Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders’ views on AI for therapy discovery in CDG.     

Characterization of charge trapping in SiO2/Al2O3 dielectric stacks by pulsed C–V technique

In this work, charge trapping in SiO₂/Al₂O₃ dielectric stacks is characterized by means of pulsed capacitance–voltage measurements. The proposed technique strongly reduces the measurement time and, as a consequence, the impact of charge trapping on the measurement results. Flat band voltage shift and fast current transient during short stress pulses are systematically monitored and the centroid and the amount of the trapped charge are extracted using a first-order model.     

Critical Role for the Protons in FRTL-5 Thyroid Cells: Nuclear Sphingomyelinase Induced-Damage

Proliferating thyroid cells are more sensitive to UV-C radiations than quiescent cells. The effect is mediated by nuclear phosphatidylcholine and sphingomyelin metabolism. It was demonstrated that proton beams arrest cell growth and stimulate apoptosis but until now there have been no indications in the literature about their possible mechanism of action. Here we studied the effect of protons on FRTL-5 cells in culture. We showed that proton beams stimulate slightly nuclear neutral sphingomyelinase activity and inhibit nuclear sphingomyelin-synthase activity in quiescent cells whereas stimulate strongly nuclear neutral sphingomyelinase activity and do not change nuclear sphingomyelin-synthase activity in proliferating cells. The study of neutral sphingomyelinase/sphingomyelin-synthase ratio, a marker of functional state of the cells, indicated that proton beams induce FRTL-5 cells in a proapoptotic state if the cells are quiescent and in an initial apoptotic state if the cells are proliferating. The changes of cell life are accompanied by a decrease of nuclear sphingomyelin and increase of bax protein.     

Role of Extracellular Vesicles in Epithelial Ovarian Cancer: A Systematic Review

Extracellular vesicles (EVs) are a heterogeneous group of cell-derived submicron vesicles released under physiological or pathological conditions. EVs mediate the cellular crosstalk, thus contributing to defining the tumor microenvironment, including in epithelial ovarian cancer (EOC). The available literature investigating the role of EVs in EOC has been reviewed following PRISMA guidelines, focusing on the role of EVs in early disease diagnosis, metastatic spread, and the development of chemoresistance in EOC. Data were identified from searches of Medline, Current Contents, PubMed, and from references in relevant articles from 2010 to 1 April 2020. The research yielded 194 results. Of these, a total of 36 papers, 9 reviews, and 27 original types of research were retained and analyzed. The literature findings demonstrate that a panel of EV-derived circulating miRNAs may be useful for early diagnosis of EOC. Furthermore, it appears clear that EVs are involved in mediating two crucial processes for metastatic and chemoresistance development: the epithelial–mesenchymal transition, and tumor escape from the immune system response. Further studies, more focused on in vivo evidence, are urgently needed to clarify the role of EV assessment in the clinical management of EOC patients.     

Detailed Insight into the Interaction of Bicyclic Somatostatin Analogue with Cu(II) Ions

Somatostatin analogues are useful pharmaceuticals in peptide receptor radionuclide therapy. In previous studies, we analyzed a new bicyclic somatostatin analogue (BCS) in connection with Cu(II) ions. Two characteristic sites were present in the peptide chain: the receptor- and the metal-binding site. We have already shown that this ligand can form very stable imidazole complexes with the metal ion. In this work, our aim was to characterize the intramolecular interaction that occurs in the peptide molecule. Therefore, we analyzed the coordination abilities of two cyclic ligands, i.e., P1 only with the metal binding site and P2 with both sites, but without the disulfide bond. Furthermore, we used magnetic circular dichroism (MCD) spectroscopy to better understand the coordination process. We applied this method to analyze spectra of P1, P2, and BCS, which we have described previously. Additionally, we analyzed the MCD spectra of P3 ligand, which has only the receptor binding site in its structure. We have unequivocally shown that the presence of the Phe-Trp-Lys-Thr motif and the disulfide bond significantly increases the metal binding efficiency.     

