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Gao C, Wang L, Fu K, Cheng S, Wang S, Feng Z, Yu S, Yang Z. N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells. Inflammation 2025; 48:464-482. [PMID: 39037665 PMCID: PMC11807027 DOI: 10.1007/s10753-024-02068-5] [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: 04/17/2024] [Revised: 05/25/2024] [Accepted: 05/28/2024] [Indexed: 07/23/2024]
Abstract
Abstract-Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in neonates, and effective strategies to prevent and treat NEC are still lacking. Studies have shown that N-acetylcysteine (NAC) has protective effects against NEC, however, the specific mechanism underlying its effects on intestinal functions remains unclear. Recently, NAC has been shown to suppress ferroptosis in many diseases, while it is unclear whether the beneficial effects of NAC on NEC are related to ferroptosis. In this study, we revealed that ferroptosis was significantly induced in intestinal samples from infants with NEC. NAC alleviated intestinal inflammation, barrier damage and ferroptosis in multifactorial NEC models in vivo and in vitro. Sestrin2 (SESN2) was identified as an important mediator of NAC-induced ferroptosis resistance in intestinal epithelial cells. Furthermore, SESN2 knockdown inhibited the inflammatory response, alleviated barrier damage and ferroptosis in intestinal epithelial cells and enhanced the protective effects of NAC to a certain extent. Conversely, cells overexpressing SESN2 showed the opposite changes. In summary, our study demonstrated that NAC attenuates NEC progression by decreasing SESN2 expression to inhibit ferroptosis in intestinal epithelial cells, suggesting that NAC might be an effective clinical treatment for NEC.
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Affiliation(s)
- Chuchu Gao
- Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Suzhou, 215002, China
- Department of Neonatology, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Lixia Wang
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Kai Fu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Shan Cheng
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Sannan Wang
- Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Suzhou, 215002, China
| | - Zongtai Feng
- Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Suzhou, 215002, China.
| | - Shenglin Yu
- Department of Neonatology, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Zuming Yang
- Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Suzhou, 215002, China.
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:28-36. [DOI: 10.11569/wcjd.v33.i1.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/25/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:34-42. [DOI: 10.11569/wcjd.v33.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Li Q, Yin J, Lin Q, He J, Shi X, Nie H. Integrated Analysis and Validation of Ferroptosis-Related Genes Associated with Ischemia/Reperfusion Injury in Lung Transplantation. J Inflamm Res 2025; 18:251-270. [PMID: 39802518 PMCID: PMC11724631 DOI: 10.2147/jir.s489827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 12/21/2024] [Indexed: 01/16/2025] Open
Abstract
Background Lung transplantation is the only effective therapeutic option for patients with end-stage lung disease. However, ischemia/reperfusion injury (IRI) during transplantation is a leading cause of primary graft dysfunction (PGD). Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has been implicated in IRI across various organs. This study aims to explore the role of ferroptosis in lung transplantation-related ischemia/reperfusion injury and to identify its potential molecular mechanisms through bioinformatics analysis. Methods Transcriptome data from lung transplant patients were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FRGs) were identified by analyzing gene expression profiles before and after reperfusion. Weighted gene co-expression network analysis (WGCNA) was used to identify module genes, and overlapping genes were further analyzed using two machine learning algorithms. The CIBERSORT algorithm was applied to assess immune cell infiltration, while Mendelian randomization (MR) analysis was used to investigate causal relationships between candidate genes and PGD. Finally, Consensus clustering based on FRGs was performed to identify subtypes. Results We identified four candidate genes associated with ferroptosis during lung reperfusion: tumor necrosis factor alpha-induced protein 3 (TNFAIP3), C-X-C motif chemokine ligand 2 (CXCL2), neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), and sestrin 2 (SESN2). These genes were closely associated with immune cell infiltration. MR analysis suggested that SESN2 might play a protective role against PGD. Additionally, consensus clustering revealed distinct immune infiltration patterns across subtypes, providing insights for personalized therapeutic approaches to lung ischemia/reperfusion injury (LIRI). Conclusion This study highlights TNFAIP3, CXCL2, NEDD4L, and SESN2 as candidate genes associated with ferroptosis during LIRI, with SESN2 potentially protecting against PGD. These findings offer promising therapeutic targets for preventing LIRI and improving outcomes in lung transplantation.
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Affiliation(s)
- Qingqing Li
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Jing Yin
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Qibin Lin
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Jilong He
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Xiu Shi
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Hanxiang Nie
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
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Tan R, Ge C, Yan Y, Guo H, Han X, Zhu Q, Du Q. Deciphering ferroptosis in critical care: mechanisms, consequences, and therapeutic opportunities. Front Immunol 2024; 15:1511015. [PMID: 39737174 PMCID: PMC11682965 DOI: 10.3389/fimmu.2024.1511015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/03/2024] [Indexed: 01/01/2025] Open
Abstract
Ischemia-reperfusion injuries (IRI) across various organs and tissues, along with sepsis, significantly contribute to the progression of critical illnesses. These conditions disrupt the balance of inflammatory mediators and signaling pathways, resulting in impaired physiological functions in human tissues and organs. Ferroptosis, a distinct form of programmed cell death, plays a pivotal role in regulating tissue damage and modulating inflammatory responses, thereby influencing the onset and progression of severe illnesses. Recent studies highlight that pharmacological agents targeting ferroptosis-related proteins can effectively mitigate oxidative stress caused by IRI in multiple organs, alleviating associated symptoms. This manuscript delves into the mechanisms and signaling pathways underlying ferroptosis, its role in critical illnesses, and its therapeutic potential in mitigating disease progression. We aim to offer a novel perspective for advancing clinical treatments for critical illnesses.
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Affiliation(s)
- Ruimin Tan
- School of Clinical Medical, North China University of Science and Technology, Tangshan, Hebei, China
- Critical Care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Chen Ge
- Critical Care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yating Yan
- School of Clinical Medical, North China University of Science and Technology, Tangshan, Hebei, China
- Critical Care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - He Guo
- Critical Care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
- School of Graduate, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xumin Han
- Critical Care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
- School of Graduate, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Qiong Zhu
- Department of Orthopaedics, The People’s Hospital Of Shizhu, Chongqing, China
| | - Quansheng Du
- Critical Care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
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Guo Z, Zhuang H, Shi X. Therapeutic efficacy of ferroptosis in the treatment of colorectal cancer (Review). Oncol Lett 2024; 28:563. [PMID: 39390976 PMCID: PMC11465226 DOI: 10.3892/ol.2024.14697] [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: 07/01/2024] [Accepted: 09/12/2024] [Indexed: 10/12/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide, and the second leading cause of cancer-associated mortality. The incidence and mortality rates of CRC remain high, posing a significant threat to humans and overall quality of life. Current therapeutic strategies, such as surgery and chemotherapy, are limited due to disease recurrence, chemotherapeutic drug resistance and toxicity. Thus, research is focused on the development of novel treatment approaches. In 2012, ferroptosis was identified as a form of regulated cell death that is iron-dependent and driven by lipid peroxidation. Notably, therapies targeting ferroptosis exhibit potential in the treatment of disease; however, their role in CRC treatment remains controversial. The present study aimed to systematically review the mechanisms and signaling pathways of ferroptosis in CRC, and the specific role within the tumor microenvironment. Moreover, the present study aimed to review the role of ferroptosis in drug resistance, offering novel perspectives for the diagnosis and treatment of CRC.
