Effect of aldose reductase inhibition on glutathione redox status in erythrocytes of diabetic patients

Diabetic patients undergo a chronic oxidative stress. This phenomenon is demonstrated by low levels of reduced glutathione (GSH) levels. The NADPH used by glutathione reductase for the reduction of oxidized glutathione (GSSG) to GSH is also used by aldose reductase for the reduction of glucose to sorbitol through the polyol pathway. The competition for NADPH could be responsible for the decreased glutathione levels found in non-insulin-dependent diabetic patients. For this purpose, we investigated the effect of polyol pathway inhibition on the glutathione redox status in these patients. We measured GSH and GSSG levels in erythrocytes of non-insulin-dependent diabetic patients (n = 15) before and after 1 week of treatment with placebo, followed by 1 week of treatment with an aldose reductase inhibitor (tolrestat 200 mg/dl). We found lower GSH levels (7.7 +/- 1.4 mumol/g hemoglobin [Hb]), higher GSSG levels (0.35 +/- 0.09 mumol/g Hb), and lower GSH/GSSG ratios (23.9 +/- 7.7) in diabetics compared with controls (n = 15; 9.8 +/- 0.8 mumol/g Hb, P < .001; 0.17 +/- 0.02, P < .001; and 58.3 +/- 9.1, P < .001, respectively). We did not demonstrate any statistical difference after 1 week of treatment with placebo. In contrast, the treatment with tolrestat induced a significant increase in GSH (8.9 +/- 0.7 mumol/g Hb, P < .01), a decrease in GSSG (0.25 +/- 0.06 mumol/g Hb, P < .02), and an increase in the GSH/GSSG ratio (37.3 +/- 8.4, P < .01). These data strongly support the hypothesis that the polyol pathway plays an important role in the impairment of the glutathione redox status in diabetic patients.     

Redispersible Polymer Powders with High Bio-Based Content from Core–Shell Nanoparticles

Redispersible polymer powders (RDPPs), i.e., additives obtained from core–shell nanoparticles and commercialized in the form of a dry powder, find intensive application in the concrete industry. However, they are mainly produced from fossil resources. Therefore, the development of bio-based RDPPs is important to reduce the carbon footprint of these additives. In this work, two types of core–shell nanoparticles with a high percentage of bio-based content are synthesized and show to be good candidates as RDPPs. In the first case, up to 75% of bio-based content is obtained by combining lauryl acrylate, derived from coconut and palm kernel oil, as main core material, with isobornyl methacrylate, coming from pine resin, exploited to create the outer harder shell. In the second case, a degradable macromonomer obtained by the ring opening polymerization of lactide using 2-hydroxyethyl methacrylate as initiator is used as the core-forming monomer to obtain degradable RDPPs. In both cases, the particles are synthesized with a two-step emulsion polymerization process conducted in one pot and then spray-dried to obtain the RDPPs of interest. The morphology and redispersibility of the powders are characterized. Finally, their use as concrete additives is preliminarily assessed by evaluating their effect on changes in the surface morphologies of concrete specimens.     

Advanced Pyrrolidine-Carbamate Self-Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release

Amine-carbamate self-immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine-carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pK_a calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state-of-art analogues.     

EPA or DHA Supplementation Increases Triacylglycerol,but not Phospholipid,Levels in Isolated Rat Cardiomyocytes

It is well recognized that a high dietary intake of long-chain polyunsaturated fatty acids (LC-PUFA) has profound benefits on health and prevention of chronic diseases. In particular, in recent years there has been a dramatic surge of interest in the health effects of n-3 LC-PUFA derived from fish, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Notwithstanding, the metabolic fate and the effects of these fatty acids once inside the cell has seldom been comprehensively investigated. Using cultured neonatal rat cardiomyocytes as model system we have investigated for the first time, by means of high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy in combination with gas chromatography (GC), the modification occurring in the cell lipid environment after EPA and DHA supplementation. The most important difference between control and n-3 LC-PUFA-supplemented cardiomyocytes highlighted by HR-MAS NMR spectroscopy is the increase of signals from mobile lipids, identified as triacylglycerols (TAG). The observed increase of mobile TAG is a metabolic response to n-3 LC-PUFA supplementation, which leads to an increased lipid storage. The sequestration of mobile lipids in lipid bodies provides a deposit of stored energy that can be accessed in a regulated fashion according to metabolic need. Interestingly, while n-3 LC-PUFA supplementation to neonatal rat cardiomyocytes causes a huge variation in the cell lipid environment, it does not induce detectable modifications in water-soluble metabolites, suggesting negligible interference with normal metabolic processes.     

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.     

Sintering behavior of Ba/Sr celsian precursor obtained from zeolite‐A by ion‐exchange method

(Ba, Sr)‐exchanged zeolite A with composition Ba_0.74Sr_0.22Na_0.04Al₂Si₂O₈ was prepared by cation exchange; a mild thermal treatment converts into an amorphous phase. Successive crystallization and sintering behavior was studied by XRD, DTA, and thermodilatometric analysis. The results point out the activation of viscous flow sintering mechanisms between 900°C and 1050°C. The densification process starts when the amorphous phase reaches its glass transition temperature (897°C) and finishes when the material crystallizes forming hexacelsian. The application of an external pressure in such temperature range allows to achieve an almost complete densification, the material transforming at 1300°C into dense monoclinic celsian much below the typical processing temperature.     

Design of a Cost‐Reduced Flexible Plant for Supercritical Fluid‐Assisted Applications

A novel batch plant for supercritical CO₂ applications is proposed which is not equipped with expensive components, such as high‐pressure pumps, making it particularly suitable for bench‐scale use. For the first time, the use of a hanging scale is suggested to weigh the amount of CO₂ required for the experiment and the use of the thermodynamics to reach the working conditions. The rig is able to cover different applications, e.g., aerogel drying, impregnation, and extraction, showing high flexibility. An approximate cost analysis has been performed considering as a reference a 150‐mL vessel. It has been calculated that both the setup and running costs are considerably lower than the common batch and semicontinuous rigs.     

Porcelain stoneware consolidation by flash sintering

Porcelain stoneware was consolidated by flash sintering under DC polarization using current densities in the range 4‐20 mA/mm². The results show the applicability of this innovative sintering technology to a material whose densification occurs by vitrification, thus allowing to extend the possible application field of flash sintering to traditional ceramics. Using appropriate current density, the flash‐ sintered samples are dense, homogeneous, and well‐vitrified. XRD and microstructural analysis points out the formation of primary mullite while secondary mullite is only sporadically observed. In addition, comparison between flash sintering and fast firing shows that the densification obtained in the selected ceramic system via the former route cannot be reproduced just by a rapid heating process.     

Increasing the X-ray Diffraction Power of Protein Crystals by Dehydration: The Case of Bovine Serum Albumin and a Survey of Literature Data

Serum albumin is one of the most widely studied proteins. It is the most abundant protein in plasma with a typical concentration of 5 g/100 mL and the principal transporter of fatty acids in plasma. While the crystal structures of human serum albumin (HSA) free and in complex with fatty acids, hemin, and local anesthetics have been characterized, no crystallographic models are available on bovine serum albumin (BSA), presumably because of the poor diffraction power of existing hexagonal BSA crystals. Here, the crystallization and diffraction data of a new BSA crystal form, obtained by the hanging drop method using MPEG 5K as precipitating agent, are presented. The crystals belong to space group C2, with unit-cell parameters a = 216.45 Å, b = 44.72 Å, c = 140.18 Å, β = 114.5°. Dehydration was found to increase the diffraction limit of BSA crystals from ~8 Å to 3.2 Å, probably by improving the packing of protein molecules in the crystal lattice. These results, together with a survey of more than 60 successful cases of protein crystal dehydration, confirm that it can be a useful procedure to be used in initial screening as a method of improving the diffraction limits of existing crystals.