A Synthetic MUC1 Glycopeptide Bearing βGalNAc‐Thr as a Tn Antigen Isomer Induces the Production of Antibodies against Tumor Cells

This study presents the synthesis of the novel protected O‐glycosylated amino acid derivatives 1 and 2 , containing βGalNAc‐SerOBn and βGalNAc‐ThrOBn units, respectively, as mimetics of the natural Tn antigen (αGalNAc‐Ser/Thr), along with the solid‐phase assembly of the glycopeptides NHAcSer‐Ala‐Pro‐Asp‐Thr[αGalNAc]‐Arg‐Pro‐Ala‐Pro‐Gly‐BSA ( 3 ‐BSA) and NHAcSer‐Ala‐Pro‐Asp‐Thr[βGalNAc]‐Arg‐Pro‐Ala‐Pro‐Gly‐BSA ( 4 ‐BSA), bearing αGalNAc‐Thr or βGalNAc‐Thr units, respectively, as mimetics of MUC1 tumor mucin glycoproteins. According to ELISA tests, immunizations of mice with βGalNAc‐glycopeptide 4 ‐BSA induced higher sera titers (1:320 000) than immunizations with αGalNAc‐glycopeptide 3 ‐BSA (1:40 000). Likewise, flow cytometry assays showed higher capacity of the obtained anti‐glycopeptide 4 ‐BSA antibodies to recognize MCF‐7 tumor cells. Cross‐recognition between immunopurified anti‐βGalNAc antibodies and αGalNAc‐glycopeptide and vice versa was also verified. Lastly, molecular dynamics simulations and surface plasmon resonance (SPR) showed that βGalNAc‐glycopeptide 4 can interact with a model antitumor monoclonal antibody (SM3). Taken together, these data highlight the improved immunogenicity of the unnatural glycopeptide 4 ‐BSA, bearing βGalNAc‐Thr as Tn antigen isomer.     

In situ growth of well-dispersed CdS nanocrystals in semiconducting polymers

A straight synthetic route to fabricate hybrid nanocomposite films of well-dispersed CdS nanocrystals (NCs) in poly[2-methoxy-5-(2''-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV) is reported. A soluble cadmium complex [Cd(SBz)₂]₂·MI, obtained by incorporating a Lewis base (1-methylimidazole, MI) on the cadmium bis(benzyl)thiol, is used as starting reagent in an in situ thermolytic process. CdS NCs with spherical shape nucleate and grow well below 200°C in a relatively short time (30 min). Photoluminescence spectroscopy measurements performed on CdS/MEH-PPV nanocomposites show that CdS photoluminescence peaks are totally quenched inside MEH-PPV, if compared to CdS/PMMA nanocomposites, as expected due to overlapping of the polymer absorption and CdS emission spectra. The CdS NCs are well-dispersed in size and homogeneously distributed within MEH-PPV matrix as proved by transmission electron microscopy. Nanocomposites with different precursor/polymer weight ratios were prepared in the range from 1:4 to 4:1. Highly dense materials, without NCs clustering, were obtained for a weight/weight ratio of 2:3 between precursor and polymer, making these nanocomposites particularly suitable for optoelectronic and solar energy conversion applications.     

Effects of Cadmium Exposure on Gut Villi in Danio rerio

In aquatic organisms, cadmium exposure occurs from ovum to death and the route of absorption is particularly wide, being represented by skin, gills and gastrointestinal tract, through which contaminated water and/or preys are ingested. It is known that cadmium interferes with the gut; however, less information is available on cadmium effects on an important component of the gut, namely goblet cells, specialized in mucus synthesis. In the present work, we studied the effects of two sublethal cadmium concentrations on the gut mucosa of Danio rerio. Particular attention was paid to changes in the distribution of glycan residues, and in metallothionein expression in intestinal cells. The results show that cadmium interferes with gut mucosa and goblet cells features. The effects are dose- and site-dependent, the anterior gut being more markedly affected than the midgut. Cadmium modifies the presence and/or distribution of glycans in the brush border and cytoplasm of enterocytes and in the goblet cells’ cytoplasm and alters the metallothionein expression and localization. The results suggest a significant interference of cadmium with mucosal efficiency, representing a health risk for the organism in direct contact with contamination and indirectly for the trophic chain.     

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.     

Cytokines from Bench to Bedside: A Retrospective Study Identifies a Definite Panel of Biomarkers to Early Assess the Risk of Negative Outcome in COVID-19 Patients

The main aim of this study was to identify the most relevant cytokines which, when assessed in the earliest stages from hospital admission, may help to select COVID-19 patients with worse prognosis. A retrospective observational study was conducted in 415 COVID-19 patients (272 males; mean age 68 ± 14 years) hospitalized between May 2020 and March 2021. Within the first 72 h from hospital admission, patients were tested for a large panel of biomarkers, including C-reactive protein (CRP), Mid-regional proadrenomedullin (MR-proADM), Interferon-γ, interleukin 6 (IL-6), IL-1β, IL-8, IL-10, soluble IL2-receptor-α (sIL2Rα), IP10 and TNFα. Extensive statistical analyses were performed (correlations, t-tests, ranking tests and tree modeling). The mortality rate was 65/415 (15.7%) and a negative outcome (death and/or orotracheal intubation) affected 98/415 (23.6%) of cases. Univariate tests showed the majority of biomarkers increased in severe patients, but ranking tests helped to select the best variables to put on decisional tree modeling which identified IL-6 as the first dichotomic marker with a cut-off of 114 pg/mL. Then, a good synergy was found between IL-10, MR-proADM, sIL2Rα, IP10 and CRP in increasing the predictive value in classifying patients at risk or not for a negative outcome. In conclusion, beside IL-6, a panel of other cytokines representing the degree of immunoparalysis and the anti-inflammatory response (IP10, sIL2Rα and IL-10) showed synergic role when combined to biomarkers of systemic inflammation and endothelial dysfunction (CRP, MR-proADM) and may also better explain disease pathogenesis and suggests targeted intervention.     

The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.     

A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases

Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.     

Glass and Jamming Rheology in Soft Particles Made of PNIPAM and Polyacrylic Acid

The phase behaviour of soft colloids has attracted great attention due to the large variety of new phenomenologies emerging from their ability to pack at very high volume fractions. Here we report rheological measurements on interpenetrated polymer network microgels composed of poly(N-isopropylacrylamide) (PNIPAM) and polyacrylic acid (PAAc) at fixed PAAc content as a function of weight concentration. We found three different rheological regimes characteristic of three different states: a Newtonian shear-thinning fluid, an attractive glass characterized by a yield stress, and a jamming state. We discuss the possible molecular mechanisms driving the formation of these states.