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Affiliation(s)
- Zhao Guo
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250000, P.R. China
| | - Haoyan Zhuang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250000, P.R. China
| | - Xuewen Shi
- Department of Anorectal, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250000, P.R. China
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Liang LD, Peng HX, Huang MJ, Su LY, Huang JW, Lao JL, Huang ZH, Liu Y. HGF ameliorates cardiomyocyte apoptosis and inflammatory response in sepsis via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Gene 2024; 928:148763. [PMID: 39002784 DOI: 10.1016/j.gene.2024.148763] [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: 02/23/2024] [Revised: 07/01/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024]
Abstract
OBJECTIVE This study aimed to analyze the impact of HGF on cardiomyocyte injury, apoptosis, and inflammatory response induced by lipopolysaccharide (LPS). METHODS Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify the levels of HGF, interleukin (IL)-6, IL-10, creatine phosphokinase-isoenzyme-MB (CK-MB), and cardiac troponin I (cTnI) in the samples. qPCR and Western blotting (WB) were employed to assess the mRNA and protein expressions of HGF, IL-10, IL-6, PI3K, AKT, p-PI3K, and p-AKT. RESULTS The outcomes of the in vivo experiment revealed that serum levels of IL-6, IL-10, HGF and SOFA scores in the SC group were elevated in contrast to the non-SC group. The correlation analysis indicated a substantial and positive association among serum HGF, IL-6, and IL-10 levels and SOFA scores. Relative to IL-6, IL-10 levels, and SOFA scores, serum HGF demonstrated the highest diagnostic value for SC. Following LPS administration to stimulate H9c2 cells across various periods (0, 12, 24, 48, and 72 h), the levels of myocardial injury markers (CK-MB and cTnI) in the cell supernatants, intracellular inflammatory factors (mRNA and protein levels of IL-10 and IL-6), apoptosis and ROS levels, exhibited a gradual increase followed by a subsequent decline. Following the overexpression of HGF, there was an increase in cell viability, and a decrease in apoptosis, inflammation, oxidative stress injuries, and the protein phosphorylation expressions of PI3K and AKT. After knockdown of HGF expression, the activity of LPS-induced H9c2 cells was further reduced, leading to increased cell injury, apoptosis, inflammation, oxidative stress,and the expression levels of PI3K and Akt protein phosphorylation were further elevated. CONCLUSION HGF was associated with decreased LPS-induced H9c2 apoptosis and inflammation in H9c2 cells, alongside an improvement in cell viability, indicating potential cytoprotective effects. The mechanism underlying these impacts may be ascribed to the suppression of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Liu-Dan Liang
- The First Clinical Medical College of Jinan University, Guangzhou 510000, China; Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Laboratory of the Atherosclerosis and Ischemic Cardiovasculaar Diseases, Baise 533000, Guangxi, China; Department of Infectious Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Hui-Xin Peng
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Mei-Jin Huang
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Laboratory of the Atherosclerosis and Ischemic Cardiovasculaar Diseases, Baise 533000, Guangxi, China; Department of Infectious Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Li-Ye Su
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Jia-Wei Huang
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Jian-le Lao
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Zhao-He Huang
- The First Clinical Medical College of Jinan University, Guangzhou 510000, China; Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Laboratory of the Atherosclerosis and Ischemic Cardiovasculaar Diseases, Baise 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China.
| | - Yan Liu
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China; Laboratory of the Atherosclerosis and Ischemic Cardiovasculaar Diseases, Baise 533000, Guangxi, China; Department of Cardiology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China.
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Liao C, He Y, Luo X, Deng G. Ferroptosis: insight into the treatment of hepatocellular carcinoma. Cancer Cell Int 2024; 24:376. [PMID: 39538215 PMCID: PMC11562710 DOI: 10.1186/s12935-024-03559-z] [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: 03/27/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignances in the world, with high morbidity and mortality. Due to the hidden onset of symptoms, there are huge obstacles in early diagnosis, recurrence, metastasis and drug resistance. Although great strides have been made in the treatment of HCC, effective treatment options are still limited and achieving longer survival for patients remains urgent. Ferroptosis is a novel type of programmed cell death that is mainly caused by iron-dependent oxidative damage. With further investigations, ferroptosis has been proved to be associated with the occurrence and development of various tumors. This article reviews the regulatory mechanism and signal transduction pathways of ferroptosis, investigates the complex relationship between autophagy, sorafenib resistance and immunotherapy with ferroptosis involved in HCC, providing new ideas and directions for the treatment of HCC.
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Affiliation(s)
- Chuanjie Liao
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, China
| | - Youwu He
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, China
| | - Xinning Luo
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, China
| | - Ganlu Deng
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, China.
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Liao C, Guo J, Li S, Rui J, Gao K, Lao J, Zhou Y. Ferroptosis Regulated by 5-HT3a Receptor via Calcium/Calmodulin Signaling Contributes to Neuropathic Pain in Brachial Plexus Avulsion Rat Models. ACS Chem Neurosci 2024. [PMID: 39370752 DOI: 10.1021/acschemneuro.4c00499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024] Open
Abstract
Neuropathic pain is a prevalent complication following brachial plexus avulsion (BPA). Ferroptosis has been implicated in various nervous system disorders. However, the association between ferroptosis and neuropathic pain induced by BPA remains unclear. This study aimed to investigate the role of ferroptosis in BPA-induced neuropathic pain. A rat model of neuropathic pain was established via BPA induction. Pain thresholds of rats were measured after BPA surgery and intraperitoneal injection of Fer-1. On day 14 postsurgery, spinal dorsal horn (SDH) samples were collected for Western blotting, biochemical analysis, and immunohistochemistry to analyze the expression and distribution of ferroptosis-related markers. The relationships among 5-HT3a receptor, calcium/calmodulin (CaM) pathway, and ferroptosis were assessed via Western blotting, biochemical analysis, and lipid peroxidation assays, including iron and calcium content, reactive oxygen species, glutathione peroxidase 4 (GPX4), ACSL, and CaM expression. BPA-induced neuropathic pain was associated with iron accumulation, increased lipid peroxidation, dysregulated expression of Acyl-CoA synthetase long-chain family member 4, and GPX4, and changes in transferrin receptor, divalent metal transporter 1, and ferroportin-1 (FPN1). Intraperitoneal administration of Fer-1 reversed all of these alterations and mitigated mechanical and cold hypersensitivity. Inhibition of the 5-HT3a receptor reduced the extent of ferroptosis. Furthermore, the 5-HT3a receptor can regulate the calcium/CaM pathway via L-type calcium channels (LTCCs), and blocking LTCCs with nifedipine also alleviated ferroptosis in the SDH of BPA rats. Taken together, in rats with BPA, the development of neuropathic pain involves ferroptosis, which is regulated by the 5-HT3a receptor through the LTCCs and the calcium/CaM signaling pathway in the SDH.
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Affiliation(s)
- Chengpeng Liao
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
| | - Jinding Guo
- NHC Key Laboratory of Limbs Reconstruction, Shanghai 200032, People's Republic of China
| | - Shenqian Li
- NHC Key Laboratory of Limbs Reconstruction, Shanghai 200032, People's Republic of China
- Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai 200032, People's Republic of China
- Institute of Hand Surgery, Shanghai 200040, People's Republic of China
| | - Jing Rui
- NHC Key Laboratory of Limbs Reconstruction, Shanghai 200032, People's Republic of China
- Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai 200032, People's Republic of China
- Institute of Hand Surgery, Shanghai 200040, People's Republic of China
- Institute of Hand Surgery, Fudan University, Shanghai 200040, People's Republic of China
| | - Kaiming Gao
- Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai 200032, People's Republic of China
- Institute of Hand Surgery, Fudan University, Shanghai 200040, People's Republic of China
| | - Jie Lao
- Institute of Hand Surgery, Shanghai 200040, People's Republic of China
- Institute of Hand Surgery, Fudan University, Shanghai 200040, People's Republic of China
| | - Yingjie Zhou
- Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People's Republic of China
- NHC Key Laboratory of Limbs Reconstruction, Shanghai 200032, People's Republic of China
- Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai 200032, People's Republic of China
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Yao H, Jiang W, Liao X, Wang D, Zhu H. Regulatory mechanisms of amino acids in ferroptosis. Life Sci 2024; 351:122803. [PMID: 38857653 DOI: 10.1016/j.lfs.2024.122803] [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: 03/12/2024] [Revised: 05/19/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Ferroptosis, an iron-dependent non-apoptotic regulated cell death process, is associated with the pathogenesis of various diseases. Amino acids, which are indispensable substrates of vital activities, significantly regulate ferroptosis. Amino acid metabolism is involved in maintaining iron and lipid homeostasis and redox balance. The regulatory effects of amino acids on ferroptosis are complex. An amino acid may exert contrasting effects on ferroptosis depending on the context. This review systematically and comprehensively summarized the distinct roles of amino acids in regulating ferroptosis and highlighted the emerging opportunities to develop clinical therapeutic strategies targeting amino acid-mediated ferroptosis.
