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Zhang F, Zhang X, Li M, Sun Q, Li Y, Fu Y, Zhang Y. Selenium-enriched Bacillus subtilis attenuates emamectin benzoate-induced liver injury in grass carp through inhibiting inflammation and ferroptosis via activating Nrf2 signaling pathway. Comp Biochem Physiol C Toxicol Pharmacol 2025; 294:110191. [PMID: 40086679 DOI: 10.1016/j.cbpc.2025.110191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/23/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
The widespread use of emamectin benzoate (EMB) has caused many pests to develop resistance to it, and there have been reports of toxic effects of methomyl on marine animals. We tested whether Se-rich B. subtilis exerted protective effects against EMB-induced liver injury in grass carp. The carps were cultured in an aquatic environment containing 2.4 μg/L of EMB for 30 days. Se-rich B. subtilis (105, 106, 107 Colony Forming Unit (CFU)/g) was given daily for 10 days. According to the results, Se-rich B. subtilis alleviated liver pathological injury, aspartate aminotransferase (AST), alanine aminotransferase (ALT), TNF-α and IL-1β production. Meanwhile, EMB-induced ferroptosis was attenuated by Se-rich B. subtilis. The subsequent experiment revealed that Se-rich B. subtilis inhibited EMB-induced nuclear factor kappa-B (NF-κB) activation. Further research demonstrated that nuclear factor erythroid-2 related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expression was increased by Se-rich B. subtilis. Taken together, Se-rich B. subtilis attenuated EMB-induced liver injury by alleviating inflammation and ferroptosis via Nrf2 signaling.
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Affiliation(s)
- Fengyan Zhang
- College of Animal Science and Technology, Jilin Agriculture Science and Technology University, Jilin City, China
| | - Xinhui Zhang
- College of Animal Science and Technology, Jilin Agriculture Science and Technology University, Jilin City, China
| | - Musen Li
- College of Animal Science and Technology, Jilin Agriculture Science and Technology University, Jilin City, China
| | - Qingsong Sun
- College of Animal Science and Technology, Jilin Agriculture Science and Technology University, Jilin City, China
| | - Yuehong Li
- College of Veterinary Medicine, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Yunhe Fu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province 130062, China
| | - Yue Zhang
- College of Animal Science and Technology, Jilin Agriculture Science and Technology University, Jilin City, China.
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2
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Ge T, Wang Y, Han Y, Bao X, Lu C. Exploring the Updated Roles of Ferroptosis in Liver Diseases: Mechanisms, Regulators, and Therapeutic Implications. Cell Biochem Biophys 2025; 83:1445-1464. [PMID: 39543068 DOI: 10.1007/s12013-024-01611-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 11/17/2024]
Abstract
Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.
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Affiliation(s)
- Ting Ge
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yang Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yiwen Han
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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3
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Xue W, Guo N, Shan L, Zhang Z, Sun Y, Wang Y, Fang X, Liu X, Liu J, Hu C. Caveolin-1 protects against liver injury and lipid accumulation in alcoholic fatty liver via ferroptosis resistance. Mol Immunol 2025; 181:53-65. [PMID: 40073697 DOI: 10.1016/j.molimm.2025.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 12/12/2024] [Accepted: 02/19/2025] [Indexed: 03/14/2025]
Abstract
Alcoholic fatty liver (AFL) is one of the most common chronic liver diseases globally with complex and controversial pathogenesis. Recent evidence suggests that iron overload and lipid peroxidation are risk factors for AFL. Caveolin-1 (CAV1) is an important signal platform that can maintain lipid homeostasis during the development of non-alcoholic fatty liver. Here, we studied the effect of CAV1 on ferroptosis in AFL. The AFL mouse model was established by chronic-plus-binge alcohol feeding. In vitro, AML-12 cells were incubated with ethanol and oleic acid for 48 h. We found alcohol-induced AFL triggered ferroptosis and decreased CAV1 expression. Overexpression of CAV1 by CAV1 scaffolding domain peptides (CSD) attenuated liver injury and hepatic steatosis, as well as inhibited ferroptosis in AFL mice. Additionally, the effects of CAV1 on ferroptosis-related protein levels (such as SLC7A11, GPX4, and ACSL4) and lipid accumulation were reversed by its small interfering RNA administration. Ferroptosis agonist (Erastin) treatment abrogated CAV1 plasmid-mediated ferroptosis resistance and steatosis alleviation. Collectively, the results revealed a crucial role of CAV1 in preventing hepatic steatosis and ferroptosis in alcohol-induced liver injury, which may identify potential targets for the treatment of AFL.
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Affiliation(s)
- Weiju Xue
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Ning Guo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Liang Shan
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Zhengsheng Zhang
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Yuquan Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Yong Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Xing Fang
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Xiuzhen Liu
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Jianjun Liu
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China.
| | - Chengmu Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.
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4
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Bai B, Tu P, Weng J, Zhang Y, Lin Q, Muskat MN, Wang J, Tang X, Cheng X. Identification of Food-Derived Electrophilic Chalcones as Nrf2 Activators Using Comprehensive Virtual Screening Techniques. Antioxidants (Basel) 2025; 14:546. [PMID: 40427428 DOI: 10.3390/antiox14050546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 04/28/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Electrophilic compounds are bioactive components commonly found in foods that are capable of covalently modifying nucleophilic sites on biologically functional macromolecules. These compounds may elicit positive bioactivity or negative biotoxicity, posing significant challenges in terms of time and resource expenditure in the de novo characterization of their biological activity. In this study, we developed a database of 332 food-derived electrophilic compounds and used a semi-supervised k-nearest neighbors (KNN) machine learning model to predict their bioactivity. Molecular docking analysis identified the three chalcone compounds with the highest potential positive activity-4-hydroxyderricin (4HD), isoliquiritigenin (ISO), and butein. Furthermore, in cell experiments, treatment with 4HD, ISO, and butein significantly reduced reactive oxygen species (ROS) levels. An RT-qPCR analysis demonstrated that these chalcones significantly upregulated the mRNA expression of Nrf2 and its downstream antioxidant genes, including Nqo1, HO-1, Gsr, Gclc, and Gclm. ISO's cytoprotective and antioxidant effects were abolished following these findings, which highlight that 4HD, ISO, and butein are effective Nrf2 activators and suggest that comprehensive virtual technology is a promising strategy for identifying functional bioactive compounds.
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Affiliation(s)
- Bingyu Bai
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Piaohan Tu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Beilun Market Supervision Administration, Ningbo 315800, China
| | - Jiayi Weng
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Yan Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Quan Lin
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | | | - Jie Wang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Xue Tang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Xiangrong Cheng
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
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5
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Zheng X, Tang X, Xu Y, Zhu H, Zhong L, Chen C, Cui J, Zhou J. Sodium aescinate induces hepatotoxicity through apoptosis and ferroptosis by inhibiting the Nrf2/CTH pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119608. [PMID: 40064321 DOI: 10.1016/j.jep.2025.119608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/08/2025] [Accepted: 03/07/2025] [Indexed: 03/15/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The seed of Aesculus wilsonii Rehd., also known as Suoluozi in China, is a traditional Chinese herb included in the Pharmacopoeia of China (2020). Sodium aescinate (SA) is derived from the Aesculus wilsonii Rehd.'s seeds and is extensively used in clinical practice. AIM OF THE STUDY The study investigated the involvement of the Nrf2/CTH pathway in SA-induced hepatotoxicity and explored potential strategies for alleviating SA-induced liver damage. MATERIALS AND METHODS The ICR mice and AML12 mouse hepatocytes were exposed to SA. The levels of Fe2+, cysteine (Cys), glutathione (GSH), hydrogen sulfide (H2S), ROS, lipid peroxides and caspase-3 activity were assessed. The effects of SA on signaling pathways related to ferroptosis and apoptosis were examined. Furthermore, genetic modification or agonists of Nrf2 and CTH were co-treated with SA. RESULTS SA triggered ferroptosis and apoptosis in AML12 cells and mouse livers, characterized by a decline in Cys, GSH, and H2S levels, as well as accumulation of Fe2+, ROS and lipid peroxides, mitochondrial dysfunction, and chromatin condensation. SA decreased Nrf2, CTH, and Bcl-2 levels, elevated Bax levels, and activated caspase-9/3. Overexpression of Nrf2 or CTH, or NAC supplementation alleviated SA-induced ferroptosis by upregulating Cys and GSH levels. Overexpression of Nrf2 or CTH, or NaHS supplementation increased H2S levels, which reduced the interaction between p616-Drp1 and VDAC1 by enhancing Drp1 S-sulfenylation, thereby alleviating SA-induced mitochondrial-dependent apoptosis. Furthermore, DMF or Met mitigated SA-induced hepatotoxicity by activating the Nrf2/CTH pathway. CONCLUSIONS SA triggers oxidative stress, mitochondrial dysfunction, apoptosis, and ferroptosis, ultimately leading to liver damage by suppressing the Nrf2/CTH pathway.
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Affiliation(s)
- Xin Zheng
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Xinyi Tang
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Yinan Xu
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Haiyan Zhu
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Lianwei Zhong
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Chen Chen
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Jiajun Cui
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Jie Zhou
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China.
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Hionides-Gutierrez A, Goikoetxea-Usandizaga N, Sanz-García C, Martínez-Chantar ML, Cubero FJ. Novel Emerging Mechanisms in Acetaminophen (APAP) Hepatotoxicity. Liver Int 2025; 45:e16167. [PMID: 39548712 DOI: 10.1111/liv.16167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Drug-induced liver injury represents a critical public health issue, marked by unpredictable and potentially severe adverse reactions to medications, herbal products or dietary supplements. AIMS Acetaminophen is notably a leading cause of hepatotoxicity, impacting over one million individuals worldwide. MATERIALS & METHODS Extensive research has elucidated the intricate mechanisms driving APAP-induced liver injury, emphasising the significant roles of endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction and cell death. RESULTS These insights pave the way for innovative therapeutic strategies, including the use of magnesium, bile acids, microbiota modulation and mesenchymal stem cells. DISCUSSION & CONCLUSION This review explores into these pathological mechanisms, proposing viable therapeutic interventions for patients suffering from APAP-induced liver injury.
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Affiliation(s)
| | - Naroa Goikoetxea-Usandizaga
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Carlos Sanz-García
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
| | - María L Martínez-Chantar
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
- Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain
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7
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Öztürk Y, Öztürk M, Dörtbudak MB, Mariotti F, Magi GE, Di Cerbo A. Astaxanthin Mitigates 5-Fluorouracil-Induced Hepatotoxicity and Oxidative Stress in Male Rats. Nutrients 2025; 17:1230. [PMID: 40218988 PMCID: PMC11990585 DOI: 10.3390/nu17071230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 03/27/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Hepatotoxicity, a significant complication of 5-fluorouracil (5-FU) treatment, is generally triggered by oxidative stress, liver damage, and apoptosis processes that take place in cancer patients. METHODS In this study, the protective effect of different astaxanthin (ASX) dosages (16 and 32/mg/kg/bw) was determined in rats with 5-FU-induced liver damage. RESULTS 5-FU induced a significant increase in the histopathological lesions severity and immunohistochemical (TNF-α and 8-OHdG) expression scores in the liver (p < 0.001), significantly increased serum liver parameters (AST, ALP, ALT, GGT, and TP) and malondialdehyde (p < 0.001), and, at the same time, significantly decreased antioxidant parameters (SOD, CAT, GST, GSR, Caspase-3, and GPx) (p < 0.001). Histopathological lesions and oxidative stress parameters significantly decreased in parallel while increasing the ASX dosage (p < 0.001). CONCLUSIONS Based on these data, our results suggest that ASX may be considered a promising and valuable agent to mitigate hepatotoxicity and resistance mechanisms during cancer treatment.
