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AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

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Circulating microRNA expression profiling revealed miR-92a-3p as a novel biomarker of Barrett's carcinogenesis

The main intent of secondary prevention strategies for Barrett's esophagus (BE) patients relies in the prompt identification of patients with dysplasia (or intra-epithelial neoplasia; IEN) and early-stage adenocarcinoma (Barrett's adenocarcinoma; BAc). Despite the adequate characterization of the molecular landscape characterizing Barrett's carcinogenesis, no tissue and/or circulating biomarker has been approved for clinical use. A series of 25 serum samples (12 BE, 5 HG-IEN and 8 BAc) were analyzed for comprehensive miRNA profiling and ten miRNAs were found to be significantly dysregulated. In particular seven were upregulated (i.e. miR-92a-3p, miR-151a-5p, miR-362-3p, miR-345-3p, miR-619-3p, miR-1260b, and miR-1276) and three downregulated (i.e. miR-381-3p, miR-502-3p, and miR-3615) in HG-IEN/BAc samples in comparison to non-dysplastic BE. All the identified miRNAs showed significant ROC curves in discriminating among groups with AUC values range of 0.75-0.83. Validation of the results were performed by droplet digital PCR in two out of three tested miRNAs. To understand the cellular source of circulating miR-92a-3p, we analyzed its expression in endoscopy biopsy samples by both qRT-PCR and ISH analyses. As observed in serum samples, miR-92a-3p was over-expressed in HG-IEN/BAc samples in comparison to na\uefve esophageal squamous mucosa and BE and was mainly localized within the epithelial cells, supporting neoplastic cells as the main source of the circulating miRNA. Our data further demonstrated that circulating miRNAs are a promising mini-invasive diagnostic tool in the secondary follow-up and management of BE patients. Larger multi-Institutional studies should validate and investigate the most adequate miRNAs profile in discriminating BE patients in specific risk classes

The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects

1. The functional characterization of hispidulin (4′,5,7-trihydroxy-6-methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. 2. After chemical synthesis, hispidulin was investigated at recombinant GABA(A)/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABA-induced chloride currents at tested receptor subtypes (α(1−3,5,6)β(2)γ(2)S) indicating positive allosteric properties. Maximal stimulation at α(1)β(2)γ(2)S was observed with 10 μM hispidulin. In contrast to diazepam, hispidulin modulated the α(6)β(2)γ(2)S-GABA(A) receptor subtype. 3. When fed to seizure-prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg(−1) body weight (BW) per day) and diazepam (2 mg kg(−1) BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). 4. Permeability across the blood–brain barrier for the chemically synthesized, (14)C-labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (K(in)) of 1.14 ml min(−1) g(−1), measurements approached the values obtained with highly penetrating compounds such as diazepam. 5. Experiments with Caco-2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 μM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites