Peptide Human Neutrophil Elastase Inhibitors from Natural Sources: An Overview

Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural lead compounds. Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC₅₀ values in a range from nM to μM values, thus representing an interesting starting point for the further development of potent bioactive compounds on human elastase enzymes.     

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.     

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.     

Azacrown Ethers with Naphthyl Branches. Fluorescence Properties,Protonation and Metal Coordination

Starting from 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, we have prepared two compounds by replacing the amine hydrogens with naphthyl or 3,5-bis(2′-oxymethylnaphthyl)benzyl units. The absorption and emission spectra of compounds 2 (N,N′-bis(2-naphthylmethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) and 3 (N,N′-bis[3,5-bis(2′-oxymethylnaphthyl)benzyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) have been studied in CH₃CN:CH₂Cl₂ 1:1 (v/v) solution. For comparison purposes, the spectroscopic properties of N-methyl(2-methylnaphthalene)ethylamine (1) have also been investigated. For each compound, the absorption spectra are qualitatively very similar to that of naphthalene, with molar absorption coefficients as expected for the presence of one (1), two (2), and four (3) naphthyl chromophoric groups. The fluorescence spectra, however, are quite different from that of naphthalene. The naphthalene-type fluorescence (λ_max = 337 nm) is strongly quenched, particularly for compounds 1 and 2 which also exhibit a broad emission band in the visible region (λ_max ≈ 480 nm) assigned to a low lying charge-transfer excited state. In the case of compound 3, a quenched naphthalene-type band is accompanied by weak exciplex and excimer emissions. Upon titration with CF₃SO₃H, the charge transfer bands of 1 and 2 and the exciplex emission of 3 disappear and the naphthalene-type bands regain intensity. Titration plots show that in compounds 2 and 3 the protonation of the two nitrogens occurs stoichiometrically in two distinct steps. Titration with Zn²⁺ gives rise to 2.Zn²⁺ and 3.Zn²⁺ complexes. This article is dedicated to Professor Dedier Astruc.     

Antioxidant activity,color chromaticity coordinates,and chemical characterization of monofloral honeys from Morocco

The bioprospecting of several monofloral Moroccan honeys was carried out. The antiradical activity expressed as mmol Trolox equivalents/kg of honey and evaluated by 2,2-diphenyl-1-picrylhydrazyl assay, ranged from 0.15 for euphorb honey to 1.08 for citrus honey. The antioxidant activity expressed as mmol Fe²⁺/kg and evaluated by ferric ion reducing antioxidant power assay, ranged from 0.96 for euphorb honey to 4.74 for orange honey. The total phenol content was evaluated by colorimetric assay, while the color attributes were evaluated as transmittance data. Significant Pearson correlation factors were found between total polyphenol amount and antioxidant activity and between color attributes and antioxidant activity. Furthermore the chemical composition of volatile organic compounds was determined. The volatile organic compounds chemical composition of the studied honeys was mainly represented by terpene and benzene derivatives, Maillard reaction products, isoprenoids, and hydrocarbons. The volatiles fingerprint, as well as a targeted high-performance liquid chromatography analysis of the polar components, was used to tentatively confirm the declared botanical origin of the samples studied.     

BETaaS: A Platform for Development and Execution of Machine-to-Machine Applications in the Internet of Things

Wireless Personal Communications - The integration of everyday objects into the Internet represents the foundation of the forthcoming Internet of Things (IoT). Smart objects will be the building...     

Influence of mineral additions on the performance of 100% recycled aggregate concrete

A judicious use of resources, by using by-products and waste materials, and a lower environmental impact, by reducing carbon dioxide emission and virgin aggregate extraction, allow to approach sustainable building development. Recycled aggregate concrete (RAC) containing supplementary cementitious materials (SCM), if satisfactory concrete properties are achieved, can be an example of such sustainable construction materials.In this work concrete specimens were manufactured by completely replacing fine and coarse aggregates with recycled aggregates from a rubble recycling plant. Also RAC with fly ash (RA + FA) or silica fume (RA + SF) were studied.Concrete properties were evaluated by means of compressive strength and modulus of elasticity in the first experimental part. In the second experimental part, compressive and tensile splitting strength, dynamic modulus of elasticity, drying shrinkage, reinforcing bond strength, carbonation, chloride penetration were studied. Satisfactory concrete properties can be developed with recycled fine and coarse aggregates with proper selection and proportioning of the concrete materials.