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Affiliation(s)
- Yasin Öztürk
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Necmettin Erbakan, Ereğli 42310, Konya, Türkiye;
| | - Merve Öztürk
- Department Internal Medicine, Faculty of Veterinary Medicine, University of Necmettin Erbakan, Ereğli 42310, Konya, Türkiye;
| | - Muhammet Bahaeddin Dörtbudak
- Department of Pathology, Faculty of Veterinary Medicine, Harran University, Şanlıurfa 63200, Şanlıurfa, Türkiye;
| | - Francesca Mariotti
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy; (F.M.); (A.D.C.)
| | - Gian Enrico Magi
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy; (F.M.); (A.D.C.)
| | - Alessandro Di Cerbo
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy; (F.M.); (A.D.C.)
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8
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Su Y, Zeng Y, Zhou M, Liao M, Qin P, Wu R, Han J, Liang X, Wang Z, Jiang J, Yu Z, Huang X, Ding K, Guo P, He Y, Du Y, Duan T, Yuan H, Ge Y, Chen A, Xiao W. Natural Polyphenol-Mediated Inhibition of Ferroptosis Alleviates Oxidative Damage and Inflammation in Acute Liver Injury. Biomater Res 2025; 29:0167. [PMID: 40103575 PMCID: PMC11913781 DOI: 10.34133/bmr.0167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 03/20/2025] Open
Abstract
Acetaminophen (APAP) overdose has long been recognized as the main cause of drug-induced liver injury (DILI), characterized by glutathione (GSH) depletion and reactive oxygen species (ROS) accumulation, leading to ferroptosis and inflammatory responses. There is an urgent need for liver-protective agents to combat ferroptosis, modulate oxidative stress, and ameliorate inflammation. Catechin, a well-known polyphenol compound, has been shown to have antioxidant potential. However, its protective role on APAP-induced liver injury (AILI) has not been elucidated. In this study, we evaluated the modulating effects of catechin on AILI and observed that catechin attenuated liver injury by reducing inflammation. Mechanistically, catechin alleviated hepatic oxidative stress by inhibiting ROS accumulation, malondialdehyde (MDA) production, and GSH depletion. Furthermore, catechin, as a hepatic injury reparative agent, could counteract APAP-induced hepatocyte ferroptosis by activating the xCT/GPX4 pathway, and is expected to be a novel natural inhibitor of ferroptosis. Additionally, the transcriptomic results indicated that the inhibition of Stat1 by catechin is important for the management of AILI. Inhibition of signal transducer and activator of transcription 1 (STAT1) expression, achieved through the use of the STAT1 inhibitor fludarabine in vivo and small interfering RNA (siRNA) in vitro, was confirmed to attenuate APAP-induced ferroptosis. In conclusion, the present study identified a novel natural drug inhibitor of ferroptosis and revealed its mechanism of action to inhibit ferroptosis, regulate oxidative stress, and ameliorate inflammation in AILI. This further provides new insights into the novel natural ferroptosis inhibitors for the treatment of ROS-related inflammatory diseases.
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Affiliation(s)
- Yangjing Su
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yunong Zeng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Minjie Zhou
- Department of Organ Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Meihui Liao
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ping Qin
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Rong Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jiaochan Han
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Xiaoqi Liang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ze Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jingjing Jiang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zhichao Yu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xintao Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Kaixin Ding
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Peiheng Guo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yi He
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510665, China
| | - Ying Du
- Consun Pharmaceutical Group, Guangzhou 510765, China
| | - Tingting Duan
- Consun Pharmaceutical Group, Guangzhou 510765, China
| | - Haitao Yuan
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yuewei Ge
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ali Chen
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Wei Xiao
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China
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9
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Li X, Tao L, Zhong M, Wu Q, Min J, Wang F. [Ferroptosis and liver diseases]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:747-755. [PMID: 39757742 PMCID: PMC11736349 DOI: 10.3724/zdxbyxb-2024-0566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 11/24/2024] [Indexed: 01/07/2025]
Abstract
As the central organ of metabolism, the liver plays a pivotal role in the regulation of the synthesis and metabolism of various nutrients within the body. Ferroptosis, as a newly discovered type of programmed cell death caused by the accumulation of iron-dependent lipid peroxides, is involved in the physiological and pathological processes of a variety of acute and chronic liver diseases. Ferroptosis can accelerate the pathogenetic process of acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, and autoimmune hepatitis; while it can slower disease progression in advanced liver fibrosis and hepatocellular carcinoma. This suggests that targeted regulation of ferroptosis may impact the occurrence and development of various liver diseases. This article reviews the latest research progress of ferroptosis in various liver diseases, including acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune hepatitis, liver fibrosis and hepatocellular carcinoma. It aims to provide insights for the prevention and treatment of acute and chronic liver diseases through targeting ferroptosis.
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Affiliation(s)
- Xin Li
- School of Pharmacy, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China.
| | - Liang Tao
- College of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Meijuan Zhong
- College of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Qian Wu
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Junjia Min
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Fudi Wang
- College of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
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10
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Xu W, Hou H, Yang W, Tang W, Sun L. Immunologic role of macrophages in sepsis-induced acute liver injury. Int Immunopharmacol 2024; 143:113492. [PMID: 39471696 DOI: 10.1016/j.intimp.2024.113492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/11/2024] [Accepted: 10/21/2024] [Indexed: 11/01/2024]
Abstract
Sepsis-induced acute liver injury (SALI), a manifestation of sepsis multi-organ dysfunction syndrome, is associated with poor prognosis and high mortality. The diversity and plasticity of liver macrophage subpopulations explain their different functional responses in different liver diseases. Kupffer macrophages, liver capsular macrophages, and monocyte-derived macrophages are involved in pathogen recognition and clearance and in the regulation of inflammatory responses, exacerbating the progression of SALI through different pathways of pyroptosis, ferroptosis, and autophagy. Concurrently, they play an important role in maintaining hepatic homeostasis and in the injury and repair processes of SALI. Other macrophages are recruited to diseased tissues under pathological conditions and are polarized into various phenotypes (mainly M1 and M2 types) under the influence of signaling molecules, transcription factors, and metabolic reprogramming, thereby exerting different roles and functions. This review provides an overview of the immune role of macrophages in SALI and discusses the multiple roles of macrophages in liver injury and repair to provide a reference for future studies.
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Affiliation(s)
- Wanling Xu
- Department of Emergency, Jilin University First Hospital, 71 Xinmin Street, Changchun 130021, Jilin, China
| | - Hailong Hou
- Emergency Department, Meihekou Central Hospital, 2668 Aimin Street, Tonghua 135000, Jilin, China
| | - Weiying Yang
- Department of Emergency, Jilin University First Hospital, 71 Xinmin Street, Changchun 130021, Jilin, China
| | - Wenjing Tang
- Department of Emergency, Jilin University First Hospital, 71 Xinmin Street, Changchun 130021, Jilin, China
| | - Lichao Sun
- Department of Emergency, Jilin University First Hospital, 71 Xinmin Street, Changchun 130021, Jilin, China.
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11
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Zheng X, Ye FC, Sun T, Liu FJ, Wu MJ, Zheng WH, Wu LF. Delay the progression of glucocorticoid-induced osteoporosis: Fraxin targets ferroptosis via the Nrf2/GPX4 pathway. Phytother Res 2024; 38:5203-5224. [PMID: 39192711 DOI: 10.1002/ptr.8310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 07/09/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.
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Affiliation(s)
- Xiang Zheng
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Fang-Chen Ye
- The First School of Medicine, Nanfang Medical University, Guangzhou, China
| | - Tao Sun
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Fei-Jun Liu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Ming-Jian Wu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Wen-Hao Zheng
- Department of Orthopaedic, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ling-Feng Wu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
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12
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Han X, Zhang Y, Li Y, Lin Z, Fu Z, Wang C, Zhang S, Shao D, Li C. MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2. Cell Prolif 2024; 57:e13700. [PMID: 38924190 PMCID: PMC11533064 DOI: 10.1111/cpr.13700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Tamoxifen resistance is a common and difficult problem in the clinical treatment of breast cancer (BC). As a novel antitumor agent, Micheliolide (MCL) has shown a better therapeutic effect on tumours; however, little is known about MCL and its role in BC therapy. With tamoxifen stimulation, drug-resistant BC cells MCF7TAMR and T47DTAMR obtained a high oxidative status and Amidohydrolase 1 (ASAH1) was abnormally activated. The inhibition of ASAH1 rescued the sensitivity of resistant cells to tamoxifen. We found that MCL inhibited the expression of ASAH1 and cell proliferation, especially in MCF7TAMR and T47DTAMR cells. The high oxidative stress status of resistant cells stimulated the expression of ASAH1 by positively regulating AKT, which was restrained by MCL. MCL activated NRF2 by directly binding to KEAP1 and promoting the antioxidant level of tamoxifen-resistant (TAMR) cells. In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. In conclusion, ASAH1 mediates tamoxifen resistance in ER-positive BC cells. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/AKT signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR-BC.
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Affiliation(s)
- Xiao Han
- Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Key Laboratory of PreventionDiagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang ProvinceHangzhouChina
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Yupeng Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Yin Li
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Zhoujun Lin
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Zhenkun Fu
- Department of Immunology & Wu Lien‐Teh Institute & Heilongjiang Provincial Key Laboratory for Infection and ImmunityHarbin Medical University & Heilongjiang Academy of Medical ScienceHarbinChina
| | - Changjun Wang
- Department of Breast SurgeryPeking Union Medical College HospitalBeijingChina
| | - Shengjie Zhang
- Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Key Laboratory of PreventionDiagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang ProvinceHangzhouChina
| | - Di Shao
- Chonggang General HospitalChongqingChina
- Chongqing Emergency Medical CenterChongqing University Central HospitalChongqingChina
| | - Chenggang Li
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
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13
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Zeng L, Jin X, Xiao QA, Jiang W, Han S, Chao J, Zhang D, Xia X, Wang D. Ferroptosis: action and mechanism of chemical/drug-induced liver injury. Drug Chem Toxicol 2024; 47:1300-1311. [PMID: 38148561 DOI: 10.1080/01480545.2023.2295230] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/12/2023] [Accepted: 11/28/2023] [Indexed: 12/28/2023]
Abstract
Drug-induced liver injury (DILI) is characterized by hepatocyte injury, cholestasis injury, and mixed injury. The liver transplantation is required for serious clinical outcomes such as acute liver failure. Current studies have found that many mechanisms were involved in DILI, such as mitochondrial oxidative stress, apoptosis, necroptosis, autophagy, ferroptosis, etc. Ferroptosis occurs when hepatocytes die from iron-dependent lipid peroxidation and plays a key role in DILI. After entry into the liver, where some drugs or chemicals are metabolized, they convert into hepatotoxic substances, consume reduced glutathione (GSH), and decrease the reductive capacity of GSH-dependent GPX4, leading to redox imbalance in hepatocytes and increase of reactive oxygen species (ROS) and lipid peroxidation level, leading to the undermining of hepatocytes; some drugs facilitated the autophagy of ferritin, orchestrating the increased ion level and ferroptosis. The purpose of this review is to summarize the role of ferroptosis in chemical- or drug-induced liver injury (chemical/DILI) and how natural products inhibit ferroptosis to prevent chemical/DILI.
