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      The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

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          Abstract

          Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH 2) is a peptide mainly produced by brain neurons. In mammals, hypophysiotropic TRH neurons of the paraventricular nucleus of the hypothalamus integrate metabolic information and drive the secretion of thyrotropin from the anterior pituitary, and thus the activity of the thyroid axis. Other hypothalamic or extrahypothalamic TRH neurons have less understood functions although pharmacological studies have shown that TRH has multiple central effects, such as promoting arousal, anorexia and anxiolysis, as well as controlling gastric, cardiac and respiratory autonomic functions. Two G-protein-coupled TRH receptors (TRH-R1 and TRH-R2) transduce TRH effects in some mammals although humans lack TRH-R2. TRH effects are of short duration, in part because the peptide is hydrolyzed in blood and extracellular space by a M1 family metallopeptidase, the TRH-degrading ectoenzyme (TRH-DE), also called pyroglutamyl peptidase II. TRH-DE is enriched in various brain regions but is also expressed in peripheral tissues including the anterior pituitary and the liver, which secretes a soluble form into blood. Among the M1 metallopeptidases, TRH-DE is the only member with a very narrow specificity; its best characterized biological substrate is TRH, making it a target for the specific manipulation of TRH activity. Two other substrates of TRH-DE, Glp-Phe-Pro-NH 2 and Glp-Tyr-Pro-NH 2, are also present in many tissues. Analogs of TRH resistant to hydrolysis by TRH-DE have prolonged central efficiency. Structure-activity studies allowed the identification of residues critical for activity and specificity. Research with specific inhibitors has confirmed that TRH-DE controls TRH actions. TRH-DE expression by β2-tanycytes of the median eminence of the hypothalamus allows the control of TRH flux into the hypothalamus-pituitary portal vessels and may regulate serum thyrotropin secretion. In this review we describe the critical evidences that suggest that modification of TRH-DE activity in tanycytes, and/or in other brain regions, may generate beneficial consequences in some central and metabolic disorders and identify potential drawbacks and missing information needed to test these hypotheses.

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          PROMO: detection of known transcription regulatory elements using species-tailored searches.

          We have developed a set of tools to construct positional weight matrices from known transcription factor binding sites in a species or taxon-specific manner, and to search for matches in DNA sequences.
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            Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides.

            Dipeptidyl-peptidase IV (DPP IV/CD26) has a dual function as a regulatory protease and as a binding protein. Its role in the inactivation of bioactive peptides was recognized 20 years ago due to its unique ability to liberate Xaa-Pro or Xaa-Ala dipeptides from the N-terminus of regulatory peptides, but further examples are now emerging from in vitro and vivo experiments. Despite the minimal N-terminal truncation by DPP IV, many mammalian regulatory peptides are inactivated--either totally or only differentially--for certain receptor subtypes. Important DPP IV substrates include neuropeptides like neuropeptide Y or endomorphin, circulating peptide hormones like peptide YY, growth hormone-releasing hormone, glucagon-like peptides(GLP)-1 and -2, gastric inhibitory polypeptide as well as paracrine chemokines like RANTES (regulated on activation normal T cell expressed and secreted), stromal cell-derived factor, eotaxin and macrophage-derived chemokine. Based on these findings the potential clinical uses of selective DPP IV inhibitors or DPP IV-resistant analogues, especially for the insulinotropic hormone GLP-1, have been tested to enhance insulin secretion and to improve glucose tolerance in diabetic animals. Thus, DPP IV appears to be a major physiological regulator for some regulatory peptides, neuropeptides, circulating hormones and chemokines.
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              A mouse knockout library for secreted and transmembrane proteins.

              Large collections of knockout organisms facilitate the elucidation of gene functions. Here we used retroviral insertion or homologous recombination to disrupt 472 genes encoding secreted and membrane proteins in mice, providing a resource for studying a large fraction of this important class of drug target. The knockout mice were subjected to a systematic phenotypic screen designed to uncover alterations in embryonic development, metabolism, the immune system, the nervous system and the cardiovascular system. The majority of knockout lines exhibited altered phenotypes in at least one of these therapeutic areas. To our knowledge, a comprehensive phenotypic assessment of a large number of mouse mutants generated by a gene-specific approach has not been described previously.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/80411
                URI : https://loop.frontiersin.org/people/695415
                URI : https://loop.frontiersin.org/people/916961
                URI : https://loop.frontiersin.org/people/730370
                URI : https://loop.frontiersin.org/people/636863
                URI : https://loop.frontiersin.org/people/640931
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                08 May 2020
                2020
                : 11
                : 640
                Affiliations
                [1]Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM) , Cuernavaca, Mexico
                Author notes

                Edited by: Jean Sévigny, Laval University, Canada

                Reviewed by: Gabor Wittmann, Tufts Medical Center, United States; Albert Eugene Pekary, VA Greater Los Angeles Healthcare System, United States

                *Correspondence: Jean-Louis Charli, charli@ 123456ibt.unam.mx

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.00640
                7225337
                32457627
                c0c68e8d-476c-4ad6-aaa8-4690a1541640
                Copyright © 2020 Charli, Rodríguez-Rodríguez, Hernández-Ortega, Cote-Vélez, Uribe, Jaimes-Hoy and Joseph-Bravo

                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
                : 04 February 2020
                : 21 April 2020
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 252, Pages: 21, Words: 12292
                Funding
                Funded by: Consejo Nacional de Ciencia y Tecnología 10.13039/501100003141
                Award ID: PN562
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                thyroid hormone,thyrotropin,thyrotropin-releasing hormone,thyrotropin-releasing hormone-degrading ectoenzyme,anxiety,depression,mood

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