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Affiliation(s)
- Heying Yao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Wei Jiang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Xiang Liao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China
| | - Dongqing Wang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
| | - Haitao Zhu
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
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Ma HD, Shi L, Li HT, Wang XD, Yang MW. Polycytosine RNA-binding protein 1 regulates osteoblast function via a ferroptosis pathway in type 2 diabetic osteoporosis. World J Diabetes 2024; 15:977-987. [PMID: 38766437 PMCID: PMC11099367 DOI: 10.4239/wjd.v15.i5.977] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/22/2024] [Accepted: 03/15/2024] [Indexed: 05/10/2024] Open
Abstract
BACKGROUND Recently, type 2 diabetic osteoporosis (T2DOP) has become a research hotspot for the complications of diabetes, but the specific mechanism of its occurrence and development remains unknown. Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP. Polycytosine RNA-binding protein 1 (PCBP1), an iron ion chaperone, is considered a protector of ferroptosis. AIM To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes. METHODS A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose (HG) and/or ferroptosis inhibitors at different concentrations and times. Transmission electron microscopy was used to examine the morphological changes in the mitochondria of osteoblasts under HG, and western blotting was used to detect the expression levels of PCBP1, ferritin, and the ferroptosis-related protein glutathione peroxidase 4 (GPX4). A lentivirus silenced and overexpressed PCBP1. Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin (OPG) and osteocalcin (OCN), whereas flow cytometry was used to detect changes in reactive oxygen species (ROS) levels in each group. RESULTS Under HG, the viability of osteoblasts was considerably decreased, the number of mitochondria undergoing atrophy was considerably increased, PCBP1 and ferritin expression levels were increased, and GPX4 expression was decreased. Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1, increased the expression levels of ferritin, GPX4, OPG, and OCN, compared with the HG group. Flow cytometry results showed a reduction in ROS, and an opposite result was obtained after silencing PCBP1. CONCLUSION PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment. Moreover, PCBP1 may be a potential therapeutic target for T2DOP.
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Affiliation(s)
- Hong-Dong Ma
- Department of Orthopedics, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Lei Shi
- Department of Orthopedics, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Hai-Tian Li
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xin-Dong Wang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Mao-Wei Yang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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12
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Xu Y, Xing Z, Abdalla Ibrahim Suliman R, Liu Z, Tang F. Ferroptosis in liver cancer: a key role of post-translational modifications. Front Immunol 2024; 15:1375589. [PMID: 38650929 PMCID: PMC11033738 DOI: 10.3389/fimmu.2024.1375589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/26/2024] [Indexed: 04/25/2024] Open
Abstract
Ferroptosis is an emerging form of regulated cell death in an oxidative stress- and iron-dependent manner, primarily induced by the over-production of reactive oxygen species (ROS). Manipulation of ferroptosis has been considered a promising therapeutic approach to inhibit liver tumor growth. Nevertheless, the development of resistance to ferroptosis in liver cancer poses a significant challenge in cancer treatment. Post-translational modifications (PTMs) are crucial enzymatic catalytic reactions that covalently regulate protein conformation, stability and cellular activities. Additionally, PTMs play pivotal roles in various biological processes and divergent programmed cell death, including ferroptosis. Importantly, key PTMs regulators involved in ferroptosis have been identified as potential targets for cancer therapy. PTMs function of two proteins, SLC7A11, GPX4 involved in ferroptosis resistance have been extensively investigated in recent years. This review will summarize the roles of PTMs in ferroptosis-related proteins in hepatocellular carcinoma (HCC) treatment.
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Affiliation(s)
- Ying Xu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Zhiyao Xing
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | | | - Zichuan Liu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China
| | - Fengyuan Tang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- Thinking Biomed (Beijing) Co., Ltd, Beijing Economic and Technological Development Zone, Beijing, China
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13
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Xi X, Chen Q, Ma J, Wang X, Zhang J, Li Y. Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis. J Mol Histol 2024; 55:169-184. [PMID: 38165565 PMCID: PMC10991044 DOI: 10.1007/s10735-023-10180-3] [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] [Received: 05/23/2023] [Accepted: 12/18/2023] [Indexed: 01/04/2024]
Abstract
Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. The aim of this study was to explore the effect of Sestrin2 on DR through the regulation of autophagy and ferroptosis levels and its mechanism. In vitro and in vivo DR models were established by high glucose (HG) and streptozotocin (STZ) induction of ARPE-19 human retinal pigment epithelial cells and C57BL/6 mice, respectively. In this study, we demonstrated that after HG treatment, the activity of ARPE-19 cells was decreased, the apoptosis rate was increased, endoplasmic reticulum (ER) stress was activated, autophagy levels were decreased, and ferroptosis levels were increased. Overexpression of Sestrin2 enhanced cell viability, reduced apoptosis and ferroptosis, and enhanced autophagy. However, the effect of overexpression of Sestrin2 was attenuated after the addition of the STAT3 phosphorylation activator Colivelin TFA (C-TFA), the mTOR pathway activator MHY1485 or the autophagy inhibitor 3-methyladenine (3-MA). In addition, the effect of Sestrin2 knockdown on cells was opposite to the effect of overexpression of Sestrin2, while the effect of Sestrin2 knockdown was attenuated after treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Animal experiments also confirmed the results of cell experiments and attenuated the effects of overexpression of Sestrin2 after injection of the ferroptosis activators erastin or 3-MA. Our study revealed that Sestrin2 inhibits ferroptosis by inhibiting STAT3 phosphorylation and ER stress and promoting autophagy levels, thereby alleviating DR.
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Affiliation(s)
- Xiaoting Xi
- Ophthalmology Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Qianbo Chen
- Ophthalmology Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Jia Ma
- Ophthalmology Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Xuewei Wang
- Ophthalmology Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Junyan Zhang
- Department of Clinical Epidemiology and Evidence-based Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, Shanxi, 030000, China
| | - Yan Li
- Ophthalmology Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China.