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Affiliation(s)
- Li Zeng
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Xueli Jin
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Qing-Ao Xiao
- Department of Interventional Radiology, the First College of Clinical Medical Science, China Three Gorges University, Yichang, China
- Yichang Central People's Hospital, Yichang, China
| | - Wei Jiang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Shanshan Han
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Jin Chao
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Ding Zhang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Xuan Xia
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Department of Physiology and Pathophysiology, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Decheng Wang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
- Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang, China
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14
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Liu YY, Zhang Y, Shan GY, Cheng JY, Wan H, Zhang YX, Li HJ. Hinokiflavone exerts dual regulation on apoptosis and pyroptosis via the SIX4/Stat3/Akt pathway to alleviate APAP-induced liver injury. Life Sci 2024; 354:122968. [PMID: 39147316 DOI: 10.1016/j.lfs.2024.122968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 07/29/2024] [Accepted: 08/10/2024] [Indexed: 08/17/2024]
Abstract
Hinokiflavone (HF), classified as a flavonoid, is a main bioactive compound in Platycladus orientalis and Selaginella. HF exhibits activities including anti-HIV, anti-inflammatory, antiviral, antioxidant and anti-tumor effects. The study aimed to explore the function and the mechanisms of HF on acetaminophen (APAP)-induced acute liver injury. Results indicated that HF treatment mitigated the impact of APAP on viability and restored levels of MDA, GSH and SOD on HepG2 cells. The accumulation of reactive oxygen species (ROS) mitochondrial membrane potential (MMP) in HepG2 cells stimulated by APAP were also blocked by HF. HF reduced the levels of pro-apoptotic and pro-pyroptotic proteins. Flow cytometry analysis and fluorescence staining results were consistent with western blot analysis. Following HF treatment in the APAP-induced cell model, there was observed an augmentation in the phosphorylation of Stat3 and an increase in the expression of SIX4. However, not only silenced the SIX4 protein in HepG2 cells by siRNA, but also adding the Stat3 inhibitor (Stattic), attenuated the anti-apoptotic and anti-pyroptotic effects of HF significantly. Furthermore, HF alleviated liver damage in C57BL/6 mice model. Overall, our study demonstrated that HF mitigates apoptosis and pyroptosis induced by APAP in drug-induced liver injury (DILI) through the SIX4/Akt/Stat3 pathway in vivo and in vitro. HF may have promising potential for for the treatment of DILI.
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Affiliation(s)
- Yi-Ying Liu
- Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China; Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun, Jilin Province 130021, China
| | - Yang Zhang
- Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun, Jilin Province 130021, China
| | - Guan-Yue Shan
- Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China
| | - Jun-Ya Cheng
- Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China; Department of Bioengineering, Jilin University School of Pharmaceutical Sciences, Changchun, Jilin Province, 130021, China
| | - Hui Wan
- Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China
| | - Yu-Xin Zhang
- Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China
| | - Hai-Jun Li
- Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China.
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15
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Lambrecht R, Jansen J, Rudolf F, El-Mesery M, Caporali S, Amelio I, Stengel F, Brunner T. Drug-induced oxidative stress actively prevents caspase activation and hepatocyte apoptosis. Cell Death Dis 2024; 15:659. [PMID: 39245717 PMCID: PMC11381522 DOI: 10.1038/s41419-024-06998-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 07/30/2024] [Accepted: 08/13/2024] [Indexed: 09/10/2024]
Abstract
Cell death is a fundamental process in health and disease. Emerging research shows the existence of numerous distinct cell death modalities with similar and intertwined signaling pathways, but resulting in different cellular outcomes, raising the need to understand the decision-making steps during cell death signaling. Paracetamol (Acetaminophen, APAP)-induced hepatocyte death includes several apoptotic processes but eventually is executed by oncotic necrosis without any caspase activation. Here, we studied this paradoxical form of cell death and revealed that APAP not only fails to activate caspases but also strongly impedes their activation upon classical apoptosis induction, thereby shifting apoptosis to necrosis. While APAP intoxication results in massive drop in mitochondrial respiration, low cellular ATP levels could be excluded as an underlying cause of missing apoptosome formation and caspase activation. In contrast, we identified oxidative stress as a key factor in APAP-induced caspase inhibition. Importantly, caspase inhibition and the associated switch from apoptotic to necrotic cell death was reversible through the administration of antioxidants. Thus, exemplified by APAP-induced cell death, our study stresses that cellular redox status is a critical component in the decision-making between apoptotic and necrotic cell death, as it directly affects caspase activity.
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Affiliation(s)
- Rebekka Lambrecht
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
- Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Jasmin Jansen
- Biochemistry and Mass Spectrometry, Department of Biology, University of Konstanz, Konstanz, Germany
- Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
| | - Franziska Rudolf
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
- Collaborative Research Center TRR 353, Konstanz, Germany
| | - Mohamed El-Mesery
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
- Collaborative Research Center TRR 353, Konstanz, Germany
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Sabrina Caporali
- Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Ivano Amelio
- Collaborative Research Center TRR 353, Konstanz, Germany
- Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Florian Stengel
- Biochemistry and Mass Spectrometry, Department of Biology, University of Konstanz, Konstanz, Germany
- Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
- Collaborative Research Center TRR 353, Konstanz, Germany
| | - Thomas Brunner
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany.
- Collaborative Research Center TRR 353, Konstanz, Germany.
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16
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Xing ZY, Zhang CJ, Liu LJ. Targeting both ferroptosis and pyroptosis may represent potential therapies for acute liver failure. World J Gastroenterol 2024; 30:3791-3798. [PMID: 39351426 PMCID: PMC11438622 DOI: 10.3748/wjg.v30.i33.3791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/10/2024] [Accepted: 08/16/2024] [Indexed: 09/02/2024] Open
Abstract
In this editorial, we comment on the article published in the recent issue of the World Journal of Gastroenterology. Acute liver failure (ALF) is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function. Ferroptosis and pyroptosis, cell death forms that can be initiated or blocked concurrently, can play significant roles in developing inflammation and various malignancies. However, their roles in ALF remain unclear. The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF, and revealed that the silent information regulator sirtuin 1 (SIRT1) inhibits both pathways through p53, dramatically reducing inflammation and protecting hepatocytes. This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF. Thus, we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms. Additionally, we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways, as well as examples of SIRT1 activators being used as disease treatment strategies, providing new insights into the therapy of ALF.
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Affiliation(s)
- Zhong-Yuan Xing
- Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Chuan-Jie Zhang
- Department of Children Health Care, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430061, Hubei Province, China
| | - Li-Juan Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
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17
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Fan B, Guo Q, Wang S. The application of alkaloids in ferroptosis: A review. Biomed Pharmacother 2024; 178:117232. [PMID: 39098181 DOI: 10.1016/j.biopha.2024.117232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024] Open
Abstract
Alkaloids have remarkable biological and pharmacological properties and have recently garnered extensive attention. Various alkaloids, including commercially available drugs such as berberine, substantially affect ferroptosis. In addition to the three main pathways of ferroptosis, iron metabolism, phospholipid metabolism, and the glutathione peroxidase 4-regulated pathway, novel mechanisms of ferroptosis are continuously being identified. Alkaloids can modulate the progression of various diseases through ferroptosis and exhibit the ability to exert varied effects depending on dosage and tissue type underscores their versatility. Therefore, this review comprehensively summarizes primary targets and the latest advancements of alkaloids in ferroptosis, as well as the dual roles of alkaloids in inhibiting and promoting ferroptosis.
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Affiliation(s)
- Bocheng Fan
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110013, China
| | - Qihao Guo
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110013, China
| | - Shu Wang
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110013, China.
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18
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He J, Feng X, Liu Y, Wang Y, Ge C, Liu S, Jiang Y. Graveoline attenuates D-GalN/LPS-induced acute liver injury via inhibition of JAK1/STAT3 signaling pathway. Biomed Pharmacother 2024; 177:117163. [PMID: 39018876 DOI: 10.1016/j.biopha.2024.117163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 07/05/2024] [Accepted: 07/15/2024] [Indexed: 07/19/2024] Open
Abstract
Graveoline exhibits various biological activities. However, only limited studies have focused on its hepatoprotective properties. This study evaluated the anti-inflammatory and hepatoprotective activities of graveoline, a minor 2-phenylquinolin-4-one alkaloid isolated from Ruta graveolens L., in a liver injury model in vitro and in vivo. A network pharmacology approach was used to investigate the potential signaling pathway associated with the hepatoprotective activity of graveoline. Subsequently, biological experiments were conducted to validate the findings. Topological analysis of the KEGG pathway enrichment revealed that graveoline mediates its hepatoprotective activity through genes associated with the hepatitis B viral infection pathway. Biological experiments demonstrated that graveoline effectively reduced the levels of alanine transaminase and aspartate transaminase in lipopolysaccharide (LPS)-induced HepG2 cells. Graveoline exerted antihepatitic activity by inhibiting the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and elevated the anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) in vitro and in vivo. Additionally, graveoline exerted its hepatoprotective activity by inhibiting JAK1 and STAT3 phosphorylation both in vitro and in vivo. In summary, graveoline can attenuate acute liver injury by inhibiting the TNF-α inflammasome, activating IL-4 and IL-10, and suppressing the JAK1/STAT3 signaling pathway. This study sheds light on the potential of graveoline as a promising therapeutic agent for treating liver injury.
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Affiliation(s)
- Jia He
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xu Feng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yanyang Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Pharmacy, Mianyang 404 Hospital, Mianyang, Sichuan 621000, China
| | - Yuxin Wang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; College of pharmacy, Dali University, Dali, Yunan 671000, China
| | - Chengyu Ge
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Yueping Jiang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; College of Pharmacy, Changsha Medical University, Changsha, Hunan 410219, China.
