Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway
Aims: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investiga...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223006340 |
| _version_ | 1797801831073579008 |
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| author | Lei Gu Xin He Yanqiu Zhang Shenglan Li Jie Tang Ruixue Ma Xinyi Yang Hao Huang Yu Peng Yanyun Xie Zhangzhe Peng Jie Meng Gaoyun Hu Lijian Tao Xiaowei Liu Huixiang Yang |
| author_facet | Lei Gu Xin He Yanqiu Zhang Shenglan Li Jie Tang Ruixue Ma Xinyi Yang Hao Huang Yu Peng Yanyun Xie Zhangzhe Peng Jie Meng Gaoyun Hu Lijian Tao Xiaowei Liu Huixiang Yang |
| author_sort | Lei Gu |
| collection | DOAJ |
| description | Aims: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms. Methods: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies. Results: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing. Conclusions: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF. |
| first_indexed | 2024-03-13T04:56:31Z |
| format | Article |
| id | doaj.art-3a3da7fc4abd45b5a61f79312c9f7fc8 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-13T04:56:31Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-3a3da7fc4abd45b5a61f79312c9f7fc82023-06-18T05:00:34ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-08-01164114844Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathwayLei Gu0Xin He1Yanqiu Zhang2Shenglan Li3Jie Tang4Ruixue Ma5Xinyi Yang6Hao Huang7Yu Peng8Yanyun Xie9Zhangzhe Peng10Jie Meng11Gaoyun Hu12Lijian Tao13Xiaowei Liu14Huixiang Yang15Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410013, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; Corresponding author at: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China.Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Respirology, Third Xiangya Hospital, Central South University, Changsha 410013, ChinaHunan Key Lab of Organ Fibrosis, Changsha 410008, China; Faculty of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaDepartment of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, ChinaDepartment of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Corresponding author at: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China.Aims: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms. Methods: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies. Results: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing. Conclusions: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.http://www.sciencedirect.com/science/article/pii/S0753332223006340Acute liver failureFluorofenidoneN-acetylcysteineMKK4JNK |
| spellingShingle | Lei Gu Xin He Yanqiu Zhang Shenglan Li Jie Tang Ruixue Ma Xinyi Yang Hao Huang Yu Peng Yanyun Xie Zhangzhe Peng Jie Meng Gaoyun Hu Lijian Tao Xiaowei Liu Huixiang Yang Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway Biomedicine & Pharmacotherapy Acute liver failure Fluorofenidone N-acetylcysteine MKK4 JNK |
| title | Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway |
| title_full | Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway |
| title_fullStr | Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway |
| title_full_unstemmed | Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway |
| title_short | Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway |
| title_sort | fluorofenidone protects against acute liver failure in mice by regulating mkk4 jnk pathway |
| topic | Acute liver failure Fluorofenidone N-acetylcysteine MKK4 JNK |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223006340 |
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