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14
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Figueredo KC, Guex CG, Graiczik J, Reginato FZ, Engelmann AM, Andrade CMD, Timmers LFSM, Bauermann LDF. Caffeic acid and ferulic acid can improve toxicological damage caused by iron overload mediated by carbonic anhydrase inhibition. Drug Chem Toxicol 2024; 47:147-155. [PMID: 36444844 DOI: 10.1080/01480545.2022.2152043] [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: 08/22/2022] [Revised: 11/04/2022] [Accepted: 11/06/2022] [Indexed: 11/30/2022]
Abstract
The iron ion is an essential element for most forms of life, however, it can damage biological systems when found in free form. Chelation therapy is very important, but it is precarious. Caffeic and ferulic acid are antioxidant compounds with many properties described in research such as anti-inflammatory, antiobesogenic, antithrombotic, vasodilator, and anti-tumor. The aim of the study was to evaluate presenting an in silico approach on the toxicity and bioavailability of caffeic and ferulic acid, subsequently, evaluating them in an iron overload model in vivo and providing a pharmacophoric model through molecular docking. The predictive in silico test did not show relevant toxicity of the compounds, therefore, the in vivo test was performed. The rats received dextran iron and the test groups received caffeic and ferulic acid orally for six weeks. Biochemical, hematological parameters, and tissue oxidative stress marker were analyzed. The experimental model showed increased serum iron levels and changes in several serum parameters such as glucose (215.8 ± 20.3 mg/dL), ALT (512.2 ± 128.7 U/L), creatine kinase (186.8 ± 30.1 U/L), and creatine kinase isoform MB (373.3 ± 69.7 U/L). Caffeic acid and, to a lessed degree, ferullic acid, attenuated the effects of iron overload on the rat serum biochemical parameters. Docking showed a pharmacophoric model where carbonic anhydrase interacted with the test molecules and caffeic acid showed less energy expenditure in this interaction. The results illustrate a new therapeutic action of phenolic compounds on iron overload. The possible interference of carbonic anhydrase in iron metabolism needs to be elucidated.
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Affiliation(s)
| | - Camille Gaube Guex
- Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
| | - James Graiczik
- Graduate Program in Pharmacy, University of Federal University of Santa Maria, Santa Maria, Brazil
| | | | | | | | | | - Liliane De Freitas Bauermann
- Graduate Program in Pharmaceutical Sciences, Federal University of Santa Maria, Santa Maria, Brazil
- Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil
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15
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Li SY, Zhao N, Wei D, Pu N, Hao XN, Huang JM, Peng GH, Tao Y. Ferroptosis in the ageing retina: A malevolent fire of diabetic retinopathy. Ageing Res Rev 2024; 93:102142. [PMID: 38030091 DOI: 10.1016/j.arr.2023.102142] [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: 09/02/2023] [Revised: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 12/01/2023]
Abstract
Ageing retina is prone to ferroptosis due to the iron accumulation and impaired efficiency of intracellular antioxidant defense system. Ferroptosis acts as a cell death modality that is characterized by the iron-dependent accumulation of lipid peroxidation. Ferroptosis is distinctively different from other types of regulated cell death (RCD) at the morphological, biochemical, and genetic levels. Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Its prevalence and severity increase progressively with age. Recent reports have shown that ferroptosis is implicated in the pathophysiology of DR. Under hyperglycemia condition, the endothelial cell and retinal pigment epithelium (RPE) cell will undergo ferroptosis, which contributes to the increased vascular permeability and the disrupted blood retinal barrier (BRB). The underlying etiology of DR can be attributed to the impaired BRB integrity and subsequent damages of the neurovascular units. In the absence of timely intervention, the compromised BRB can ultimately cause profound visual impairments. In particular, the ageing retina is vulnerable to ferroptosis, and hyperglycemia will accelerate the progression of this pathological process. In this article, we discuss the contributory role of ferroptosis in DR pathogenesis, and summarize recent therapeutic trials that targeting the ferroptosis. Further study on the ferroptosis mediated damage would enrich our knowledge of DR pathology, and promote the development of clinical treatment for this degenerative retinopathy.
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Affiliation(s)
- Si-Yu Li
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Na Zhao
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Dong Wei
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Ning Pu
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Xiao-Na Hao
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Jie-Min Huang
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Guang-Hua Peng
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
| | - Ye Tao
- Department of Physiology and Neurobiology, Laboratory of Visual Cell Differentiation and Regulation. School of Basic Medical Sciences, College of medicine, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
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16
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Li T, Yang Q, Liu Y, Jin Y, Song B, sun Q, Wei S, Wu J, Li X. Machine Learning Identify Ferroptosis-Related Genes as Potential Diagnostic Biomarkers for Gastric Intestinal Metaplasia. Technol Cancer Res Treat 2024; 23:15330338241272036. [PMID: 39169865 PMCID: PMC11342439 DOI: 10.1177/15330338241272036] [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: 04/22/2024] [Revised: 05/02/2024] [Accepted: 05/28/2028] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Gastric intestinal metaplasia(GIM) is an independent risk factor for GC, however, its pathogenesis is still unclear. Ferroptosis is a new type of programmed cell death, which may be involved in the process of GIM. The purpose of this study was to analyze the expression of ferroptosis-related genes (FRGs) in GIM tissues and to explore the relationship between ferroptosis and GIM. METHOD The results of GIM tissue full transcriptome sequencing were downloaded from Gene Expression Omnibus(GEO) database. R software (V4.2.0) and R packages were used for screening and enrichment analysis of differentially expressed genes(DEGs). The key genes were screened by least absolute shrinkage and selection operator(LASSO) and support vector machine-recursive feature elimination(SVM-RFE) algorithm. Receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficacy of key genes in GIM. Clinical samples were used to further validate hub genes. RESULTS A total of 12 differentially expressed ferroptosis-related genes (DEFRGs) were identified. Using two machine learning algorithms, GOT1, ALDH3A2, ACSF2 and SESN2 were identified as key genes. The area under ROC curve (AUC) of GOT1, ALDH3A2, ACSF2 and SESN2 in the training set were 0.906, 0.955, 0.899 and 0.962 respectively, and the AUC in the verification set were 0.776, 0.676, 0.773 and 0.880, respectively. Clinical samples verified the differential expression of GOT1, ACSF2, and SESN2 in GIM. CONCLUSION We found that there was a significant correlation between ferroptosis and GIM. GOT1, ACSF2 and SESN2 can be used as diagnostic markers to effectively identify GIM.
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Affiliation(s)
- Tingting Li
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Qi Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yun Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yueping Jin
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Biao Song
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Qin sun
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Siyuan Wei
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Jing Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Xuejun Li
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
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17
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Wang Z, Zhou C, Zhang Y, Tian X, Wang H, Wu J, Jiang S. From synergy to resistance: Navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma. Biomed Pharmacother 2024; 170:116074. [PMID: 38147732 DOI: 10.1016/j.biopha.2023.116074] [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: 11/04/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.
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Affiliation(s)
- Zijian Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunyang Zhou
- Department of Radiation Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Yiming Zhang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Haochen Wang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Jibiao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
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Dai G, Li M, Xu H, Quan N. Status of Research on Sestrin2 and Prospects for its Application in Therapeutic Strategies Targeting Myocardial Aging. Curr Probl Cardiol 2023; 48:101910. [PMID: 37422038 DOI: 10.1016/j.cpcardiol.2023.101910] [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: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/10/2023]
Abstract
Cardiac aging is accompanied by changes in the heart at the cellular and molecular levels, leading to alterations in cardiac structure and function. Given today's increasingly aging population, the decline in cardiac function caused by cardiac aging has a significant impact on quality of life. Antiaging therapies to slow the aging process and attenuate changes in cardiac structure and function have become an important research topic. Treatment with drugs, including metformin, spermidine, rapamycin, resveratrol, astaxanthin, Huolisu oral liquid, and sulforaphane, has been demonstrated be effective in delaying cardiac aging by stimulating autophagy, delaying ventricular remodeling, and reducing oxidative stress and the inflammatory response. Furthermore, caloric restriction has been shown to play an important role in delaying aging of the heart. Many studies in cardiac aging and cardiac aging-related models have demonstrated that Sestrin2 has antioxidant and anti-inflammatory effects, stimulates autophagy, delays aging, regulates mitochondrial function, and inhibits myocardial remodeling by regulation of relevant signaling pathways. Therefore, Sestrin2 is likely to become an important target for antimyocardial aging therapy.
