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Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway

BACKGROUND: Ulinastatin, a urinary trypsin inhibitor, is one of the widely used auxiliary drugs in the rescue of acute circulatory failure. This study aims to explore the protective mechanisms of ulinastatin on cerebral ischemia-reperfusion (I/R) injury. METHODS: A cerebral MCAO was established with...

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Autores principales: Cui, Lei, Cao, Wei, Xia, Yanmin, Li, Xiaofang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576027/
https://www.ncbi.nlm.nih.gov/pubmed/33240985
http://dx.doi.org/10.21037/atm-20-5115
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author Cui, Lei
Cao, Wei
Xia, Yanmin
Li, Xiaofang
author_facet Cui, Lei
Cao, Wei
Xia, Yanmin
Li, Xiaofang
author_sort Cui, Lei
collection PubMed
description BACKGROUND: Ulinastatin, a urinary trypsin inhibitor, is one of the widely used auxiliary drugs in the rescue of acute circulatory failure. This study aims to explore the protective mechanisms of ulinastatin on cerebral ischemia-reperfusion (I/R) injury. METHODS: A cerebral MCAO was established with middle cerebral artery occlusion (MCAO) in Sprague Dawley (SD) rats. Western blotting was employed to show protein expression. Oxidative stress markers [reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)] and inflammatory cytokines (IL-6, IL-1β, and IL-18) were analyzed to show oxidative stress and inflammation. Hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and triphenyltetrazolium chloride (TTC) staining were applied to show brain injury. RESULTS: HE, TUNEL and TTC staining indicated that ulinastatin significantly ameliorated cerebral I/R injury and reduced apoptotic cells in the MCAO brain tissue. Ulinastatin also reduced the MCAO-induced expression of intercellular adhesion molecule 1(ICAM-1)/caspase-3. Additionally, the highly expressed ROS, MDA and inflammatory cytokines (IL-6, IL-1β and IL-18) were significantly suppressed, and the inhibited SOD and GSH were recovered with ulinastatin treatment. Consequently, the expression of nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) (which was significantly inhibited by MCAO) was re-activated by ulinastatin and/or TBHQ (an Nrf-2 activator), and treatment with ML-385 (an Nrf-2 inhibitor) blocked the inhibition of apoptosis, inflammation, and oxidative stress by ulinastatin. Our results indicate that the Nrf-2/HO-1 signaling pathway may be involved in the pharmacological mechanism of ulinastatin in cerebral I/R injury. CONCLUSIONS: Ulinastatin protected against inflammation and oxidative stress in cerebral I/R injuries via activation of the Nrf-2/HO-1 signaling pathway.
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spelling pubmed-75760272020-11-24 Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway Cui, Lei Cao, Wei Xia, Yanmin Li, Xiaofang Ann Transl Med Original Article BACKGROUND: Ulinastatin, a urinary trypsin inhibitor, is one of the widely used auxiliary drugs in the rescue of acute circulatory failure. This study aims to explore the protective mechanisms of ulinastatin on cerebral ischemia-reperfusion (I/R) injury. METHODS: A cerebral MCAO was established with middle cerebral artery occlusion (MCAO) in Sprague Dawley (SD) rats. Western blotting was employed to show protein expression. Oxidative stress markers [reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)] and inflammatory cytokines (IL-6, IL-1β, and IL-18) were analyzed to show oxidative stress and inflammation. Hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and triphenyltetrazolium chloride (TTC) staining were applied to show brain injury. RESULTS: HE, TUNEL and TTC staining indicated that ulinastatin significantly ameliorated cerebral I/R injury and reduced apoptotic cells in the MCAO brain tissue. Ulinastatin also reduced the MCAO-induced expression of intercellular adhesion molecule 1(ICAM-1)/caspase-3. Additionally, the highly expressed ROS, MDA and inflammatory cytokines (IL-6, IL-1β and IL-18) were significantly suppressed, and the inhibited SOD and GSH were recovered with ulinastatin treatment. Consequently, the expression of nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) (which was significantly inhibited by MCAO) was re-activated by ulinastatin and/or TBHQ (an Nrf-2 activator), and treatment with ML-385 (an Nrf-2 inhibitor) blocked the inhibition of apoptosis, inflammation, and oxidative stress by ulinastatin. Our results indicate that the Nrf-2/HO-1 signaling pathway may be involved in the pharmacological mechanism of ulinastatin in cerebral I/R injury. CONCLUSIONS: Ulinastatin protected against inflammation and oxidative stress in cerebral I/R injuries via activation of the Nrf-2/HO-1 signaling pathway. AME Publishing Company 2020-09 /pmc/articles/PMC7576027/ /pubmed/33240985 http://dx.doi.org/10.21037/atm-20-5115 Text en 2020 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Original Article
Cui, Lei
Cao, Wei
Xia, Yanmin
Li, Xiaofang
Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway
title Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway
title_full Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway
title_fullStr Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway
title_full_unstemmed Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway
title_short Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway
title_sort ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the nrf-2/ho-1 signaling pathway
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576027/
https://www.ncbi.nlm.nih.gov/pubmed/33240985
http://dx.doi.org/10.21037/atm-20-5115
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