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1.
Food Funct ; 14(4): 1884-1896, 2023 Feb 21.
Article in English | MEDLINE | ID: mdl-36723004

ABSTRACT

Acetaminophen (APAP)-induced liver injury (AILI) has become a growing public health problem. Ferroptosis, an iron-dependent form of cell death associated with lipid peroxide accumulation, has been recently implicated in AILI. The activation of the Nrf2 signaling pathway is a potential therapy for AILI. Kaempferol (KA), a flavonoid widely existing in edible plants, has been reported to exert profound anti-inflammatory and antioxidant activities. This study aimed to investigate whether KA exerts anti-AILI effects via the Nrf2 signaling pathway. Mice were fasted for 22 h and injected intraperitoneally with APAP (250 mg kg-1) to induce AILI. Mice were pre-injected intragastrically with KA for 2 h followed by APAP injection. The hepatic injury was observed by H&E staining. Biochemical parameters of the serum and liver were measured using kits. KA alleviated hepatic injury and inflammatory response in AILI mice and ameliorated APAP-induced hepatic iron overload and oxidative stress in mice. In addition, the protective effects of KA against APAP-induced hepatotoxicity were examined in L02 cells in vitro. Cell viability was assayed by the CCK8 assay. Mitochondrial reactive oxygen species (ROS) in L02 cells were detected by MitoSox fluorescence. KA reversed the APAP-induced decrease in cell viability and GSH levels and inhibited the accumulation of intracellular ROS. Furthermore, KA activated the Nrf2 pathway and upregulated Gpx4 in mouse livers and L02 cells to inhibit ferroptosis induced by APAP. Finally, molecular docking indicated the potential interaction of KA with Keap1. Taken together, KA ameliorated oxidative stress and ferroptosis-mediated AILI by activating Nrf2 signaling.


Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Ferroptosis , Animals , Mice , Acetaminophen/metabolism , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Hepatocytes/metabolism , Kaempferols/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , Liver/metabolism , Mice, Inbred C57BL , Molecular Docking Simulation , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism
2.
J Hepatol ; 76(2): 407-419, 2022 02.
Article in English | MEDLINE | ID: mdl-34656650

ABSTRACT

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated. METHODS: Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. In vitro and in vivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH. RESULTS: We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction. CONCLUSIONS: These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH. CLINICAL TRIAL NUMBER: IIT-2021-277. LAY SUMMARY: New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis.


Subject(s)
Glutathione Transferase/pharmacology , MAP Kinase Kinase Kinase 5/antagonists & inhibitors , Non-alcoholic Fatty Liver Disease/prevention & control , Animals , Biopsy/methods , Biopsy/statistics & numerical data , Disease Models, Animal , Gene Targeting/methods , Gene Targeting/standards , Gene Targeting/statistics & numerical data , Glutathione Transferase/metabolism , Hepatocytes/metabolism , Hepatocytes/physiology , Liver/pathology , MAP Kinase Kinase Kinase 5/therapeutic use , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Sequence Analysis, RNA/methods , Sequence Analysis, RNA/statistics & numerical data
3.
Hepatology ; 76(1): 155-171, 2022 07.
Article in English | MEDLINE | ID: mdl-34717002

ABSTRACT

BACKGROUND AND AIMS: NAFLD is a key component of metabolic syndrome, ranging from nonalcoholic fatty liver to NASH, and is now becoming the leading cause of cirrhosis and HCC worldwide. However, due to the complex and unclear pathophysiological mechanism, there are no specific approved agents for treating NASH. Breviscapine, a natural flavonoid prescription drug isolated from the traditional Chinese herb Erigeron breviscapus, exhibits a wide range of pharmacological properties, including effects on metabolism. However, the anti-NASH efficacy and mechanisms of breviscapine have not yet been characterized. APPROACH AND RESULTS: We evaluated the effects of breviscapine on the development of hepatic steatosis, inflammation, and fibrosis in vivo and in vitro under metabolic stress. Breviscapine treatment significantly reduced lipid accumulation, inflammatory cell infiltration, liver injury, and fibrosis in mice fed a high-fat diet, a high-fat/high-cholesterol diet, or a methionine- and choline-deficient diet. In addition, breviscapine attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes undergoing metabolic stress. RNA-sequencing and multiomics analyses further indicated that the key mechanism linking the anti-NASH effects of breviscapine was inhibition of TGF-ß-activated kinase 1 (TAK1) phosphorylation and the subsequent mitogen-activated protein kinase signaling cascade. Treatment with the TAK1 inhibitor 5Z-7-oxozeaenol abrogated breviscapine-mediated hepatoprotection under metabolic stress. Molecular docking illustrated that breviscapine directly bound to TAK1. CONCLUSION: Breviscapine prevents metabolic stress-induced NASH progression through direct inhibition of TAK1 signaling. Breviscapine might be a therapeutic candidate for the treatment of NASH.


Subject(s)
Flavonoids , MAP Kinase Kinase Kinases , Non-alcoholic Fatty Liver Disease , Animals , Diet, High-Fat/adverse effects , Flavonoids/pharmacology , Inflammation/metabolism , Lipid Metabolism , Liver/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Liver Cirrhosis/prevention & control , MAP Kinase Kinase Kinases/metabolism , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology
4.
Hepatology ; 74(2): 686-703, 2021 08.
Article in English | MEDLINE | ID: mdl-33576035

ABSTRACT

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases. APPROACH AND RESULTS: We evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose-dependently decreased the elevated levels of serum aminotransferases in mice with diet-induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation-dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin-induced hepatoprotection in hepatocytes and mice with NASH. CONCLUSION: Cordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.


Subject(s)
Deoxyadenosines/pharmacology , Liver Cirrhosis/prevention & control , Liver/drug effects , Non-alcoholic Fatty Liver Disease/drug therapy , AMP-Activated Protein Kinases/metabolism , Animals , Cell Line , Deoxyadenosines/therapeutic use , Hepatocytes , Humans , Liver/immunology , Liver/pathology , Liver Cirrhosis/immunology , Liver Cirrhosis/pathology , Mice , Non-alcoholic Fatty Liver Disease/immunology , Non-alcoholic Fatty Liver Disease/pathology , Signal Transduction/drug effects , Signal Transduction/immunology
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