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Affiliation(s)
- Gaoying Dai
- Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun, China
| | - Meina Li
- Department of Infection Control, The First Hospital of Jilin University, Changchun, China
| | - He Xu
- Department of Integrative Medicine, Lequn Branch, The First Hospital of Jilin University, Changchun, China
| | - Nanhu Quan
- Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun, China.
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Wang Y, Wang T, Xiang Q, Li N, Wang J, Liu J, Zhang Y, Yang T, Bian J. GPR116 promotes ferroptosis in sepsis-induced liver injury by suppressing system Xc -/GSH/GPX4. Cell Biol Toxicol 2023; 39:3015-3030. [PMID: 37266730 DOI: 10.1007/s10565-023-09815-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
The disease sepsis is caused by an infection that damages organs. Liver injury, with ferroptosis playing a key role, is an early sign of sepsis. G protein-coupled receptor 116 (GPR116) is essential in the maintenance of functional homeostasis in various systems of the body and has been proven to play a protective role in septic lung injury. However, it's role in septic liver injury remains unclear. In this study, we found that hepatic ferroptosis during sepsis was accompanied by GPR116 upregulation. Hepatocyte-specific GPR116 gene deletion can prevent hepatic ferroptosis, thereby alleviating sepsis-induced liver dysfunction and improving mouse survival, which was verified in vivo. Mechanistically, GPR116 aggravated mitochondrial damage and lipid peroxidation in hepatocytes by inhibiting system Xc-/GSH/GPX4 in overexpression experiments. In conclusion, we have identified GPR116 as a vital mediator of ferroptosis in sepsis-induced liver injury. It is thus an attractive therapeutic target in sepsis.
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Affiliation(s)
- Ying Wang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Ting Wang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Qian Xiang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Na Li
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jun Wang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jiahao Liu
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yan Zhang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Tao Yang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jinjun Bian
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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Yang Y, Lin X. Potential relationship between autophagy and ferroptosis in myocardial ischemia/reperfusion injury. Genes Dis 2023; 10:2285-2295. [PMID: 37554184 PMCID: PMC10404879 DOI: 10.1016/j.gendis.2022.02.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/19/2022] [Accepted: 02/08/2022] [Indexed: 11/19/2022] Open
Abstract
Autophagy is an evolutionarily conserved process involved in the degradation of long-lived proteins and excessive or dysfunctional organelles. As a pivotal cellular response, autophagy has been extensively studied and is known to be involved in various diseases. Ferroptosis is a recently discovered form of regulated cell death characterized by iron overload, leading to the accumulation of lethal levels of lipid hydroperoxides. Recently, an increasing number of studies have revealed a link between autophagy and ferroptosis. Myocardial ischemia/reperfusion injury (MIRI) is an urgent dilemma after myocardial infarction recanalization, which is regulated by several cell death pathways, including autophagy and ferroptosis. However, the potential relationship between autophagy and ferroptosis in MIRI remains unexplored. In this study, we briefly review the mechanisms of autophagy and ferroptosis, including their roles in MIRI. Moreover, we provide an overview of the potential crosstalk in MIRI. Clarifying the relationship between different cell death pathways may provide new ideas for the treatment of MIRI in the future.
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Affiliation(s)
- Yu Yang
- Cardiology Department, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
- Anhui Medical University, Hefei, Anhui 230032, China
| | - Xianhe Lin
- Cardiology Department, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
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Li Q, Chen K, Zhang T, Jiang D, Chen L, Jiang J, Zhang C, Li S. Understanding sorafenib-induced ferroptosis and resistance mechanisms: Implications for cancer therapy. Eur J Pharmacol 2023; 955:175913. [PMID: 37460053 DOI: 10.1016/j.ejphar.2023.175913] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/20/2023] [Accepted: 07/13/2023] [Indexed: 07/22/2023]
Abstract
Sorafenib is an important first-line treatment option for liver cancer due to its well-characterized safety profile. While novel first-line drugs may have better efficacy than Sorafenib, they also have limitations such as worse safety and cost-effectiveness. In addition to inducing apoptosis, Sorafenib can also trigger ferroptosis, which has recently been recognized as an immunogenic cell death, unleashing new possibilities for cancer treatment. However, resistance to Sorafenib-induced ferroptosis remains a major challenge. To overcome this resistance and augment the efficacy of Sorafenib, a wide range of nanomedicines has been developed to amplify its pro-ferroptotic effects. This review highlights the mechanisms underlying Sorafenib-triggered ferroptosis and its resistance, and outlines innovative strategies, particularly nanomedicines, to overcome ferroptosis resistance. Moreover, we summarize molecular biomarkers that signify resistance to Sorafenib-mediated ferroptosis, which can assist in predicting therapeutic outcomes.
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Affiliation(s)
- Qiuhong Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Kexin Chen
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Tianyi Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Donghui Jiang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Ligang Chen
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
| | - Chunxiang Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China; Nucleic Acid Medicine of Luzhou Key Laboratory, Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Shengbiao Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China; Nucleic Acid Medicine of Luzhou Key Laboratory, Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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22
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El-Horany HES, Atef MM, Abdel Ghafar MT, Fouda MH, Nasef NA, Hegab II, Helal DS, Elseady W, Hafez YM, Hagag RY, Seleem MA, Saleh MM, Radwan DA, Abd El-Lateef AE, Abd-Ellatif RN. Empagliflozin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by Modulating Sesn2/AMPK/Nrf2 Signaling and Targeting Ferroptosis and Autophagy. Int J Mol Sci 2023; 24:ijms24119481. [PMID: 37298433 DOI: 10.3390/ijms24119481] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/19/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate the ameliorative effect of EMPA against bleomycin (BLM)-induced PF and the potential mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA treated, and EMPA+BLM treated. EMPA significantly improved the histopathological injuries illustrated by both hematoxylin and eosin and Masson's trichrome-stained lung tissue sections, as confirmed by electron microscopic examination. It significantly reduced the lung index, hydroxyproline content, and transforming growth factor β1 levels in the BLM rat model. It had an anti-inflammatory effect, as evidenced by a decrease in the inflammatory cytokines' tumor necrosis factor alpha and high mobility group box 1, inflammatory cell infiltration into the bronchoalveolar lavage fluid, and the CD68 immunoreaction. Furthermore, EMPA mitigated oxidative stress, DNA fragmentation, ferroptosis, and endoplasmic reticulum stress, as evidenced by the up-regulation of nuclear factor erythroid 2-related factor expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, and a decrease in C/EBP homologous protein levels. This protective potential could be explained on the basis of autophagy induction via up-regulating lung sestrin2 expression and the LC3 II immunoreaction observed in this study. Our findings indicated that EMPA protected against BLM-induced PF-associated cellular stress by enhancing autophagy and modulating sestrin2/adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling.