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19
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Liu P, Liang WL, Huang RT, Chen XX, Zou DH, Kurihara H, Li YF, Xu YH, Ouyang SH, He RR. Hepatic microcirculatory disturbance in liver diseases: intervention with traditional Chinese medicine. Front Pharmacol 2024; 15:1399598. [PMID: 39108760 PMCID: PMC11300221 DOI: 10.3389/fphar.2024.1399598] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/25/2024] [Indexed: 04/18/2025] Open
Abstract
The liver, a complex parenchymal organ, possesses a distinctive microcirculatory system crucial for its physiological functions. An intricate interplay exists between hepatic microcirculatory disturbance and the manifestation of pathological features in diverse liver diseases. This review updates the main characteristics of hepatic microcirculatory disturbance, including hepatic sinusoidal capillarization, narrowing of sinusoidal space, portal hypertension, and pathological angiogenesis, as well as their formation mechanisms. It also summarized the detection methods for hepatic microcirculation. Simultaneously, we have also reviewed the characteristics of microcirculatory disturbance in diverse liver diseases such as acute liver failure, hepatic ischemia-reperfusion injury, viral hepatitis, non-alcoholic fatty liver disease, hepatic fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Finally, this review also summarizes the advancement in hepatic microcirculation attributed to traditional Chinese medicine (TCM) and its active metabolites, providing novel insights into the application of TCM in treating liver diseases.
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Affiliation(s)
- Pei Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Wan-Li Liang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Rui-Ting Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Xin-Xing Chen
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - De-Hua Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Hiroshi Kurihara
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Yi-Fang Li
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - You-Hua Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
| | - Shu-Hua Ouyang
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Rong-Rong He
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
- Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine, Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
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20
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Laddha AP, Wu H, Manautou JE. Deciphering Acetaminophen-Induced Hepatotoxicity: The Crucial Role of Transcription Factors like Nuclear Factor Erythroid 2-Related Factor 2 as Genetic Determinants of Susceptibility to Drug-Induced Liver Injury. Drug Metab Dispos 2024; 52:740-753. [PMID: 38857948 DOI: 10.1124/dmd.124.001282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/20/2024] [Accepted: 06/06/2024] [Indexed: 06/12/2024] Open
Abstract
Acetaminophen (APAP) is the most commonly used over-the-counter medication throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy and safety of APAP are influenced by multifactorial processes dependent upon dosing, namely frequency and total dose. APAP poisoning by repeated ingestion of supratherapeutic doses, depletes glutathione stores in the liver and other organs capable of metabolic bioactivation, leading to hepatocellular death due to exhausted antioxidant defenses. Numerous genes, encompassing transcription factors and signaling pathways, have been identified as playing pivotal roles in APAP toxicity, with the liver being the primary organ studied due to its central role in APAP metabolism and injury. Nuclear factor erythroid 2-related factor 2 (NRF2) and its array of downstream responsive genes are crucial in counteracting APAP toxicity. NRF2, along with its negative regulator Kelch-like ECH-associated protein 1, plays a vital role in regulating intracellular redox homeostasis. This regulation is significant in modulating the oxidative stress, inflammation, and hepatocellular death induced by APAP. In this review, we provide an updated overview of the mechanisms through which NRF2 activation and signaling critically influence the threshold for developing APAP toxicity. We also describe how genetically modified rodent models for NRF2 and related genes have been pivotal in underscoring the significance of this antioxidant response pathway. While NRF2 is a primary focus, the article comprehensively explores other genetic factors involved in phase I and phase II metabolism of APAP, inflammation, oxidative stress, and related pathways that contribute to APAP toxicity, thereby providing a holistic understanding of the genetic landscape influencing susceptibility to this condition. SIGNIFICANCE STATEMENT: This review summarizes the genetic elements and signaling pathways underlying APAP-induced liver toxicity, focusing on the crucial protective role of the transcription factor NRF2. This review also delves into the genetic intricacies influencing APAP safety and potential liver harm. It also emphasizes the need for deeper insight into the molecular mechanisms of hepatotoxicity, especially the interplay of NRF2 with other pathways.
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Affiliation(s)
- Ankit P Laddha
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
| | - Hangyu Wu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
| | - José E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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21
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Zhou QQ, Wu YP, Liu P, Deng WZ, Lu YH, Gong HB, Lin XM, Sun WY, Wang R, Huang F, Cao YF, Li YF, Kurihara H, Ouyang SH, Liang L, He RR. Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155613. [PMID: 38703659 DOI: 10.1016/j.phymed.2024.155613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/20/2024] [Accepted: 04/07/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.
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Affiliation(s)
- Qing-Qing Zhou
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Yan-Ping Wu
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Pei Liu
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Wen-Zhe Deng
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Yu-Hui Lu
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Hai-Biao Gong
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Xiao-Min Lin
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Wan-Yang Sun
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Rong Wang
- School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Feng Huang
- School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Yun-Feng Cao
- Shanghai Institute for Biomedical and Pharmaceutical Technologies, NHC Key Laboratory of Reproduction Regulation, Shanghai 200032, China
| | - Yi-Fang Li
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Hiroshi Kurihara
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
| | - Shu-Hua Ouyang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China.
| | - Lei Liang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China.
| | - Rong-Rong He
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
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22
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Yang L, Liu Q, Lu Q, Xiao JJ, Fu AY, Wang S, Ni L, Hu JW, Yu H, Wu X, Zhang BF. Scavenger Receptor Class B Type I Deficiency Induces Iron Overload and Ferroptosis in Renal Tubular Epithelial Cells via Hypoxia-Inducible Factor-1α/Transferrin Receptor 1 Signaling Pathway. Antioxid Redox Signal 2024; 41:56-73. [PMID: 38062756 DOI: 10.1089/ars.2023.0380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Aims: Scavenger receptor class B type I (SRBI) promotes cell cholesterol efflux and the clearance of plasma cholesterol. Thus, SRBI deficiency causes abnormal cholesterol metabolism and hyperlipidemia. Studies have suggested that ferroptosis is involved in lipotoxicity; however, whether SRBI deficiency could induce ferroptosis remains to be investigated. Results: We knocked down or knocked out SRBI in renal HK-2 cells and C57BL/6 mice to determine the expression levels of ferroptosis-related regulators. Our results demonstrated that SRBI deficiency upregulates transferrin receptor 1 (TFR1) expression and downregulates ferroportin expression, which induces iron overload and subsequent ferroptosis in renal tubular epithelial cells. TFR1 is known to be regulated by hypoxia-inducible factor-1α (HIF-1α). Next, we investigated whether SRBI deletion affected HIF-1α. SRBI deletion upregulated the mRNA and protein expression of HIF-1α, and promoted its translocation to the nucleus. To determine whether HIF-1α plays a key role in SRBI-deficiency-induced ferroptosis, we used HIF-1α inhibitor and siHIF-1α in HK-2 cells, and found that downregulation of HIF-1α prevented SRBI-silencing-induced TFR1 upregulation and iron overload, and eventually reduced ferroptosis. The underlying mechanism of HIF-1α activation was explored next, and the results showed that SRBI knockout or knockdown may upregulate the expression of HIF-1α, and promote HIF-1α translocation from the cytoplasm into the nucleus via the PKC-β/NF-κB signaling pathway. Innovation and Conclusion: Our study showed, for the first time, that SRBI deficiency induces iron overload and subsequent ferroptosis via the HIF-1α/TFR1 pathway.
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Affiliation(s)
- LiJiao Yang
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qing Liu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University TaiKang Medical School, Wuhan, China
| | - QianYu Lu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jing-Jie Xiao
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University TaiKang Medical School, Wuhan, China
| | - An-Yao Fu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University TaiKang Medical School, Wuhan, China
| | - Shan Wang
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University TaiKang Medical School, Wuhan, China
| | - LiHua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jun-Wei Hu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hong Yu
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University TaiKang Medical School, Wuhan, China
| | - XiaoYan Wu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bai-Fang Zhang
- Department of Biochemistry and Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University TaiKang Medical School, Wuhan, China
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23
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Sheng XH, Han LC, Gong A, Meng XS, Wang XH, Teng LS, Sun XH, Xu KC, Liu ZH, Wang T, Ma JP, Zhang L. Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities. J Med Chem 2024; 67:9536-9551. [PMID: 38822802 DOI: 10.1021/acs.jmedchem.4c00600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2024]
Abstract
The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.
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Affiliation(s)
- Xie-Huang Sheng
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Li-Cong Han
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Ao Gong
- Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan 250001, China
| | - Xiang-Shuai Meng
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Xin-Hui Wang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Lin-Song Teng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan 250014, China
| | - Xiao-Han Sun
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Kuo-Chen Xu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan 250014, China
| | - Zhao-Hua Liu
- The Model Animal Research Center, Cheeloo College of Medicine, Shandong University, Jinan 250014, China
| | - Ting Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China
| | - Jian-Ping Ma
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Lei Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan 250014, China
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24
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Huang Y, Zhang Y, Wu K, Tan X, Lan T, Wang G. Role of Gut Microecology in the Pathogenesis of Drug-Induced Liver Injury and Emerging Therapeutic Strategies. Molecules 2024; 29:2663. [PMID: 38893536 PMCID: PMC11173750 DOI: 10.3390/molecules29112663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/01/2024] [Accepted: 06/01/2024] [Indexed: 06/21/2024] Open
Abstract
Drug-induced liver injury (DILI) is a common clinical pharmacogenic disease. In the United States and Europe, DILI is the most common cause of acute liver failure. Drugs can cause hepatic damage either directly through inherent hepatotoxic properties or indirectly by inducing oxidative stress, immune responses, and inflammatory processes. These pathways can culminate in hepatocyte necrosis. The role of the gut microecology in human health and diseases is well recognized. Recent studies have revealed that the imbalance in the gut microecology is closely related to the occurrence and development of DILI. The gut microecology plays an important role in liver injury caused by different drugs. Recent research has revealed significant changes in the composition, relative abundance, and distribution of gut microbiota in both patients and animal models with DILI. Imbalance in the gut microecology causes intestinal barrier destruction and microorganism translocation; the alteration in microbial metabolites may initiate or aggravate DILI, and regulation and control of intestinal microbiota can effectively mitigate drug-induced liver injury. In this paper, we provide an overview on the present knowledge of the mechanisms by which DILI occurs, the common drugs that cause DILI, the gut microbiota and gut barrier composition, and the effects of the gut microbiota and gut barrier on DILI, emphasizing the contribution of the gut microecology to DILI.
