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      Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor

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          Abstract

          Xenobiotic nuclear receptors (NR) are intracellular players involved in an increasing number of physiological processes. Examined and characterized in peripheral organs where they govern metabolic, transport and detoxification mechanisms, accumulating data suggest a functional expression of specific NR at the neurovascular unit (NVU). Here, we focus on the Constitutive Androstane Receptor (CAR), expressed in detoxifying organs such as the liver, intestines and kidneys. By direct and indirect activation, CAR is implicated in hepatic detoxification of xenobiotics, environmental contaminants, and endogenous molecules (bilirubin, bile acids). Importantly, CAR participates in physiological stress adaptation responses, hormonal and energy homeostasis due to glucose and lipid sensing. We next analyze the emerging evidence supporting a role of CAR in NVU cells including the blood–brain barrier (BBB), a key vascular interface regulating communications between the brain and the periphery. We address the emerging concept of how CAR may regulate specific P450 cytochromes at the NVU and the associated relevance to brain diseases. A clear understanding of how CAR engages during pathological conditions could enable new mechanistic, and perhaps pharmacological, entry-points within a peripheral–brain axis.

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          Most cited references140

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          Structure and function of the blood-brain barrier.

          Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.
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            Bile salt biotransformations by human intestinal bacteria.

            Secondary bile acids, produced solely by intestinal bacteria, can accumulate to high levels in the enterohepatic circulation of some individuals and may contribute to the pathogenesis of colon cancer, gallstones, and other gastrointestinal (GI) diseases. Bile salt hydrolysis and hydroxy group dehydrogenation reactions are carried out by a broad spectrum of intestinal anaerobic bacteria, whereas bile acid 7-dehydroxylation appears restricted to a limited number of intestinal anaerobes representing a small fraction of the total colonic flora. Microbial enzymes modifying bile salts differ between species with respect to pH optima, enzyme kinetics, substrate specificity, cellular location, and possibly physiological function. Crystallization, site-directed mutagenesis, and comparisons of protein secondary structure have provided insight into the mechanisms of several bile acid-biotransforming enzymatic reactions. Molecular cloning of genes encoding bile salt-modifying enzymes has facilitated the understanding of the genetic organization of these pathways and is a means of developing probes for the detection of bile salt-modifying bacteria. The potential exists for altering the bile acid pool by targeting key enzymes in the 7alpha/beta-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.
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              Blood-Brain Barrier: From Physiology to Disease and Back

              The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of the central nervous system (CNS), which maintains tightly controlled chemical composition of the neuronal milieu that is required for proper neuronal functioning. In this review, we first examine molecular and cellular mechanisms underlying the establishment of the BBB. Then, we focus on BBB transport physiology, endothelial and pericyte transporters, and perivascular and paravascular transport. Next, we discuss rare human monogenic neurological disorders with the primary genetic defect in BBB-associated cells demonstrating the link between BBB breakdown and neurodegeneration. Then, we review the effects of genes underlying inheritance and/or increased susceptibility for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis (ALS) on BBB in relation to other pathologies and neurological deficits. We next examine how BBB dysfunction relates to neurological deficits and other pathologies in the majority of sporadic AD, PD, and ALS cases, multiple sclerosis, other neurodegenerative disorders, and acute CNS disorders such as stroke, traumatic brain injury, spinal cord injury, and epilepsy. Lastly, we discuss BBB-based therapeutic opportunities. We conclude with lessons learned and future directions, with emphasis on technological advances to investigate the BBB functions in the living human brain, and at the molecular and cellular level, and address key unanswered questions.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                06 November 2020
                November 2020
                : 9
                : 11
                Affiliations
                [1 ]Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France; fabiana.oliviero@ 123456inrae.fr (F.O.); celine.lukowicz@ 123456unil.ch (C.L.)
                [2 ]Cerebrovascular and Glia Research, Institute of Functional Genomics (UMR 5203 CNRS–U 1191 INSERM, University of Montpellier), 34094 Montpellier, France; badreddine.boussadia@ 123456gmail.com (B.B.); Isabel.Forner-Piquer@ 123456igf.cnrs.fr (I.F.-P.); jean-marc.pascussi@ 123456inserm.fr (J.-M.P.)
                Author notes
                [* ]Correspondence: Nicola.Marchi@ 123456igf.cnrs.fr (N.M.); laila.lakhal@ 123456inrae.fr (L.M.-L.); Tel.: +33-4-34-35-92-20 (N.M.); +33-5-61-19-39-15 (L.M.-L.)
                [†]

                These authors contributed equally to this work.

                Article
                cells-09-02426
                10.3390/cells9112426
                7694609
                33171992
                3b6cdac1-197c-4131-bef2-723ba1bd54bd
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                constitutive androstane receptor,liver,brain,neurovascular unit,blood-brain barrier, stress sensor,environmental contaminants

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