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      Orexin-A Prevents Lipopolysaccharide-Induced Neuroinflammation at the Level of the Intestinal Barrier

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          Abstract

          In states of intestinal dysbiosis, a perturbation of the normal microbiome composition, the intestinal epithelial barrier (IEB) permeability is increased as a result of the disruption of the epithelial tight junction protein network, in which occludin is mostly affected. The loss of IEB integrity promotes endotoxemia, that is, bacterial lipopolysaccharide (LPS) translocation from the intestinal lumen to the circulatory system. This condition induces an enhancement of pro-inflammatory cytokines, which leads to neuroinflammation through the gut-brain axis. Orexin-A (OX-A), a neuropeptide implicated in many physiological functions and produced mainly in the brain lateral hypothalamic area, is expressed also in several peripheral tissues. Orexin-producing neurons have been found in the myenteric plexus to project to orexin receptor 1 (OX-1R)-expressing enterocytes of the intestinal villi. In the present study we investigated the protective role of OX-A against LPS-induced increase of IEB permeability and microglia activation in both an in vivo and in vitro model of the gut-brain axis. By exploiting biochemical, immunocytochemical, immunohistochemical, and functional approaches, we demonstrate that OX-A preserves the IEB and occludin expression, thus preventing endotoxemia and subsequent neuroinflammation.

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          Most cited references23

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          Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

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            The developmental role of serotonin: news from mouse molecular genetics.

            New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.
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              Architecture of tight junctions and principles of molecular composition.

              The tight junction creates an intercellular barrier limiting paracellular movement of solutes and material across epithelia. Currently many proteins have been identified as components of the tight junction and understanding their architectural organization and interactions is critical to understanding the biology of the barrier. In general the architecture can be conceptualized into compartments with the transmembrane barrier proteins (claudins, occludin, JAM-A, etc.), linked to peripheral scaffolding proteins (such as ZO-1, afadin, MAGI1, etc.) which are in turned linked to actin and microtubules through numerous linkers (cingulin, myosins, protein 4.1, etc.). Within this complex network are associated many signaling proteins that affect the barrier and broader cell functions. The PDZ domain is a commonly used motif to specifically link individual junction protein pairs. Here we review some of the key proteins defining the tight junction and general themes of their organization with the perspective that much will be learned about function by characterizing the detailed architecture and subcompartments within the junction. Published by Elsevier Ltd.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                10 April 2019
                2019
                : 10
                : 219
                Affiliations
                [1] 1Department of Veterinary Medicine and Animal Productions, University of Naples Federico II , Naples, Italy
                [2] 2Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR) , Pozzuoli, Italy
                [3] 3Department of Agricultural Science, University of Naples Federico II , Portici, Italy
                [4] 4Stazione Zoologica Anton Dohrn , Naples, Italy
                [5] 5Department of Pharmacy, University of Novi Sad , Novi Sad, Serbia
                [6] 6Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axus in Metabolic Health, Faculty of Medicine and Faculty of Agricultural and Food Sciences, Université Laval , Québec City, QC, Canada
                [7] 7Department of Biomolecular Sciences, University of Urbino Carlo Bo , Urbino, Italy
                Author notes

                Edited by: Paul Forsythe, McMaster University, Canada

                Reviewed by: Carla Cirillo, INSERM U1214 Centre d'Imagerie Neuro Toulouse (ToNIC), France; Inmaculada Posadas, University of Castilla La Mancha, Spain

                *Correspondence: Letizia Palomba letizia.palomba@ 123456uniurb.it

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00219
                6467935
                b47e2c46-0b16-4963-b2a5-f874a283d26c
                Copyright © 2019 Tunisi, Forte, Fernández-Rilo, Mavaro, Capasso, D'Angelo, Milić, Cristino, Di Marzo and Palomba.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 December 2018
                : 18 March 2019
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 37, Pages: 8, Words: 5475
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                gut-brain axis,gut microbiota,orexins,lipopolysaccharides,microglia
                Endocrinology & Diabetes
                gut-brain axis, gut microbiota, orexins, lipopolysaccharides, microglia

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