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Affiliation(s)
- Yuqiao Huang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yu Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Kaireng Wu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinxin Tan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Guixiang Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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25
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Sun G, Liu C, Lu Z, Zhang J, Cao H, Huang T, Dai M, Liu H, Feng T, Tang W, Xia Y. Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma. Cancer Cell Int 2024; 24:192. [PMID: 38822322 PMCID: PMC11143590 DOI: 10.1186/s12935-024-03342-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/23/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Immunotherapy combined with molecular targeted therapy is increasingly popular in patients with advanced hepatocellular carcinoma (HCC). However, immune-related adverse events(irAEs) brought on by immunotherapy increase the likelihood of side effects, thus it is important to look into ways to address this issue. METHODS Different metabolite patterns were established by analyzing metabolomics data in liver tissue samples from 10 patients(divided into severe and mild liver injury) before and after immuno-targeted therapy. After establishing a subcutaneous tumor model of HCC, the mice were divided into PBS group, ascorbic acid(AA) group, and anti-PD1 + tyrosine kinase inhibitor (TKI) group, anti-PD1 + TKI + AA group. Liver tissue were stained with hematoxylin-eosin staining(HE) and the content of aspartate transaminase (AST) and alanine transaminase(ALT) in blood were determined. The mechanism was confirmed by western blotting, mass cytometry, and other techniques. RESULTS Through metabolomics analysis, AA was significantly reduced in the sample of patients with severe liver injury caused by immuno-targeted therapy compared to patients with mild liver injury. The addition of AA in vivo experiments demonstrated a reduction in liver injury in mice. In the liver tissues of the anti-PD1 + TKI + AA group, the protein expressions of SLC7A11,GPX4 and the level of glutathione(GSH) were found to be higher compared to the anti-PD1 + TKI group. Mass cytometry analysis revealed a significant increase in the CD11b+CD44+ PD-L1+ cell population in the AA group when compared to the PBS group. CONCLUSIONS AA could reduce liver injury by preventing hepatocyte SLC7A11/GPX4 ferroptosis and improve the immunotherapy effect of anti-PD1 by boosting CD11b+CD44+PD-L1+cell population in HCC.
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Affiliation(s)
- Guoqiang Sun
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuan Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China
| | - Zhengqing Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China
| | - Jinyu Zhang
- Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hengsong Cao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China
| | - Tian Huang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China
| | - Mingrui Dai
- Stomatological college of Nanjing Medical University, Nanjing, China
| | - Hanyuan Liu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tingting Feng
- Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Weiwei Tang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China.
| | - Yongxiang Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China.
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Zhang L, Luo YL, Xiang Y, Bai XY, Qiang RR, Zhang X, Yang YL, Liu XL. Ferroptosis inhibitors: past, present and future. Front Pharmacol 2024; 15:1407335. [PMID: 38846099 PMCID: PMC11153831 DOI: 10.3389/fphar.2024.1407335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/06/2024] [Indexed: 06/09/2024] Open
Abstract
Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.
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Affiliation(s)
- Lei Zhang
- School of Medicine, Yan’an University, Yan’an, China
| | - Yi Lin Luo
- School of Medicine, Yan’an University, Yan’an, China
| | - Yang Xiang
- College of Physical Education, Yan’an University, Yan’an, China
| | - Xin Yue Bai
- School of Medicine, Yan’an University, Yan’an, China
| | | | - Xin Zhang
- School of Medicine, Yan’an University, Yan’an, China
| | - Yan Ling Yang
- School of Medicine, Yan’an University, Yan’an, China
| | - Xiao Long Liu
- School of Medicine, Yan’an University, Yan’an, China
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Zhao L, Zhang X, Chen Z, Lai Y, Xu J, Zhou R, Ma P, Cai W, Zeng Y, Wu X, Ying H, Yu F. Cynarin alleviates acetaminophen-induced acute liver injury through the activation of Keap1/Nrf2-mediated lipid peroxidation defense via the AMPK/SIRT3 signaling pathway. Food Funct 2024; 15:4954-4969. [PMID: 38602356 DOI: 10.1039/d3fo05025d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2024]
Abstract
Overdose of Acetaminophen (APAP) is a major contributor to acute liver injury (ALI), a complex pathological process with limited effective treatments. Emerging evidence links lipid peroxidation to APAP-induced ALI. Cynarin (Cyn), a hydroxycinnamic acid derivative, exhibits liver protective effects, but whether it mitigates APAP-induced ALI is unclear. Our aim was to verify the protective impact of Cyn on APAP-induced ALI and elucidate the molecular mechanisms governing this process. Herein, the regulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) interaction was determined to be a novel mechanism underlying this protective impact of Cyn against APAP-induced ALI. Nrf2 deficiency increased the severity of APAP-induced ALI and lipid peroxidation and counteracted the protective effect of Cyn against this pathology. Additionally, Cyn promoted the dissociation of Nrf2 from Keap1, enhancing the nuclear translocation of Nrf2 and the transcription of downstream antioxidant proteins, thereby inhibiting lipid peroxidation. Molecular docking demonstrated that Cyn bound competitively to Keap1, and overexpression of Keap1 reversed Nrf2-activated anti-lipid peroxidation. Additionally, Cyn activated the adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)3 signaling pathway, which exhibits a protective effect on APAP-induced ALI. These findings propose that Cyn alleviates APAP-induced ALI by enhancing the Keap1/Nrf2-mediated lipid peroxidation defense via activation of the AMPK/SIRT3 signaling pathway.
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Affiliation(s)
- Luying Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiangting Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Zhuofeng Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Yuning Lai
- The First Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Jun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Ruoru Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Peipei Ma
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Weimin Cai
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Yuan Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Huiya Ying
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Fujun Yu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Liu JJ, Zhang X, Cai BL, Qi MM, Chi YB, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. JOURNAL OF INTEGRATIVE MEDICINE 2024; 22:286-294. [PMID: 38565435 DOI: 10.1016/j.joim.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 11/27/2023] [Indexed: 04/04/2024]
Abstract
OBJECTIVE Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity. METHODS In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis. RESULTS Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells. CONCLUSION One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.
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Affiliation(s)
- Jia-Jia Liu
- School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China
| | - Xue Zhang
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China; School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Bang-Lan Cai
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China; School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Man-Man Qi
- School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China
| | - Yong-Bin Chi
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China
| | - Bin Peng
- School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China.
| | - Deng-Hai Zhang
- School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Secondary Military Medical University, Shanghai 200135, China; School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China.
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Qian ZB, Li JF, Xiong WY, Mao XR. Ferritinophagy: A new idea for liver diseases regulated by ferroptosis. Hepatobiliary Pancreat Dis Int 2024; 23:160-170. [PMID: 37903710 DOI: 10.1016/j.hbpd.2023.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 07/31/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND The discovery of regulatory cell death has led to a breakthrough in the therapeutic field. Various forms of cell death, such as necrosis, apoptosis, pyroptosis, autophagy, and ferroptosis, play an important role in the development of liver diseases. In general, more than one form of cell death pathways is responsible for the disease state. Therefore, it is particularly important to study the regulation and interaction of various cell death forms in liver diseases. DATA SOURCES We performed a PubMed search up to November 2022 with the following keywords: ferritinophagy, ferroptosis, and liver disease. We also used terms such as signal path, inducer, and inhibitor to supplement the query results. RESULTS This review summarized the basic characteristics of ferritinophagy and ferroptosis and the regulation of ferroptosis by ferritinophagy and reviewed the key targets and treatment strategies of ferroptosis in different liver diseases. CONCLUSIONS Ferritinophagy is a potential therapeutic target in ferroptosis-related liver diseases.
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Affiliation(s)
- Zi-Bing Qian
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
| | - Jun-Feng Li
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Wan-Yuan Xiong
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
| | - Xiao-Rong Mao
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou 730000, China.
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Wang Y, Chen G, Zhou D, Xu L, Meng Q, Lin B, Hao J, Sun F, Hou Y, Li N. Chemical profile of the roots of Clausena lansium and their inhibitory effects of the over-activation in BV-2 microglial cells. PHYTOCHEMISTRY 2024; 220:114008. [PMID: 38346545 DOI: 10.1016/j.phytochem.2024.114008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/29/2024] [Accepted: 02/01/2024] [Indexed: 02/18/2024]
Abstract
From the 95% ethanol aqueous extract of the roots of Clausena lansium, six previously undescribed alkaloids (1, 2a, 2b, 15, 24a, 24b), a pair of prenylated phenylpropenols (26a, 26b), two coumarins (27, 28), and two undescribed sesquiterpenes (37, 38) were isolated and identified using spectroscopic and electron circular dichroism data, together with thirty-two known compounds. The absolute configurations of three alkaloids (3a, 3b, 4a) were determined for the first time. In vitro assay showed that alkaloids 7, 10, 12, 19, and furanocoumarins 34, 35 displayed inhibitory effects on the production of nitric oxide in lipopolysaccharide (LPS)-induced BV-2 microglial cells, which were stronger than that of the minocycline (positive control). RT-PCR results indicated that indizoline (7) could inhibit the expression of pro-inflammatory factors (IL-1β, TNF-α, and IL-6) in LPS-treated BV-2 cells.
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Affiliation(s)
- Yingjie Wang
- School of Traditional Chinese Materia Medica, Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning Province, Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning Province, Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning Province, Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Libin Xu
- College of Life and Health Sciences, Northeastern University, Shenyang, 110004, PR China.
| | - Qingqi Meng
- College of Life and Health Sciences, Northeastern University, Shenyang, 110004, PR China.
| | - Bin Lin
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Jinle Hao
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Fuxin Sun
- School of Traditional Chinese Materia Medica, Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning Province, Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Yue Hou
- College of Life and Health Sciences, Northeastern University, Shenyang, 110004, PR China.
| | - Ning Li
- School of Traditional Chinese Materia Medica, Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning Province, Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
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Yang H, Liu Y, Yao J, Wang Y, Wang L, Ren P, Bai B, Wen Q. Mesenchymal stem cells inhibit ferroptosis by activating the Nrf2 antioxidation pathway in severe acute pancreatitis-associated acute lung injury. Eur J Pharmacol 2024; 967:176380. [PMID: 38311279 DOI: 10.1016/j.ejphar.2024.176380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 02/10/2024]
Abstract
Severe acute pancreatitis-associated acute lung injury (SAP-ALI) remains a significant challenge for healthcare practitioners because of its high morbidity and mortality; therefore, there is an urgent need for an effective treatment. Mesenchymal stem cells (MSCs) have shown significant potential in the treatment of a variety of refractory diseases, including lung diseases. This study aimed to investigate the protective effects of MSCs against SAP-ALI and its underlying mechanisms. Our results suggest that MSCs mitigate pathological injury, hemorrhage, edema, inflammatory response in lung tissue, and lipopolysaccharide (LPS)-induced cell damage in RLE-6TN cells (a rat alveolar epithelial cell line). The results also showed that MSCs, similar to the effects of ferrostatin-1 (ferroptosis inhibitor), suppressed the ferroptosis response, which was manifested as down-regulated Fe2+, malondialdehyde, and reactive oxygen species (ROS) levels, and up-regulated glutathione peroxidase 4 (GPX4) and glutathione (GSH) levels in vivo and in vitro. The activation of ferroptosis by erastin (a ferroptosis agonist) reversed the protective effect of MSCs against SAP-ALI. Furthermore, MSCs activated the nuclear factor erythroid 2 associated factor 2 (Nrf2) transcription factor, and blocking the Nrf2 signaling pathway with ML385 abolished the inhibitory effect of MSCs on ferroptosis in vitro. Collectively, these results suggest that MSCs have therapeutic effects against SAP-ALI. The specific mechanism involves inhibition of ferroptosis by activating the Nrf2 transcription factor.