Dihydrotanshinone,a Natural Diterpenoid,Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor

Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2′(3′)-O-(4-Benzoylbenzoyl)adenosine-5′-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1β, IL-6, TNF-α, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions.     

Synthesis and Characterizations of Melamine-Based Epoxy Resins

A new, easy and cost-effective synthetic procedure for the preparation of thermosetting melamine-based epoxy resins is reported. By this innovative synthetic method, different kinds of resins can be obtained just by mixing the reagents in the presence of a catalyst without solvent and with mild curing conditions. Two types of resins were synthesized using melamine and a glycidyl derivative (resins I) or by adding a silane derivative (resin II). The resins were characterized by means of chemical-physical and thermal techniques. Experimental results show that all the prepared resins have a good thermal stability, but differ for their mechanical properties: resin I exhibits remarkable stiffness with a storage modulus value up to 830 MPa at room temperature, while lower storage moduli were found for resin II, indicating that the presence of silane groups could enhance the flexibility of these materials. The resins show a pot life higher than 30 min, which makes these resins good candidates for practical applications. The functionalization with silane terminations can be exploited in the formulation of hybrid organic-inorganic composite materials.     

The influence of drying air temperature on the physical properties of dried and rehydrated eggplant

Drying processes generally cause volume and surface change of foodstuffs. Information on the porous structure and the mechanical properties of dried food products is needed for determining food quality, process design and estimating properties such as density and moisture diffusivity.In this work we investigated the structural changes induced in eggplant by convective air drying at four different temperatures (40, 50, 60 and 70 °C) and their effect on the subsequent rehydration process. Drying and rehydration kinetic curves were also measured.The changes in physical properties, such as porosity, pore-size distribution and bulk density were determined by Hg porosimetry, scanning electron microscopy and optical microscopy while their effect on the textural characteristics by dynamometric measurements.As expected, the increase of the drying air temperature causes shorter drying times. The drying temperature influences strongly the microstructure of dried samples: the porosity increases with the air temperature, but the structure is better preserved at intermediate temperature (60 °C) as confirmed by the lower firmness values with respect to the other dehydrated samples (40, 50 and 70 °C). In these latter, the longer drying time and the higher temperature, respectively, causes the development of a wrinkled structure. In particular, at 70 °C the structure of dehydrated samples appears totally broken with a consequent faster water uptake during rehydration.     

Combined Treatment with Dif1stat<Superscript>®</Superscript> and Diet Reduce Plasma Lipid Indicators of Moderate Hypercholesterolemia More Effectively than Diet Alone: A Randomized Trial in Parallel Groups

An open-labeled randomized trial with parallel groups was carried out to study the effects of Dif1stat^® (Monascus purpureus–Linear aliphatic alcohols–Niacin) in the treatment of primary moderate hypercholesterolemia. The trial lasted 8 months. The patients, males and females, were assigned to two groups: A (#130), treated with diet, and B (#110) submitted to diet + Dif1stat^®. After 4 months, group A did not show significant changes in Total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC) or non-HDL-cholesterol (non-HDLC). The same group, showed a reduction in TC (–22%), LDLC (–30%) and non-HDLC (–27%) after 8 months (P ≤ 0.001). After 4 months, TC (–21.3%), LDLC (–29%), and non-HDLC (–26%) were significantly lowered in group B (P ≤ 0.001). In group B, TC, LDLC and non-HDLC showed a further reduction after 8 months: –29.4, –38 and –37%, respectively (P ≤ 0.001). Even triglycerides (TG) decreased significantly (–33%) (P ≤ 0.001). After 8 months, group B showed a significant reduction of TG (–33%) (P ≤ 0.001), when compared to group A. Some safety parameters were significantly reduced in both groups: AST and γ-GT in group A after 4 and 8 months, as well as ALT, AST and γ-GT in group B after 8 months (P ≤ 0.001). Dif1stat^®, given with a suitable diet, was well tolerated in the long-term and induced an anti-atherogenic plasma lipid and lipoprotein profile, in patients with moderate hypercholesterolemia.