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Affiliation(s)
- Hemat El-Sayed El-Horany
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
- Department of Biochemistry, College of Medicine, Ha'il University, Hail 81411, Saudi Arabia
| | - Marwa Mohamed Atef
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | | | - Mohamed H Fouda
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | - Nahla Anas Nasef
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | - Islam Ibrahim Hegab
- Physiology Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
- Department of Bio-Physiology, Ibn Sina National College for Medical Studies, Jeddah 22421, Saudi Arabia
| | - Duaa S Helal
- Pathology Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | - Walaa Elseady
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | - Yasser Mostafa Hafez
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | - Rasha Youssef Hagag
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | | | - Mai Mahmoud Saleh
- Chest Diseases Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | - Doaa A Radwan
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
| | | | - Rania Nagi Abd-Ellatif
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt
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23
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Wang K, Shen K, Han F, Bai X, Fang Z, Jia Y, Zhang J, Li Y, Cai W, Wang X, Luo L, Guo K, Wang H, Yang X, Wang H, Hu D. Activation of Sestrin2 accelerates deep second-degree burn wound healing through PI3K/AKT pathway. Arch Biochem Biophys 2023; 743:109645. [PMID: 37225009 DOI: 10.1016/j.abb.2023.109645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/07/2023] [Accepted: 05/21/2023] [Indexed: 05/26/2023]
Abstract
Deep second-degree burns heal slowly, and promoting the healing process is a focus of clinical research. Sestrin2 is a stress-inducible protein with antioxidant and metabolic regulatory effects. However, its role during acute dermal and epidermal re-epithelialization in deep second-degree burns is unknown. In this study, we aimed to explore the role and molecular mechanism of sestrin2 in deep second-degree burns as a potential treatment target for burn wounds. To explore the effects of sestrin2 on burn wound healing, we established a deep second-degree burn mouse model. Then we detected the expression of sestrin2 by western blot and immunohistochemistry after obtaining the wound margin of full-thickness burned skin. The effects of sestrin2 on burn wound healing were explored in vivo and in vitro through interfering sestrin2 expression using siRNAs or the small molecule agonist of sestrin2, eupatilin. We also investigated the molecular mechanism of sestrin2 in promoting burn wound healing by western blot and CCK-8 assay. Our in vivo and in vitro deep second-degree burn wound healing model demonstrated that sestrin2 was promptly induced at murine skin wound edges. The small molecule agonist of sestrin2 accelerated the proliferation and migration of keratinocytes, as well as burn wound healing. Conversely, the healing of burn wounds was delayed in sestrin2-deficient mice and was accompanied by the secretion of inflammatory cytokines as well as the suppression of keratinocyte proliferation and migration. Mechanistically, sestrin2 promoted the phosphorylation of the PI3K/AKT pathway, and inhibition of PI3K/AKT pathway abrogated the promoting role of sestrin2 in keratinocyte proliferation and migration. Therefore, sestrin2 plays a critical role in activation of the PI3K/AKT pathway to promote keratinocyte proliferation and migration, as well as re-epithelialization in the process of deep second-degree burn wound repair.
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Affiliation(s)
- Kejia Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Fu Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Xiaozhi Bai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Zhuoqun Fang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Yanhui Jia
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Jian Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Yan Li
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Weixia Cai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Xujie Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Liang Luo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Kai Guo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Hongtao Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Xuekang Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Huina Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China.
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710038, China.
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24
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Yang J, Guo Q, Wang L, Yu S. POU Domain Class 2 Transcription Factor 2 Inhibits Ferroptosis in Cerebral Ischemia Reperfusion Injury by Activating Sestrin2. Neurochem Res 2023; 48:658-670. [PMID: 36306010 DOI: 10.1007/s11064-022-03791-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/12/2022] [Accepted: 10/12/2022] [Indexed: 02/07/2023]
Abstract
Cerebral ischemia reperfusion injury (CIRI) is the commonest cause of brain dysfunction. Up-regulation of POU domain class 2 transcription factor 2 (POU2F2) has been reported in patients with cerebral ischemia, while the role of POU2F2 in CIRI remains elusive. Middle cerebral artery occlusion/reperfusion (MCAO/R) in mice and oxygen and glucose deprivation/reperfusion (OGD/R) in mouse primary cortical neurons were used as models of CIRI injury in vivo and in vitro. Lentivirus-mediated POU2F2 knockdown further impaired CIRI induced by MCAO/R in mice, which was accompanied by increased-neurological deficits, cerebral infarct volume and neuronal loss. Our evidence suggested that POU2F2 deficiency deteriorated oxidative stress and ferroptosis according to the phenomenon such as the abatement of SOD, GSH, glutathione peroxidase 4 (GPX4) activity and accumulation of ROS, lipid ROS, 4-hydroxynonenal (4-HNE) and MDA. In vivo, primary cortical neurons with POU2F2 knockdown also showed worse neuronal damage, oxidative stress and ferroptosis. Sestrin2 (Sesn2) was reported as a neuroprotection gene and involved in ferroptosis mechanism. Up-regulation of Sesn2 was observed in the ischemic penumbra and OGD/R-induced neuronal cells. Further, we proved that POU2F2, as a transcription factor, could bind to Sesn2 promoter and positively regulate its expression. Sesn2 overexpression relieved oxidative stress and ferroptosis induced by POU2F2 knockdown in OGD/R-treated neurons. This research demonstrated that CIRI induced a compensatory increase of POU2F2 and Sesn2. Down-regulated POU2F2 exacerbated CIRI through the acceleration of oxidative stress and ferroptosis possibly by decreasing Sesn2 expression, which offers new sights into therapeutic mechanisms for CIRI.
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Affiliation(s)
- Jinghui Yang
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qian Guo
- Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, Jilin Province, China
| | - Lu Wang
- Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, Jilin Province, China
| | - Shan Yu
- Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, Jilin Province, China.
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25
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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26
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Kuang W, Jiang C, Yu C, Hu J, Duan Y, Chen Z. A microarray data analysis investigating the pathogenesis and potential biomarkers of autophagy and ferroptosis in intervertebral disc degeneration. Front Genet 2023; 13:1090467. [PMID: 36685932 PMCID: PMC9846041 DOI: 10.3389/fgene.2022.1090467] [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: 11/05/2022] [Accepted: 12/13/2022] [Indexed: 01/05/2023] Open
Abstract
Background: Intervertebral disc degeneration (IDD) entails complex pathological changes and causes lower back pain (LBP). However, there is still a lack of understanding of the mechanisms involved in IDD, particularly regarding the roles of autophagy and ferroptosis. The current study used microarray data to investigate the pathogenesis of IDD and potential biomarkers related to autophagy and ferroptosis in IDD. Methods: Differentially expressed genes (DEGs) were identified by analyzing the mRNA and miRNA expression profiles of IDD patients from the Gene Expression Omnibus (GEO). The protein-protein interaction network, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were utilized. The Human Autophagy Database (HADb) and Ferroptosis Database were used in conjunction with hub genes to identify autophagy- and ferroptosis-related genes. The Transcription Factor -hub gene-miRNA network was constructed. Lastly, the expression of DEGs in normal and degenerated nucleus pulposus cells (NPCs) was investigated via the quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: A total of 362 DEGs associated with IDD were identified. GO and KEGG analyses indicated that oxidative stress, extracellular matrix, PI3K-AKT signaling pathway, and ferroptosis were key factors in IDD occurrence. GSEA indicated that IDD was associated with changes in autophagy, iron ion homeostasis, extracellular matrix, and oxidative stress. Eighty-nine hub genes were obtained, including five that were autophagy-related and three that were ferroptosis-related. Of these, TP53 and SESN2 were the intersections of autophagy- and ferroptosis-related genes. In qRT-PCR analysis, CANX, SLC38A1, and TP53 were downregulated in degenerative NPCs, whereas GNAI3, SESN2, and VAMP3 were upregulated. Conclusion: The current study revealed aspects of autophagy- and ferroptosis-related genes involved in IDD pathogenesis, warranting further investigation.
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Affiliation(s)
| | | | | | | | | | - Zhong Chen
- Department of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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27
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Dodson M, Shakya A, Chen J, Chen WT, McKee NW, Zhang DD. The NRF2-anti-ferroptosis Axis in Health and Disease. FERROPTOSIS IN HEALTH AND DISEASE 2023:213-239. [DOI: 10.1007/978-3-031-39171-2_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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28
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Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4435161. [PMID: 36238640 PMCID: PMC9553355 DOI: 10.1155/2022/4435161] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022]
Abstract
Background Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.