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Affiliation(s)
- Hongfang Yang
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Anesthesiology, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Yan Liu
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Anesthesiology Department, Dalian Medical University, Dalian, China
| | - Jiaqi Yao
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yin Wang
- Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xian, China
| | - Lihong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Penghui Ren
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Anesthesiology Department, Dalian Medical University, Dalian, China
| | - Buyue Bai
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Anesthesiology Department, Dalian Medical University, Dalian, China
| | - Qingping Wen
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Chen YL, Xiong LA, Ma LF, Fang L, Zhan ZJ. Natural product-derived ferroptosis mediators. PHYTOCHEMISTRY 2024; 219:114002. [PMID: 38286199 DOI: 10.1016/j.phytochem.2024.114002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 01/31/2024]
Abstract
It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.
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Affiliation(s)
- Yi-Li Chen
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Lin-An Xiong
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Lie-Feng Ma
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Luo Fang
- Department of Pharmacy, Zhejiang Cancer Hospital, PR China.
| | - Zha-Jun Zhan
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China.
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Cui Q, Liu HC, Liu WM, Ma F, Lv Y, Ma JC, Wu RQ, Ren YF. Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes. World J Gastroenterol 2024; 30:728-741. [PMID: 38515944 PMCID: PMC10950629 DOI: 10.3748/wjg.v30.i7.728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/18/2023] [Accepted: 01/15/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP via binding to αvβ3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy. AIM To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux. METHODS SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 μg/kg cerulein plus lipopolysaccharide. mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvβ3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8. RESULTS The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8's beneficial effects in SAP-induced liver injury. CONCLUSION MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVβ3/5.
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Affiliation(s)
- Qing Cui
- Department of Cardiology, Xi’an Central Hospital Affiliated to Xi’an Jiaotong University, Xi’an 710003, Shaanxi Province, China
| | - Hang-Cheng Liu
- Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Wu-Ming Liu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Feng Ma
- Department of Cardiology, Xi’an Central Hospital Affiliated to Xi’an Jiaotong University, Xi’an 710003, Shaanxi Province, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Jian-Cang Ma
- Department of Vascular Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Rong-Qian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi-Fan Ren
- Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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Cui M, Chen F, Shao L, Wei C, Zhang W, Sun W, Wang J. Mesenchymal stem cells and ferroptosis: Clinical opportunities and challenges. Heliyon 2024; 10:e25251. [PMID: 38356500 PMCID: PMC10864896 DOI: 10.1016/j.heliyon.2024.e25251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/16/2024] Open
Abstract
Objective This review discusses recent experimental and clinical findings related to ferroptosis, with a focus on the role of MSCs. Therapeutic efficacy and current applications of MSC-based ferroptosis therapies are also discussed. Background Ferroptosis is a type of programmed cell death that differs from apoptosis, necrosis, and autophagy; it involves iron metabolism and is related to the pathogenesis of many diseases, such as Parkinson's disease, cancers, and liver diseases. In recent years, the use of mesenchymal stem cells (MSCs) and MSC-derived exosomes has become a trend in cell-free therapies. MSCs are a heterogeneous cell population isolated from a diverse range of human tissues that exhibit immunomodulatory functions, regulate cell growth, and repair damaged tissues. In addition, accumulating evidence indicates that MSC-derived exosomes play an important role, mainly by carrying a variety of bioactive substances that affect recipient cells. The potential mechanism by which MSC-derived exosomes mediate the effects of MSCs on ferroptosis has been previously demonstrated. This review provides the first overview of the current knowledge on ferroptosis, MSCs, and MSC-derived exosomes and highlights the potential application of MSCs exosomes in the treatment of ferroptotic conditions. It summarizes their mechanisms of action and techniques for enhancing MSC functionality. Results obtained from a large number of experimental studies revealed that both local and systemic administration of MSCs effectively suppressed ferroptosis in injured hepatocytes, neurons, cardiomyocytes, and nucleus pulposus cells and promoted the survival and regeneration of injured organs. Methods We reviewed the role of ferroptosis in related tissues and organs, focusing on its characteristics in different diseases. Additionally, the effects of MSCs and MSC-derived exosomes on ferroptosis-related pathways in various organs were reviewed, and the mechanism of action was elucidated. MSCs were shown to improve the disease course by regulating ferroptosis.
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Affiliation(s)
- Mengling Cui
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, PR China
| | - Fukun Chen
- Department of Radiology, Kunming Medical University & the Third Affiliated Hospital, Kunming, Yunnan, 650101, PR China
| | - Lishi Shao
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, PR China
| | - Chanyan Wei
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, PR China
| | - Weihu Zhang
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, PR China
| | - Wenmei Sun
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, PR China
| | - Jiaping Wang
- Department of Radiology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, PR China
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Liang Y, Qiu S, Zou Y, Luo L. Targeting ferroptosis with natural products in liver injury: new insights from molecular mechanisms to targeted therapies. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155134. [PMID: 37863001 DOI: 10.1016/j.phymed.2023.155134] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 09/26/2023] [Accepted: 10/03/2023] [Indexed: 10/22/2023]
Abstract
BACKGROUND Ferroptosis is a brand-new type of controlled cell death that is distinguished by its reliance on iron and the production of lipid peroxidation. The role of ferroptosis in damaging liver disorders has attracted a lot of attention in recent years. One effective strategy to reduce liver damage is to target ferroptosis. PURPOSE The purpose of this review is to clarify the connection between ferroptosis and liver damage and to look into the potential contribution of natural products to the clinical management of liver damage and the discovery of novel medications. METHODS To study the methods by which natural products operate on ferroptosis to cure liver damage and their main signaling pathways, we searched databases from the time of initial publication to August 2023 in PubMed, EMBASE, Web of Science, Ovid, ScienceDirect, and China National Knowledge Infrastructure. The liver illness that each natural product treats is categorized and summarized. It's interesting to note that several natural compounds, such Artemether, Fucoidan sulfate, Curcumin, etc., have the benefit of having many targets and multiple pathways of action. RESULTS We saw that in human samples or animal models of liver injury, ferroptosis indicators were activated, lipid peroxidation levels were elevated, and iron inhibitors had the ability to reduce liver damage. Liver damage can be treated with natural products by regulating ferroptosis. This is mostly accomplished through the modulation of Nrf2-related pathways (e.g., Conclusions and Astaxanthin), biological enzymes like GPX4 and the SIRT family (e.g., Chrysophanol and Decursin), and transcription factors like P53 (e.g., Artemether and Zeaxanthin). CONCLUSIONS This review proposes a promising path for the therapeutic therapy of liver damage by providing a theoretical foundation for the management of ferroptosis utilizing natural ingredients.
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Affiliation(s)
- Yongyi Liang
- The First Clinical College, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Shaojun Qiu
- The First Clinical College, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Youwen Zou
- The First Clinical College, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Lianxiang Luo
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, Guangdong, China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, Guangdong, China.
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Zhu F, Li Z, Wu XF. Nickel-Catalyzed Aminofluoroalkylative Cyclization of Styrenes with Ethyl Fluoroacetate and Anilines toward Fluoro-γ-Lactams. Org Lett 2023; 25:8535-8539. [PMID: 37985463 DOI: 10.1021/acs.orglett.3c03589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
A novel method for the nickel-catalyzed multicomponent aminofluoroalkylation/cyclization of styrenes with ethyl fluoroacetate and anilines has been developed. This protocol provides general and efficient access to a diverse range of fluoro-γ-lactams from simple and readily available starting materials. Control experiments prove the involvement of radical intermediates and excluded the presence of 2-fluoro-N-phenylacetamide.
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Affiliation(s)
- Fengxiang Zhu
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Ziyan Li
- School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
| | - Xiao-Feng Wu
- Institution Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
- Leibniz-Institut für Katalyse e.V., Rostock 18059, Germany
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Tang J, Long G, Xiao D, Liu S, Xiao L, Zhou L, Tao Y. ATR-dependent ubiquitin-specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance. MedComm (Beijing) 2023; 4:e463. [PMID: 38124786 PMCID: PMC10732327 DOI: 10.1002/mco2.463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 12/02/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron-dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA-resistant HCC cells. High expression of USP20 in HCC was associated with poor prognosis. USP20 contributes OXA resistance and suppress ferroptosis in HCC. Pharmacological inhibition or knockdown of USP20 triggered ferroptosis and increased the sensitivity of HCC cells to OXA both in vitro and in vivo. Coimmunoprecipitation results revealed that the UCH domain of USP20 interacted with the N terminal of SLC7A11. USP20 stabilized SLC7A11 via removing K48-linked polyubiquitination of SLC7A11 protein at K30 and K37. Most importantly, DNA damage-induced ATR activation was required for Ser132 and Ser368 phosphorylation of USP20. USP20 phosphorylation at Ser132 and Ser368 enhanced its stability and thus conferred OXA and ferroptosis resistance of HCC cells. Our study reveals a previously undiscovered association between OXA and ferroptosis and provides new insight into mechanisms regarding how DNA damage therapies always lead to therapeutic resistance. Therefore, targeting USP20 may mitigate the development of drug resistance and promote ferroptosis of HCC in patients receiving chemotherapy.
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Affiliation(s)
- Jianing Tang
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Guo Long
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Desheng Xiao
- Department of PathologyXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Shuang Liu
- Department of OncologyInstitute of Medical SciencesNational Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Liang Xiao
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Ledu Zhou
- Department of Liver SurgeryXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Yongguang Tao
- Department of PathologyKey Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Xiangya HospitalCentral South UniversityHunanChina
- Cancer Research Institute and School of Basic MedicineNHC Key Laboratory of Carcinogenesis (Central South University)Central South UniversityChangshaHunanChina
- Department of Thoracic SurgeryHunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer and Hunan Key Laboratory of Tumor Models and Individualized MedicineSecond Xiangya HospitalCentral South UniversityChangshaHunanChina
- Hunan Key Laboratory of Cancer MetabolismHunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunanChina
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38
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Xiang Y, Zhou X, Zhou H, Li D, Zhong M, Hong X, Song D, Long Y, Zeng X, Chen Y, Zhou J, Liang D, Fu H. Limonin ameliorates cisplatin-induced acute liver injury by inhibiting 11β-hydroxysteroid dehydrogenase type 1. Biomed Pharmacother 2023; 168:115680. [PMID: 37832403 DOI: 10.1016/j.biopha.2023.115680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/28/2023] [Accepted: 10/07/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Acute liver injury (ALI) is a common side effect of cisplatin treatment in the clinic and can lead to liver failure if not treated promptly. Previous studies have revealed that Limonin, a critical bioactive substance in citrus fruits, can protect multiple organs from various medical conditions. However, whether Limonin could ameliorate cisplatin-induced ALI remains unclear. METHODS In vivo and in vitro models were induced by cisplatin in the present study. Non-targeted metabolomics was employed to analyze the metabolic changes in the liver after ALI. In addition, molecular docking was utilized to predict the potential targets of Limonin. RESULTS Limonin attenuated hepatic histopathological injury by reducing hepatocyte apoptosis, lipid peroxidation, and inflammation in cisplatin-challenged mice. Employing metabolomics, we revealed that Limonin mediated the balance of various disturbed metabolic pathways in the liver after cisplatin-induced ALI. Integrating public data mining, molecular docking studies, and in vitro experiments demonstrated that Limonin suppressed the expression and activity of its direct target, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in the liver, thus reducing the production of corticosterone (CORT), a key metabolite promoted hepatocyte apoptosis. CONCLUSIONS Limonin improves the liver metabolic microenvironment by inhibiting 11β-HSD1 to protect against cisplatin-induced ALI.
