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Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice
Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl(4))-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9452542/ https://www.ncbi.nlm.nih.gov/pubmed/36071041 http://dx.doi.org/10.1038/s41420-022-01173-4 |
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author | Zhao, Tianming Yu, Zihan Zhou, Lei Wang, Xiaoyu Hui, Yangyang Mao, Lihong Fan, Xiaofei Wang, Bangmao Zhao, Xingliang Sun, Chao |
author_facet | Zhao, Tianming Yu, Zihan Zhou, Lei Wang, Xiaoyu Hui, Yangyang Mao, Lihong Fan, Xiaofei Wang, Bangmao Zhao, Xingliang Sun, Chao |
author_sort | Zhao, Tianming |
collection | PubMed |
description | Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl(4))-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In this study, bicyclol, a proprietary hepatoprotectant in China, and ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) were administered in CCl(4)-injured mice. A panel of ferroptosis-related markers, including mitochondria morphology, reactive oxygen species production, protein adducts in response to lipid peroxidation, and key modulators of ferroptotic process, was determined in vivo. Erastin-treated L-O2 hepatocytes were transfected with glutathione peroxidase 4 (GPx4) or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA to delineate the pathway of bicyclol against ferroptosis in vitro. As a result, CCl(4) led to iron accumulation, excessive reactive oxygen species production, enhanced lipid peroxidation, and characteristic morphological changes in mitochondria, along with a decrease in GPx4 and xCT protein levels in ALI mice liver, all of which were generally observed in ferroptosis. The use of Fer-1 further corroborated that ferroptosis is responsible for liver damage. Bicyclol exerted its hepatoprotection by preventing the aforesaid ferroptotic process. Furthermore, bicyclol alleviated erastin-induced cellular inviability, destruction, and lipid peroxidation in vitro. Knockdown of GPx4 diminished these protective activities against perturbations associated with ferroptosis in L-O2 hepatocytes. Additionally, Nrf2 silencing drastically reduced GPx4 levels, and further impeded the medicinal effects of bicyclol. In summary, positively regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in CCl(4)-induced ALI in mice. [Image: see text] |
format | Online Article Text |
id | pubmed-9452542 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94525422022-09-09 Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice Zhao, Tianming Yu, Zihan Zhou, Lei Wang, Xiaoyu Hui, Yangyang Mao, Lihong Fan, Xiaofei Wang, Bangmao Zhao, Xingliang Sun, Chao Cell Death Discov Article Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl(4))-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In this study, bicyclol, a proprietary hepatoprotectant in China, and ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) were administered in CCl(4)-injured mice. A panel of ferroptosis-related markers, including mitochondria morphology, reactive oxygen species production, protein adducts in response to lipid peroxidation, and key modulators of ferroptotic process, was determined in vivo. Erastin-treated L-O2 hepatocytes were transfected with glutathione peroxidase 4 (GPx4) or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA to delineate the pathway of bicyclol against ferroptosis in vitro. As a result, CCl(4) led to iron accumulation, excessive reactive oxygen species production, enhanced lipid peroxidation, and characteristic morphological changes in mitochondria, along with a decrease in GPx4 and xCT protein levels in ALI mice liver, all of which were generally observed in ferroptosis. The use of Fer-1 further corroborated that ferroptosis is responsible for liver damage. Bicyclol exerted its hepatoprotection by preventing the aforesaid ferroptotic process. Furthermore, bicyclol alleviated erastin-induced cellular inviability, destruction, and lipid peroxidation in vitro. Knockdown of GPx4 diminished these protective activities against perturbations associated with ferroptosis in L-O2 hepatocytes. Additionally, Nrf2 silencing drastically reduced GPx4 levels, and further impeded the medicinal effects of bicyclol. In summary, positively regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in CCl(4)-induced ALI in mice. [Image: see text] Nature Publishing Group UK 2022-09-07 /pmc/articles/PMC9452542/ /pubmed/36071041 http://dx.doi.org/10.1038/s41420-022-01173-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhao, Tianming Yu, Zihan Zhou, Lei Wang, Xiaoyu Hui, Yangyang Mao, Lihong Fan, Xiaofei Wang, Bangmao Zhao, Xingliang Sun, Chao Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
title | Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
title_full | Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
title_fullStr | Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
title_full_unstemmed | Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
title_short | Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
title_sort | regulating nrf2-gpx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9452542/ https://www.ncbi.nlm.nih.gov/pubmed/36071041 http://dx.doi.org/10.1038/s41420-022-01173-4 |
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