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29
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Zhao T, Yu Z, Zhou L, Wang X, Hui Y, Mao L, Fan X, Wang B, Zhao X, Sun C. Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice. Cell Death Dis 2022; 8:380. [PMID: 36071041 PMCID: PMC9452542 DOI: 10.1038/s41420-022-01173-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 11/09/2022]
Abstract
Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl4)-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In this study, bicyclol, a proprietary hepatoprotectant in China, and ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) were administered in CCl4-injured mice. A panel of ferroptosis-related markers, including mitochondria morphology, reactive oxygen species production, protein adducts in response to lipid peroxidation, and key modulators of ferroptotic process, was determined in vivo. Erastin-treated L-O2 hepatocytes were transfected with glutathione peroxidase 4 (GPx4) or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA to delineate the pathway of bicyclol against ferroptosis in vitro. As a result, CCl4 led to iron accumulation, excessive reactive oxygen species production, enhanced lipid peroxidation, and characteristic morphological changes in mitochondria, along with a decrease in GPx4 and xCT protein levels in ALI mice liver, all of which were generally observed in ferroptosis. The use of Fer-1 further corroborated that ferroptosis is responsible for liver damage. Bicyclol exerted its hepatoprotection by preventing the aforesaid ferroptotic process. Furthermore, bicyclol alleviated erastin-induced cellular inviability, destruction, and lipid peroxidation in vitro. Knockdown of GPx4 diminished these protective activities against perturbations associated with ferroptosis in L-O2 hepatocytes. Additionally, Nrf2 silencing drastically reduced GPx4 levels, and further impeded the medicinal effects of bicyclol. In summary, positively regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in CCl4-induced ALI in mice.
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Affiliation(s)
- Tianming Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.,Department of Gastroenterology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Zhongshan Road 321,Gulou District, 210008, Nanjing, Jiangsu, China
| | - Zihan Yu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China
| | - Lei Zhou
- Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China
| | - Xiaoyu Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China
| | - Yangyang Hui
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China
| | - Lihong Mao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China
| | - Xiaofei Fan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. .,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.
| | - Xingliang Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. .,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China.
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. .,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, 300052, Tianjin, China. .,Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, 300308, Tianjin, China.
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30
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Liu W, Xu C, Zou Z, Weng Q, Xiao Y. Sestrin2 suppresses ferroptosis to alleviate septic intestinal inflammation and barrier dysfunction. Immunopharmacol Immunotoxicol 2022; 45:123-132. [PMID: 36066109 DOI: 10.1080/08923973.2022.2121927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE Alterations in intestinal function play a crucial role in the pathogenesis of sepsis, and the repair of the intestinal barrier is a potential strategy for the treatment of sepsis. Sestrin2 (SESN2), a highly conserved stress-responsive protein, can be induced in response to stress. AIM This paper aimed to explore the role and mechanism of SESN2 in septic intestinal dysfunction. Methods: Blood samples were collected from patients with septic intestinal dysfunction, and Caco-2 cells were subjected to lipopolysaccharide (LPS) to construct in vitro models. The expression level of SESN2 was determined in the blood samples and cells. The impacts of SESN2 overexpression on cell inflammation, oxidative stress, barrier integrity, and MAPK/Nrf2 signaling were evaluated. To determine the mediated role of MAPK signaling and ferroptosis, AMPK inhibitor (Compound C) and ferroptosis inducer (erastin) were separately used to treat cells, and the influences on the above aspects in cells were assessed. RESULTS The expression level of SESN2 was down-regulated in patients with septic intestinal dysfunction and LPS-induced cells. SESN2 overexpression was found to suppress cell inflammation and oxidative stress, maintain barrier integrity and activate AMPK/Nrf2 signaling. Following the AMPK signaling was inhibited or the ferroptosis was triggered, the effects of SESN2 overexpression on the cells were both reversed. CONCLUSION Reduced SESN2 contributed to inflammatory response and barrier dysfunction in septic intestinal dysfunction by promoting ferroptosis via activating the AMPK/Nrf2 signaling pathway.
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Affiliation(s)
- Wei Liu
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Chanchan Xu
- Department of Internal Medicine, Shanghai Raffles Hospital, Shanghai 201208, P.R. China
| | - Zhiqiang Zou
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Qinyong Weng
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Ying Xiao
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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31
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Zhang G, Dong D, Wan X, Zhang Y. Cardiomyocyte death in sepsis: Mechanisms and regulation (Review). Mol Med Rep 2022; 26:257. [PMID: 35703348 PMCID: PMC9218731 DOI: 10.3892/mmr.2022.12773] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 05/20/2022] [Indexed: 11/06/2022] Open
Abstract
Sepsis‑induced cardiac dysfunction is one of the most common types of organ dysfunction in sepsis; its pathogenesis is highly complex and not yet fully understood. Cardiomyocytes serve a key role in the pathophysiology of cardiac function; due to the limited ability of cardiomyocytes to regenerate, their loss contributes to decreased cardiac function. The activation of inflammatory signalling pathways affects cardiomyocyte function and modes of cardiomyocyte death in sepsis. Prevention of cardiomyocyte death is an important therapeutic strategy for sepsis‑induced cardiac dysfunction. Thus, understanding the signalling pathways that activate cardiomyocyte death and cross‑regulation between death modes are key to finding therapeutic targets. The present review focused on advances in understanding of sepsis‑induced cardiomyocyte death pathways, including apoptosis, necroptosis, mitochondria‑mediated necrosis, pyroptosis, ferroptosis and autophagy. The present review summarizes the effect of inflammatory activation on cardiomyocyte death mechanisms, the diversity of regulatory mechanisms and cross‑regulation between death modes and the effect on cardiac function in sepsis to provide a theoretical basis for treatment of sepsis‑induced cardiac dysfunction.
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Affiliation(s)
- Geping Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Dan Dong
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xianyao Wan
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Yongli Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Identification of a Ferroptosis-Related Prognostic Signature in Sepsis via Bioinformatics Analyses and Experiment Validation. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8178782. [PMID: 35663048 PMCID: PMC9159884 DOI: 10.1155/2022/8178782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/05/2022] [Indexed: 12/29/2022]
Abstract
Ferroptosis is a new type of programmed cell death that is different from apoptosis, cell necrosis, and autophagy, which might be involved in development of sepsis. However, the potential role of ferroptosis-related genes (FRGs) in sepsis remained unclear. We identified 41 ferroptosis-related differential expression genes by weighted correlation network and differential expression analysis. The hub module of 41 ferroptosis-related differential expression genes in the protein-protein interaction network was identified. Next, we estimated diagnostic values of genes in hub modules. TLR4, WIPI1, and GABARAPL2 with high diagnostic value were selected for construction of risk prognostic model. The high risk-scored patients had significantly higher mortality than the patients with low risk scores in discovery dataset. Furthermore, the risk scores of nonsurvivor were higher than those of survivor in validation dataset. It suggested that risk score was significantly correlated to prognosis in sepsis. Then, we constructed a nomogram for improving the clinical applicability of risk signature. Moreover, the risk score was significantly associated with immune infiltration in sepsis. Our comprehensive analysis of FRGs in sepsis demonstrated the potential roles in diagnosis, prognosis, and immune infiltration. This work may benefit in understanding FRGs in sepsis and pave a new path for diagnosis and assessment of prognosis.