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Affiliation(s)
- Yadie Xiang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xianke Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hong Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dier Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Menghua Zhong
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue Hong
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dongyan Song
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yinyi Long
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xi Zeng
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yudan Chen
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayi Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dongning Liang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haiyan Fu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Shan X, Li J, Liu J, Feng B, Zhang T, Liu Q, Ma H, Wu H, Wu H. Targeting ferroptosis by poly(acrylic) acid coated Mn 3O 4 nanoparticles alleviates acute liver injury. Nat Commun 2023; 14:7598. [PMID: 37990003 PMCID: PMC10663555 DOI: 10.1038/s41467-023-43308-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 11/06/2023] [Indexed: 11/23/2023] Open
Abstract
Ferroptosis, a newly characterized form of regulated cell death, is induced by excessive accumulation of lipid peroxidation catalyzed by intracellular bioactive iron. Increasing evidence has suggested that ferroptosis is involved in the pathogenesis of several human diseases, including acute liver injury. Targeted inhibition of ferroptosis holds great promise for the clinical treatment of these diseases. Herein, we report a simple and one-pot synthesis of ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles (PAA@Mn3O4-NPs, PMO), which perform multiple antioxidant enzyme-mimicking activities and can scavenge broad-spectrum reactive oxygen species. PMO could potently suppress ferroptosis. Mechanistically, after being absorbed mainly through macropinocytosis, PMO are largely enriched in lysosomes, where PMO detoxify ROS, inhibit ferritinophagy-mediated iron mobilization and preserve mTOR activation, which collectively confer the prominent inhibition of ferroptosis. Additionally, PMO injection potently counteracts lipid peroxidation and alleviates acetaminophen- and ischaemia/reperfusion-induced acute liver injury in mice. Collectively, our results reveal that biocompatible PMO act as potent ferroptosis inhibitors through multifaceted mechanisms, which ensures that PMO have great translational potential for the clinical treatment of ferroptosis-related acute liver injury.
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Affiliation(s)
- Xinyi Shan
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Jiahuan Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Jiahao Liu
- Hubei Hongshan Laboratory, Wuhan, 430070, China
- MOA Key Laboratory of Crop Ecophysiology and Farming System in the Middle Reaches of the Yangtze River, College of Plant Science & Technology, Huazhong Agricultural University, Wuhan, 430070, China
- College of Agriculture, Tarim University, Alar, 843300, China
| | - Baoli Feng
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Ting Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Qian Liu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Huixin Ma
- Hubei Hongshan Laboratory, Wuhan, 430070, China
- MOA Key Laboratory of Crop Ecophysiology and Farming System in the Middle Reaches of the Yangtze River, College of Plant Science & Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Honghong Wu
- Hubei Hongshan Laboratory, Wuhan, 430070, China.
- MOA Key Laboratory of Crop Ecophysiology and Farming System in the Middle Reaches of the Yangtze River, College of Plant Science & Technology, Huazhong Agricultural University, Wuhan, 430070, China.
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan, 430070, China.
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, 518120, China.
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
- Hubei Hongshan Laboratory, Wuhan, 430070, China.
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40
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Tang J, Long G, Hu K, Xiao D, Liu S, Xiao L, Zhou L, Tao Y. Targeting USP8 Inhibits O-GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302953. [PMID: 37867237 PMCID: PMC10667802 DOI: 10.1002/advs.202302953] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 09/10/2023] [Indexed: 10/24/2023]
Abstract
Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB-IN-3 shows the most effective anti-cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB-IN-3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O-GlcNAc transferase (OGT) via inhibiting K48-specific poly-ubiquitination process on OGT protein at K117 site, and STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O-GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment.
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Affiliation(s)
- Jianing Tang
- Department of Liver SurgeryXiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410078China
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Guo Long
- Department of Liver SurgeryXiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410078China
| | - Kuan Hu
- Department of Liver SurgeryXiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410078China
| | - Desheng Xiao
- Department of PathologyXiangya HospitalCentral South UniversityChangshaHunan410078China
| | - Shuang Liu
- Department of OncologyInstitute of Medical SciencesNational Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunan410078China
| | - Liang Xiao
- Department of Liver SurgeryXiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410078China
| | - Ledu Zhou
- Department of Liver SurgeryXiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410078China
| | - Yongguang Tao
- Department of PathologyKey Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Xiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410078China
- NHC Key Laboratory of Carcinogenesis (Central South University)Cancer Research Institute and School of Basic MedicineCentral South University110 Xiangya RoadChangshaHunan410078China
- Department of Thoracic SurgeryHunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer and Hunan Key Laboratory of Tumor Models and Individualized MedicineSecond Xiangya HospitalCentral South University110 Xiangya RoadChangshaHunan410011China
- Hunan Key Laboratory of Cancer MetabolismHunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University110 Xiangya RoadChangshaHunan410078China
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Shi P, Zhu W, Fu J, Liang A, Zheng T, Wen Z, Wu X, Peng Y, Yuan S, Wu X. Avicularin alleviates acute liver failure by regulation of the TLR4/MyD88/NF-κB and Nrf2/HO-1/GPX4 pathways to reduce inflammation and ferroptosis. J Cell Mol Med 2023; 27:3326-3338. [PMID: 37644784 PMCID: PMC10623517 DOI: 10.1111/jcmm.17905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 05/04/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
Acute liver failure (ALF) is an inflammation-mediated hepatocyte death process associated with ferroptosis. Avicularin (AL), a Chinese herbal medicine, exerts anti-inflammatory and antioxidative effects. However, the protective effect of AL and the mechanism on ALF have not been reported. Our in vivo results suggest that AL significantly alleviated lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced hepatic pathological injury, liver enzymes, inflammatory cytokines, reactive oxygen species and iron levels and increased the antioxidant enzyme activities (malondialdehyde and glutathione). Our further in vitro experiments demonstrated that AL suppressed inflammatory response in LPS-stimulated RAW 264.7 cells via blocking the toll-like receptor 4 (TLR4)/myeloid differentiation protein-88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. Moreover, AL attenuated ferroptosis in D-GalN-induced HepG2 cells by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway. Therefore, AL can alleviate inflammatory response and ferroptosis in LPS/D-GalN-induced ALF, and its protective effects are associated with blocking TLR4/MyD88/NF-κB pathway and activating Nrf2/HO-1/GPX4 pathway. Moreover, AL is a promising therapeutic option for ALF and should be clinically explored.
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Affiliation(s)
- Pei Shi
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
- Medical Innovation CenterThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Wentao Zhu
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
- Medical Innovation CenterThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Jiwei Fu
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
- Medical Innovation CenterThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - An Liang
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
- Medical Innovation CenterThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Ting Zheng
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Zhilong Wen
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xincheng Wu
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yuchen Peng
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Songsong Yuan
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xiaoping Wu
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangChina
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Xu J, Zhao L, Zhang X, Ying K, Zhou R, Cai W, Wu X, Jiang H, Xu Q, Miao D, Zeng Y, Yu F. Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 262:115331. [PMID: 37556956 DOI: 10.1016/j.ecoenv.2023.115331] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/14/2023] [Accepted: 08/02/2023] [Indexed: 08/11/2023]
Abstract
Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress is a systemic response triggered by the accumulation of unfolded or misfolded proteins in the ER. Ferroptosis and ER stress have been proven to contribute to the progression of APAP-induced acute liver injury (ALI). It was reported that salidroside protects against APAP-induced ALI, but the potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) to induce an ALI model. Salidroside was i.p. injected at a dose of 100 mg/kg 2 h prior to APAP administration. Mice were sacrificed 12 h after APAP injection and the liver and serum of the mice were obtained for histological and biochemistry analysis. AML12 cells were used in in vitro assays. The results indicated that salidroside mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) to attenuate ferroptosis, and simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated ER stress, thus alleviating APAP-induced ALI. However, PERK activator CCT020312 and overexpression of ATF4 inhibited the protective function of salidroside on CHAC1-mediated ferroptosis. Besides this, activation of the AMPK/SIRT1 signaling pathway by salidroside was demonstrated to have a protective effect against APAP-induced ALI. Interestingly, selective inhibition of SIRT1 ameliorated the protective effects of salidroside on ER stress and ferroptosis. Overall, salidroside plays a significant part in the mitigation of APAP-induced ALI by activating the AMPK/SIRT1 signaling to inhibit ER stress-mediated ferroptosis in the ATF4-CHAC1 axis.
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Affiliation(s)
- Jun Xu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Luying Zhao
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangting Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Kanglei Ying
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruoru Zhou
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weimin Cai
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao Wu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haoran Jiang
- Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qian Xu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Dan Miao
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuan Zeng
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Fujun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Fuertes-Agudo M, Luque-Tévar M, Cucarella C, Martín-Sanz P, Casado M. Advances in Understanding the Role of NRF2 in Liver Pathophysiology and Its Relationship with Hepatic-Specific Cyclooxygenase-2 Expression. Antioxidants (Basel) 2023; 12:1491. [PMID: 37627486 PMCID: PMC10451723 DOI: 10.3390/antiox12081491] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
Oxidative stress and inflammation play an important role in the pathophysiological changes of liver diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes, thus playing a key role in protecting against oxidative damage. Cyclooxygenase-2 (COX-2) is a key enzyme in prostaglandin biosynthesis. Its expression has always been associated with the induction of inflammation, but we have shown that, in addition to possessing other benefits, the constitutive expression of COX-2 in hepatocytes is beneficial in reducing inflammation and oxidative stress in multiple liver diseases. In this review, we summarized the role of NRF2 as a main agent in the resolution of oxidative stress, the crucial role of NRF2 signaling pathways during the development of chronic liver diseases, and, finally we related its action to that of COX-2, where it appears to operate as its partner in providing a hepatoprotective effect.
