Assessing the Potential of -Butyl-l-deoxynojirimycin (l-NBDNJ) in Models of Cystic Fibrosis as a Promising Antibacterial Agent.

Over the past few years, l-iminosugars have revealed attractive pharmacological properties for managing rare diseases including Cystic Fibrosis (CF). The iminosugar -butyl-l-deoxynojirimycin (l-NBDNJ, -), prepared by a carbohydrate-based route, was herein evaluated for its anti-inflammatory and anti-infective potential in models of CF lung disease infection. A significant decrease in the bacterial load in the airways was observed in the murine model of chronic infection in the presence of l-NBDNJ, also accompanied by a modest reduction of inflammatory cells.

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited.

SARS-CoV-2 viral entry and replication is impaired in Cystic Fibrosis airways due to ACE2 downregulation.

As an inherited disorder characterized by severe pulmonary disease, cystic fibrosis could be considered a comorbidity for coronavirus disease 2019. Instead, current clinical evidence seems to be heading in the opposite direction. To clarify whether host factors expressed by the Cystic Fibrosis epithelia may influence coronavirus disease 2019 progression, here we describe the expression of SARS-CoV-2 receptors in primary airway epithelial cells.

New TMA (4,6,4'-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease.

A series of new-generation TMA (4,6,4'-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker of lung inflammation in Cystic Fibrosis (CF), the use of agents able to interfere with the NF-κB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-κB/DNA complex.

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening.

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects.

Combined Treatment of Bronchial Epithelial Calu-3 Cells with Peptide Nucleic Acids Targeting miR-145-5p and miR-101-3p: Synergistic Enhancement of the Expression of the Cystic Fibrosis Transmembrane Conductance Regulator ( Gene.

The Cystic Fibrosis Transmembrane Conductance Regulator () gene encodes for a chloride channel defective in Cystic Fibrosis (CF). Accordingly, upregulation of its expression might be relevant for the development of therapeutic protocols for CF. MicroRNAs are deeply involved in the CFTR regulation and their targeting with miRNA inhibitors (including those based on Peptide Nucleic Acids, PNAs)is associated with CFTR upregulation.

β-sitosterol ameliorates inflammation and Pseudomonas aeruginosa lung infection in a mouse model.

We previously demonstrated that β-sitosterol (BSS) inhibits the expression of the chemokine IL-8 in CF bronchial epithelial cells exposed to P. aeruginosa. In the mouse model of lung chronic infection, herein shown, BSS significantly reduced leukocyte recruitment in the bronchoalveolar lavage fluid and decreased bacteria recovered in the airways.

miRNAs in Serum Exosomes for Differential Diagnosis of Brain Metastases.

Circulating miRNAs are increasingly studied and proposed as tumor markers with the aim of investigating their role in monitoring the response to therapy as well as the natural evolution of primary or secondary brain tumors. This study aimed to evaluate the modulation of the expression of three miRNAs, miR-21, miR-222 and miR-124-3p, in the serum exosomes of patients with high-grade gliomas (HGGs) and brain metastases (BMs) to verify their usefulness in the differential diagnosis of brain masses; then, it focused on their variations following the surgical and/or radiosurgical treatment of the BMs. A total of 105 patients with BMs from primary lung or breast cancer, or melanoma underwent neurosurgery or radiosurgery treatment, and 91 patients with HGGs were enrolled, along with 30 healthy controls.

Overview of CF lung pathophysiology.

Defects of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein affect the homeostasis of chloride, bicarbonate, sodium, and water in the airway surface liquid, influencing the mucus composition and viscosity, which induces a severe condition of infection and inflammation along the whole life of CF patients. The introduction of CFTR modulators, novel drugs directly intervening to rescue the function of CFTR protein, opens a new era of experimental research. The review summarizes the most recent advancements to understand the characteristics of the infective and inflammatory pathology of CF lungs.

Serum Exosomal microRNA-21, 222 and 124-3p as Noninvasive Predictive Biomarkers in Newly Diagnosed High-Grade Gliomas: A Prospective Study.

High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are described in patients with HGG.

A Peptide-Nucleic Acid Targeting miR-335-5p Enhances Expression of Cystic Fibrosis Transmembrane Conductance Regulator () Gene with the Possible Involvement of the CFTR Scaffolding Protein NHERF1.

