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      Reduced Expression of the Melanocortin-1 Receptor in Human Liver during Brain Death

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          Abstract

          Objective: There is evidence that brain death has detrimental effects on peripheral organs. Clinical and experimental studies on organ donors showed marked inflammation in tissue samples of livers and kidneys collected during brain death. The inflammatory reaction is characterized by release of cytokines and inflammatory cell infiltration. Because melanocortins and their receptors are significant modulators of inflammation, we hypothesized that downregulation of melanocortin receptors during brain death could contribute to enhance inflammation. Methods: Using real-time polymerase chain reaction (PCR) analysis, we determined expression of melanocortin receptors in liver biopsies obtained from brain-dead organ donors before cold ischemia and in normal liver tissue during resection of benign focal lesions of the liver. Tissue biopsies were also analyzed for expression of intercellular adhesion molecule-1 (ICAM-1), which has a central function in inflammatory cell migration. Results: Expression of melanocortin-1 receptor (MC1R) mRNA was markedly reduced in liver samples obtained from brain-dead organ donors compared to hepatic tissue collected during resection of benign focal lesions of the liver. Conversely, expression of the adhesion molecule ICAM-1 was significantly increased in livers of brain-dead organ donors. Conclusions: Disruption of the endogenous anti-inflammatory circuit based on MC1R could contribute to tissue damage during brain death.

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          Most cited references 34

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          The cloning of a family of genes that encode the melanocortin receptors.

          Melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) regulate pigmentation and adrenal cortical function, respectively. These peptides also have a variety of biological activities in other areas, including the brain, the pituitary, and the immune system. A complete understanding of the biological activities of these hormones requires the isolation and characterization of their corresponding receptors. The murine and human MSH receptors (MSH-Rs) and a human ACTH receptor (ACTH-R) were cloned. These receptors define a subfamily of receptors coupled to guanine nucleotide-binding proteins that may include the cannabinoid receptor.
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            High survival rates of kidney transplants from spousal and living unrelated donors.

            In the United States, increasing numbers of persons are donating kidneys to their spouses. Despite greater histoincompatibility, the survival rates of these kidneys are higher than those of cadaveric kidneys. We examined the factors influencing the high survival rates of spousal-donor kidneys. Kidney-transplant data from the United Network for Organ Sharing Renal Transplant Registry were used to calculate graft-survival rates with Kaplan-Meier analysis. The three-year survival rates were 85 percent for kidneys from 368 spouses, 81 percent for kidneys from 129 living unrelated donors who were not married to the recipients, 82 percent for kidneys from 3368 parents, and 70 percent for 43,341 cadaveric kidneys. The three-year survival rate for wife-to-husband grafts was 87 percent, which was the same as for husband-to-wife grafts if the wife had never been pregnant. If the wife had previously been pregnant, the three-year graft-survival rate was 76 percent (P = 0.40). The three-year graft-survival rate among recipients of spousal grafts who did not receive transfusions preoperatively was 81 percent, as compared with 90 percent for recipients who received 1 to 10 transfusions preoperatively (P = 0.008). The superior survival rate of grafts from unrelated donors could not be attributed to better HLA matching, white race, younger donor age, or shorter cold-ischemia times, but might be explained by damage due to shock before removal in 10 percent of the cadaveric kidneys. Spouses are an important source of living-donor kidney grafts because, despite poor HLA matching, the graft-survival rate is similar to that of parental-donor kidneys. This high rate of survival is attributed to the fact that the kidneys were uniformly healthy.
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              Targeting melanocortin receptors as a novel strategy to control inflammation.

              Adrenocorticotropic hormone and alpha-, beta-, and gamma-melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor kappaB to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2006
                August 2006
                08 August 2006
                : 13
                : 1
                : 51-55
                Affiliations
                aLiver Transplantation Unit, bCenter for Preclinical Investigation, and cScientific Direction, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy, and dZengen Inc., Woodland Hills, Calif., USA
                Article
                94513 Neuroimmunomodulation 2006;13:51–55
                10.1159/000094513
                16864968
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, References: 42, Pages: 5
                Categories
                Original Paper

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