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Affiliation(s)
- Marina Fuertes-Agudo
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - María Luque-Tévar
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Carme Cucarella
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Paloma Martín-Sanz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
- Instituto de Investigaciones Biomédicas (IIB) “Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Marta Casado
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
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Li J, Huang Q, Lv M, Ma W, Sun J, Zhong X, Hu R, Ma M, Han Z, Zhang W, Feng W, Sun X, Zhou X. Role of liensinine in sensitivity of activated macrophages to ferroptosis and in acute liver injury. Cell Death Discov 2023; 9:189. [PMID: 37353487 DOI: 10.1038/s41420-023-01481-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/14/2023] [Accepted: 06/12/2023] [Indexed: 06/25/2023] Open
Abstract
Acute liver injury (ALI) is an acute inflammatory liver disease with a high mortality rate. Alternatively, activated macrophages (AAMs) have been linked to the inflammation and recovery of ALI. However, the mechanism underlying AAM death in ALI has not been studied sufficiently. We used liensinine (Lie) as a drug of choice after screening a library of small-molecule monomers with 1488 compounds from traditional Chinese remedies. In ALI, we evaluated the potential therapeutic effects and underlying mechanisms of action of the drug in ALI and found that it effectively inhibited RSL3-induced ferroptosis in AAM. Lie significantly reduced lipid peroxidation in RSL3-generated AAM. It also improved the survival rate of LPS/D-GalN-treated mice, reduced serum transaminase activity, suppressed inflammatory factor production, and may have lowered AAM ferroptosis in ALI. Lie also inhibited ferritinophagy and blocked Fe2+ synthesis. Following combined treatment with RSL3 and Lie, super-resolution microscopy revealed a close correlation between ferritin and LC3-positive vesicles in the AAM. The co-localization of ferritin and LC3 with LAMP1 was significantly reduced. These findings suggest that Lie may ameliorate ALI by inhibiting ferritinophagy and enhancing AMM resistance to ferroptosis by inhibiting autophagosome-lysosome fusion. Therefore, Lie may be used as a potential therapeutic agent for patients with ALI.
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Affiliation(s)
- Jing Li
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
- Macau University of Science and Technology, Faculty of Chinese Medicine, Taipa, Macao, 999078, China
| | - Qi Huang
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Minling Lv
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Wenfeng Ma
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Jialing Sun
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Xin Zhong
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Rui Hu
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - MengQing Ma
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Zhiyi Han
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Wei Zhang
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Wenxing Feng
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Xinfeng Sun
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Xiaozhou Zhou
- Department of Liver Disease, The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518033, China.
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China.
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Lu Y, Hu J, Chen L, Li S, Yuan M, Tian X, Cao P, Qiu Z. Ferroptosis as an emerging therapeutic target in liver diseases. Front Pharmacol 2023; 14:1196287. [PMID: 37256232 PMCID: PMC10225528 DOI: 10.3389/fphar.2023.1196287] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/02/2023] [Indexed: 06/01/2023] Open
Abstract
Ferroptosis is an iron-dependently nonapoptotic cell death characterized by excessive accumulation of lipid peroxides and cellular iron metabolism disturbances. Impaired iron homeostasis and dysregulation of metabolic pathways are contributors to ferroptosis. As a major metabolic hub, the liver synthesizes and transports plasma proteins and endogenous fatty acids. Also, it acts as the primary location of iron storage for hepcidin generation and secretion. To date, although the intricate correlation between ferroptosis and liver disorders needs to be better defined, there is no doubt that ferroptosis participates in the pathogenesis of liver diseases. Accordingly, pharmacological induction and inhibition of ferroptosis show significant potential for the treatment of hepatic disorders involved in lipid peroxidation. In this review, we outline the prominent features, molecular mechanisms, and modulatory networks of ferroptosis and its physiopathologic functions in the progression of liver diseases. Further, this review summarizes the underlying mechanisms by which ferroptosis inducers and inhibitors ameliorate liver diseases. It is noteworthy that natural active ingredients show efficacy in preclinical liver disease models by regulating ferroptosis. Finally, we analyze crucial concepts and urgent issues concerning ferroptosis as a novel therapeutic target in the diagnosis and therapy of liver diseases.
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Affiliation(s)
- Yuzhen Lu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Junjie Hu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Liang Chen
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Shan Li
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
- Department of Biochemistry, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Ming Yuan
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Xianxiang Tian
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
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Huang T, Zhang K, Wang J, He K, Zhou X, Nie S. Quercetin Alleviates Acrylamide-Induced Liver Injury by Inhibiting Autophagy-Dependent Ferroptosis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:7427-7439. [PMID: 37134181 DOI: 10.1021/acs.jafc.3c01378] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Acrylamide (ACR) generated in carbohydrate-rich foods during thermal processing has been demonstrated to exhibit hepatotoxicity. As one of the most consumed flavonoids with diet, quercetin (QCT) possesses the ability to protect against ACR-induced toxicity, albeit its mechanism is unclear. Herein, we discovered that QCT alleviated ACR-induced elevated levels of reactive oxygen species (ROS), AST, and ALT in mice. RNA-seq analysis revealed that QCT reversed the ferroptosis signaling pathway upregulated by ACR. Subsequently, experiments indicated that QCT inhibited ACR-induced ferroptosis through the reduction of oxidative stress. With autophagy inhibitor chloroquine, we further confirmed that QCT suppressed ACR-induced ferroptosis by inhibiting oxidative stress-driven autophagy. Additionally, QCT specifically reacted with autophagic cargo receptor NCOA4, blocked the degradation of iron storage protein FTH1, and eventually downregulated the intracellular iron levels and the consequent ferroptosis. Collectively, our results presented a unique approach to alleviate ACR-induced liver injury by targeting ferroptosis with QCT.
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Affiliation(s)
- Tongwen Huang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China
| | - Ke Zhang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China
| | - Junqiao Wang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China
| | - Kaihong He
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China
| | - Xingtao Zhou
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China
| | - Shaoping Nie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China
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Li K, Wang M, Huang ZH, Wang M, Sun WY, Kurihara H, Huang RT, Wang R, Huang F, Liang L, Li YF, Duan WJ, He RR. ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis. Pharmacol Res 2023:106779. [PMID: 37121496 DOI: 10.1016/j.phrs.2023.106779] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/06/2023] [Accepted: 04/21/2023] [Indexed: 05/02/2023]
Abstract
Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.), which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKCα-phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons.
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Affiliation(s)
- Kun Li
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Meng Wang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Zi-Han Huang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Min Wang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Wan-Yang Sun
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Hiroshi Kurihara
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Rui-Ting Huang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Rong Wang
- School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Feng Huang
- School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Lei Liang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.
| | - Yi-Fang Li
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.
| | - Wen-Jun Duan
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research.
| | - Rong-Rong He
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China; School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China.
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Li J, Lu Q, Peng M, Liao J, Zhang B, Yang D, Huang P, Yang Y, Zhao Q, Han B, Li J. Water extract from Herpetospermum pedunculosum attenuates oxidative stress and ferroptosis induced by acetaminophen via regulating Nrf2 and NF-κB pathways. JOURNAL OF ETHNOPHARMACOLOGY 2023; 305:116069. [PMID: 36572326 DOI: 10.1016/j.jep.2022.116069] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/22/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The seeds of Herpetospermum pedunculosum seeds is a traditional Tibetan medicine possessing hepatoprotective effect, but their protective effect on APAP-induced liver injury has not yet been explored. AIM OF THE STUDY This study aimed at exploring the protective effect and mechanism of the water extract from the seeds of Herpetospermum pedunculosum (HPWE) on APAP-induced liver injury in vitro and in vivo. MATERIALS AND METHODS In vitro and in vivo models of liver injury were established by APAP treatment of BRL-3A cells or mice. The effect and mechanism of action of HPWE were explored by using cell viability assay, ELISA, immunofluorescence assay, RT-qPCR, histological observation and immunohistochemistry staining, western blotting and high-content imaging system. RESULTS In vitro experiments showed that HPWE treatment significantly promoted the cell viability, decreased ALT/AST level, and inhibited the ROS accumulation induced by APAP. Furthermore, HPWE and Fer-1 alleviated erastin-induced cell ferroptosis, upregulated GPX4 and SLC7A11 expression, and reduced lipid peroxides production. Further study showed that APAP could also downregulate the expression of GPX4 and SLC7A11, causing cell ferroptosis, and HPWE and Fer-1 counteracted this process. Our in vivo experiments showed that pretreatment with HPWE in APAP-treated mice significantly alleviated the serum ALT/AST level, decreased necrotic cells and inflammatory cell infiltration, upregulated the expression of GPX4 and SLC7A11. Further, it was demonstrated that HPWE treatment downregulated Nrf2 and its downstream target genes, i.e. HO-1 and NQO1 expression at the mRNA and protein levels. HPWE treatment also inhibited the activation of NF-κB p65 and downregulated its target genes, i.e. TNF-α and IL-1β, expression. CONCLUSION The present study showed that HPWE could relieve oxidative stress and ferroptosis via activating Nrf2 signaling pathway and inhibiting NF-κB mediated pathway.
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Affiliation(s)
- Jintao Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Qiuxia Lu
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Meihao Peng
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Jiaqing Liao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Bowen Zhang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Di Yang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Peng Huang
- Tibet Rhodiola Pharmaceutical Holding Company, Lhasa, Tibet, 850000, China
| | - Yixi Yang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Qi Zhao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Jian Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Basic Medical Sciences, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China.
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49
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An Y, Luo Q, Han D, Guan L. Abietic acid inhibits acetaminophen-induced liver injury by alleviating inflammation and ferroptosis through regulating Nrf2/HO-1 axis. Int Immunopharmacol 2023; 118:110029. [PMID: 36963265 DOI: 10.1016/j.intimp.2023.110029] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 03/26/2023]
Abstract
Abietic acid has been known to exhibit anti-inflammatory activity. This study was designed to investigate the protective effects of abietic acid on acetaminophen (APAP)-induced liver injury. The data demonstrated that abietic acid significantly ameliorated APAP-induced liver pathological changes, TNF-α and IL-1β production. APAP could increase malondialdehyde (MDA) and Fe2+ levels, and decrease ATP and glutathione (GSH) levels, as well as glutathione peroxidase 4 (GPX4) and xCT expression. However, these changes induced by APAP were prevented by abietic acid, indicating abietic acid could inhibit APAP-induced ferroptosis. Furthermore, abietic acid inhibited APAP-induced NF-κB activation and increased the expression of Nrf2 and HO-1. Additionally, the inhibitory effects of abietic acid on APAP-induced liver injury were prevented in Nrf2-/- mice. In vitro, the inhibition of abietic acid on APAP-induced inflammation and ferroptosis were reversed when Nrf2 was knockdown. In summary, abietic acidexhibited a therapeutic effectagainst liver injury by attenuating inflammation and ferroptosis.
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Affiliation(s)
- Yuan An
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Qiang Luo
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Donghai Han
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Lianyue Guan
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
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50
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Li H, Weng Q, Gong S, Zhang W, Wang J, Huang Y, Li Y, Guo J, Lan T. Kaempferol prevents acetaminophen-induced liver injury by suppressing hepatocyte ferroptosis via Nrf2 pathway activation. Food Funct 2023; 14:1884-1896. [PMID: 36723004 DOI: 10.1039/d2fo02716j] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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.
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Affiliation(s)
- Huiyi Li
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Qiqing Weng
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Shuai Gong
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Weixian Zhang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Jiaqi Wang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Yuqiao Huang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Yuanjun Li
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Jiao Guo
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Tian Lan
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
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