(1) Background: Up-regulation of the Cystic Fibrosis Transmembrane Conductance Regulator gene () might be of great relevance for the development of therapeutic protocols for cystic fibrosis (CF). MicroRNAs are deeply involved in the regulation of CFTR and scaffolding proteins (such as NHERF1, NHERF2 and Ezrin). (2) Methods: Content of miRNAs and mRNAs was analyzed by RT-qPCR, while the CFTR and NHERF1 production was analyzed by Western blotting.

Treatment of human airway epithelial Calu-3 cells with a peptide-nucleic acid (PNA) targeting the microRNA miR-101-3p is associated with increased expression of the cystic fibrosis Transmembrane Conductance Regulator () gene.

Since the identification of microRNAs (miRNAs) involved in the regulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, miRNAs known to down-regulate the expression of the CFTR and associated proteins have been investigated as potential therapeutic targets. Here we show that miR-101-3p, targeting the 3'-UTR sequence of the CFTR mRNA, can be selectively inhibited by a peptide nucleic acid (PNA) carrying a full complementary sequence. With respect to clinical relevance of microRNA targeting, it is expected that reduction in concentration of miRNAs (the anti-miRNA approach) could be associated with increasing amounts of target mRNAs.

Role of Cystic Fibrosis Bronchial Epithelium in Neutrophil Chemotaxis.

A hallmark of cystic fibrosis (CF) chronic respiratory disease is an extensive neutrophil infiltrate in the mucosa filling the bronchial lumen, starting early in life for CF infants. The genetic defect of the CF Transmembrane conductance Regulator (CFTR) ion channel promotes dehydration of the airway surface liquid, alters mucus properties, and decreases mucociliary clearance, favoring the onset of recurrent and, ultimately, chronic bacterial infection. Neutrophil infiltrates are unable to clear bacterial infection and, as an adverse effect, contribute to mucosal tissue damage by releasing proteases and reactive oxygen species.

A molecular signature associated with prolonged survival in glioblastoma patients treated with regorafenib.

Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival (OS) benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.

GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization.

Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis.

Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum-mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that infection increases endoplasmic reticulum-mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein-associated protein B-protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy.

A Peptide Nucleic Acid (PNA) Masking the miR-145-5p Binding Site of the 3'UTR of the Cystic Fibrosis Transmembrane Conductance Regulator () mRNA Enhances CFTR Expression in Calu-3 Cells.

Peptide nucleic acids (PNAs) have been demonstrated to be very useful tools for gene regulation at different levels and with different mechanisms of action. In the last few years the use of PNAs for targeting microRNAs (anti-miRNA PNAs) has provided impressive advancements. In particular, targeting of microRNAs involved in the repression of the expression of the cystic fibrosis transmembrane conductance regulator () gene, which is defective in cystic fibrosis (CF), is a key step in the development of new types of treatment protocols.

Targeting miR‑155‑5p and miR‑221‑3p by peptide nucleic acids induces caspase‑3 activation and apoptosis in temozolomide‑resistant T98G glioma cells.

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase‑3 mRNA regulation (miR‑155‑5p and miR‑221‑3p) in the temozolomide (TMZ)‑resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug‑resistance phenotype was obtained.

Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease.

In the frame of a research program aimed to explore the relationship between chirality of iminosugars and their therapeutic potential, herein we report the synthesis of N-akyl l-deoxyiminosugars and the evaluation of the anti-inflammatory properties of selected candidates for the treatment of Pseudomonas aeruginosa infections in Cystic Fibrosis (CF) lung disease. Target glycomimetics were prepared by the shortest and most convenient approach reported to date, relying on the use of the well-known PS-TPP/I reagent system to prepare reactive alkoxyalkyl iodides, acting as key intermediates. Iminosugars ent-1-3 demonstrated to efficiently reduce the inflammatory response induced by P.

Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure.

Cystic fibrosis (CF), a life-threatening multiorgan genetic disease, is facing a new era of research and development using innovative gene-directed personalized therapies. The priority organ to cure is the lung, which suffers recurrent and chronic bacterial infection and inflammation since infancy, representing the main cause of morbidity and precocious mortality of these individuals. After the disappointing failure of gene-replacement approaches using gene therapy vectors, no single drug is presently available to repair all the CF gene defects.

Molecular basis of cystic fibrosis: from bench to bedside.

Cystic fibrosis (CF), is an autosomal recessive disease affecting different organs. The lung disease, characterized by recurrent and chronic bacterial infection and inflammation since infancy, is the main cause of morbidity and precocious mortality of these individuals. The innovative therapies directed to repair the defective CF gene should account for the presence of more than 200 disease-causing mutations of the CF transmembrane conductance regulator () gene.

Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators.

The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis.