathione (acyl‐SG) derivatives, which consist of an acyl chain (of variable length and saturation) linked via a thioester bond to GSH, increase intracellular levels of reduced GSH in primary skin fibroblasts, adenocarcinoma HeLa and neuroblastoma SH‐SY5Y cells. Consistent with this, acyl‐SG derivatives protect against UV‐induced reactive oxygen species (ROS) production and UV‐B/C‐mediated lipid peroxidation and caspase‐3 activation in the analyzed cell lines, with unsaturated thioesters displaying a significantly greater protective effect. Taken together, our findings suggest that acyl‐SG thioesters may be therapeutically effective in the treatment of UV‐related skin disorders and oxidative stress‐mediated conditions in general.     

Stereocontrolled Transformations of trans α,β‐Aziridine Aldehydes toward Different Amino Hydroxylated Structures

The stereocontrolled condensation of methyl ketones to trans α,β‐aziridine aldehydes creates functionalized aldols, valuable precursors for different amino hydroxylated structures, such as amino alcohols, amino diols, α‐tetrahydrofuryl amides, and α‐furyl amides.     

Quantification of micafungin in human plasma by liquid chromatography-tandem mass spectrometry

Micafungin (MCF) is an antifungal agent of the echinocandin class approved in Europe both in adults and in children for the treatment of invasive candidiasis. Few analytical methods for therapeutic drug monitoring (TDM) of this drug have been described so far. In this paper, we describe a rapid and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the measurement of MCF in plasma. MCF was analyzed in 100-μL plasma samples over a wide range of concentrations (0.1–20 μg/mL) by LC-MS/MS after protein precipitation. The suitability of the assay for TDM was evaluated by using plasma samples from pediatric patients who received MCF for the treatment of invasive candidiasis. The overall turnaround time for the assay was 20 min. The lower limit of quantification of the method was 0.1 ng/mL. No ion suppression due to matrix effects was found with different pre-analytical conditions, such as hemolysis, lipemia, and hyperuricemia. A simple and rapid LC-MS/MS method which provides high specificity, precision, and accuracy for quantification of MCF in plasma has been developed and validated.     

Synergistic Strategies in Aminocatalysis

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.     

In Vitro Effects of Sulforaphane on Interferon-Driven Inflammation and Exploratory Evaluation in Two Healthy Volunteers

Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.     

A feasibility study of X‐ray phase‐contrast mammographic tomography at the Imaging and Medical beamline of the Australian Synchrotron

Results are presented of a recent experiment at the Imaging and Medical beamline of the Australian Synchrotron intended to contribute to the implementation of low‐dose high‐sensitivity three‐dimensional mammographic phase‐contrast imaging, initially at synchrotrons and subsequently in hospitals and medical imaging clinics. The effect of such imaging parameters as X‐ray energy, source size, detector resolution, sample‐to‐detector distance, scanning and data processing strategies in the case of propagation‐based phase‐contrast computed tomography (CT) have been tested, quantified, evaluated and optimized using a plastic phantom simulating relevant breast‐tissue characteristics. Analysis of the data collected using a Hamamatsu CMOS Flat Panel Sensor, with a pixel size of 100 µm, revealed the presence of propagation‐based phase contrast and demonstrated significant improvement of the quality of phase‐contrast CT imaging compared with conventional (absorption‐based) CT, at medically acceptable radiation doses.     

Interaction with plasmid DNA of Hoechst-TACN conjugates

ABSTRACT

A new family of conjugates between the Hoechst minor groove binder and the TACN metal ion ligand connected through hydrophobic alkyl or more hydrophilic oxyethyl linkers of different length has been prepared. The linkers are connected to the convex side of the Hoechst skeleton thus forcing the TACN ligand to exit the minor groove and interact with the phosphate backbone of DNA. The conjugates preserve the binding mode of Hoechst with an affinity influenced by the nature of the linker, the more hydrophobic being the more efficient. Coordination of Cu(II) or Zn(II) poorly affect these parameters. Nevertheless, the Zn(II) complex bearing a C6 linear alkyl linker induced a modest but reproducible acceleration of the hydrolytic cleavage of DNA which can be ascribed to the ability of the conjugate to deliver the hydrolytic subunit close to the DNA phosphodiester bonds.     

Sui probleimi ellittici non lineari con coefficienti crescenti «rapidamente» o «lentamente»

Summary We study boundary value problems in variational form for nonlinear elliptic operators in the case the nonlinearity is not of polynomial type. We give some examples of applications of abstract theorems for homogeneous problems obtained by other authors (e.g. Donaldson, Grossez) to homogeneous «intermediate» and «mixed» problems. Furthermore we prove some existence theorems for non homogeneous problems.

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Lavoro eseguito nell'ambito del G.N.A.F.A. del C.N.R.