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Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice

Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-i...

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Autores principales: Zhang, Jingyao, Song, Sidong, Pang, Qing, Zhang, Ruiyao, Zhou, Lei, Liu, Sushun, Meng, Fandi, Wu, Qifei, Liu, Chang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309973/
https://www.ncbi.nlm.nih.gov/pubmed/25631548
http://dx.doi.org/10.1038/srep08098
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author Zhang, Jingyao
Song, Sidong
Pang, Qing
Zhang, Ruiyao
Zhou, Lei
Liu, Sushun
Meng, Fandi
Wu, Qifei
Liu, Chang
author_facet Zhang, Jingyao
Song, Sidong
Pang, Qing
Zhang, Ruiyao
Zhou, Lei
Liu, Sushun
Meng, Fandi
Wu, Qifei
Liu, Chang
author_sort Zhang, Jingyao
collection PubMed
description Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)).Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH(2)-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.
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spelling pubmed-43099732015-02-09 Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice Zhang, Jingyao Song, Sidong Pang, Qing Zhang, Ruiyao Zhou, Lei Liu, Sushun Meng, Fandi Wu, Qifei Liu, Chang Sci Rep Article Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)).Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH(2)-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration. Nature Publishing Group 2015-01-29 /pmc/articles/PMC4309973/ /pubmed/25631548 http://dx.doi.org/10.1038/srep08098 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Zhang, Jingyao
Song, Sidong
Pang, Qing
Zhang, Ruiyao
Zhou, Lei
Liu, Sushun
Meng, Fandi
Wu, Qifei
Liu, Chang
Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice
title Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice
title_full Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice
title_fullStr Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice
title_full_unstemmed Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice
title_short Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice
title_sort serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309973/
https://www.ncbi.nlm.nih.gov/pubmed/25631548
http://dx.doi.org/10.1038/srep08098
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