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Abstract
AbstractSestrin2 is a conserved antioxidant, metabolism regulator, and downstream of P53. Sestrin2 can suppress oxidative stress and inflammation, thereby preventing the development and progression of cancer. However, Sestrin2 attenuates severe oxidative stress by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thereby enhancing cancer cells survival and chemoresistance. Sestrin2 inhibits endoplasmic reticulum stress and activates autophagy and apoptosis in cancer cells. Attenuation of endoplasmic reticulum stress and augmentation of autophagy hinders cancer development but can either expedite or impede cancer progression under specific conditions. Furthermore, Sestrin2 can vigorously inhibit oncogenic signaling pathways through downregulation of mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1-alpha (HIF-1α). Conversely, Sestrin2 decreases the cytotoxic activity of T cells and natural killer cells which helps tumor cells immune evasion. Sestrin2 can enhance tumor cells viability in stress conditions such as glucose or glutamine deficiency. Cancer cells can also upregulate Sestrin2 during chemotherapy or radiotherapy to attenuate severe oxidative stress and ER stress, augment autophagy and resist the treatment. Recent studies unveiled that Sestrin2 is involved in the development and progression of several types of human cancer. The effect of Sestrin2 may differ depending on the type of tumor, for instance, several studies revealed that Sestrin2 protects against colorectal cancer, whereas results are controversial regarding lung cancer. Furthermore, Sestrin2 expression correlates with metastasis and survival in several types of human cancer such as colorectal cancer, lung cancer, and hepatocellular carcinoma. Targeted therapy for Sestrin2 or regulation of its expression by new techniques such as non-coding RNAs delivery and vector systems may improve cancer chemotherapy and overcome chemoresistance, metastasis and immune evasion that should be investigated by future trials.
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Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis. Cell Death Dis 2022; 8:234. [PMID: 35477568 PMCID: PMC9046379 DOI: 10.1038/s41420-022-01011-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 01/22/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a state of simple steatosis that progresses to inflammation and liver injury accompanied by ferroptosis. Bone morphogenetic protein 4 (BMP4) plays an important role in adipogenesis and differentiation, as well as in hepatic steatosis and iron regulation. However, the direct impact of BMP4 on NASH remains unclear. In this study, our aim was to investigate the effect of BMP4 on NASH and its underlying mechanism. We first explored BMP4 expression in vivo in mice and patients and in vitro in HepG2 and LO2 cell lines, and then, determined whether ferroptosis occurs in NASH. Further overexpression or inhibition of BMP4 was induced to observe the effect of BMP4 on liver ferroptosis in NASH. BMP4 expression was upregulated in patients and mice with nonalcoholic fatty liver disease, and free fatty acid (FFA)-induced HepG2 and LO2 cell lines. We observed ferroptosis in high-fat diet and high-fructose diet-fed mice and FFA-induced HepG2 and LO2 cell lines. BMP4 overexpressing plasmid was constructed and the HepG2 and LO2 cells were transfected with lentivirus (oe-BMP4), or treated with exogenously added recombinant human BMP4 or BMP antagonist noggin. BMP4 suppressed the markers of hepatic steatosis, liver inflammation, and liver injury. Upregulated BMP4 expression in HepG2 and LO2 cells reduced reactive oxygen species and malondialdehyde content and relieved ferroptosis. Mechanistically, BMP4 overexpression in hepatocytes upregulated the mRNA and protein levels of glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis, while exogenous inhibition of BMP4 by noggin decreased their levels. Immunoprecipitation assays demonstrated a physical interaction between BMP4 and GPX4 in HepG2 and LO2 cells, and confocal imaging confirmed colocalization of BMP4 and GPX4. Consistently, BMP4 overexpression plays an important role in NASH by increasing GPX4 expression, therefore decreasing hepatic ferroptosis. This study proposes BMP4 as a therapeutic target for preventing steatohepatitis.
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Reactive Oxygen Species and Oxidative Stress in Vascular-Related Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7906091. [PMID: 35419169 PMCID: PMC9001081 DOI: 10.1155/2022/7906091] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/21/2022] [Indexed: 12/14/2022]
Abstract
Oxidative stress (OS) refers to the enhancement of oxidation and the decreased of related antioxidant enzymes activity under pathological conditions, resulting in relatively excess reactive oxygen species (ROS), causing cytotoxicity, which leads to tissue damage and is linked to neurodegenerative diseases, cardiovascular diseases, diabetes, cancers, and many other pathologies. As an important intracellular signaling molecule, ROS can regulate numerous physiological actions, such as vascular reactivity and neuronal function. According to several studies, the uncontrolled production of ROS is related to vascular injury. The growing evidence revealing how traditional risk factors translate into ROS and lead to vasculitis and other vascular diseases. In this review, we sought to mainly discuss the role of ROS and antioxidant mechanisms in vascular-related diseases, especially cardiovascular and common macrovascular diseases.
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Qian L, Yang F, Lin X, Jiang S, Zhang Y, Tang Y. Pyrroloquinoline quinone ameliorates liver injury in mice induced by cyclophosphamide. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:30383-30393. [PMID: 34997497 DOI: 10.1007/s11356-021-17990-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/03/2021] [Indexed: 06/14/2023]
Abstract
The current study aimed to investigate the potential ameliorative effects of pyrroloquinoline quinone (PQQ) on cyclophosphamide (CTX)-induced liver injury in mice. The liver injury model was established by injecting mice with CTX (80 mg/kg/day). Liver function indices, antioxidant enzyme activities, and inflammatory cytokines were evaluated. In addition, protein expression levels of the nuclear factor E2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) pathways in the liver tissues were determined using western blot. The results indicated that PQQ decreased the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) levels in the liver tissues. Moreover, PQQ enhanced the activities of oxidative stress markers to alleviate CTX induced oxidative stress. Furthermore, the expression levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H quinone oxidoreductase 1 (NQO1) were significantly increased, and the expression levels of NF-κB p50, NF-κB p65, and inhibitor of NF-κB kinase alpha (IKKα) were significantly decreased after PQQ administration, suggesting that PQQ alleviated CTX-induced liver injury via activating the Nrf2-mediated antioxidant response pathway, and inhibiting the NF-κB-mediated inflammation pathway. Therefore, PQQ can be potentially used as a dietary supplement or functional foods for alleviating the CTX-induced liver injury.
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Affiliation(s)
- Li Qian
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, People's Republic of China
| | - Fei Yang
- Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Neonatal Intensive Care Unit, Hangzhou, 310008, People's Republic of China
| | - Xinhui Lin
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, People's Republic of China
| | - Su Jiang
- ECA Healthcare Inc, Shanghai, 201101, People's Republic of China
| | - Yun Zhang
- Qianjiang College, Hangzhou Normal University, Hangzhou, 310012, People's Republic of China.
| | - Yunping Tang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, People's Republic of China.
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Huang L, Liu J, Bie C, Liu H, Ji Y, Chen D, Zhu M, Kuang W. Advances in cell death - related signaling pathways in acute-on-chronic liver failure. Clin Res Hepatol Gastroenterol 2022; 46:101783. [PMID: 34339873 DOI: 10.1016/j.clinre.2021.101783] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 07/14/2021] [Indexed: 02/04/2023]
Abstract
Acute-on-chronic liver failure (ACLF) has been a hot spot in the field of liver disease research in recent years, with high morbidity, rapid course change and high mortality. Currently, there is the absence of specific treatment in clinical practice. Liver transplantation has the best therapeutic effect, but it is prone to have internal environment disorder and liver cell death after transplantation, which leads to the failure of transplantation.In recent years, with the development of molecular biology, scholars have explored the treatment of ACLF at the molecular level, and more and more molecular signaling pathways related to the treatment of ACLF have been discovered. Modulating the relevant signaling pathways to reduce the mortality of liver cells after transplantation may effectively improve the success rate of transplantation. In this review, we introduce some signaling pathways related to cell death and their research progress in acute-on-chronic liver failure.
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Affiliation(s)
- Liqiao Huang
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Key Laboratory of Research and Development of New Medical Materials of Guangdong Medical University, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Jie Liu
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 518104, China; The First Affiliated Hospital, Guangzhou TCM University, Guangzhou 510006, China
| | - Caiqun Bie
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 518104, China
| | - Helu Liu
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 518104, China
| | - Yichun Ji
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Dongfeng Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Meiling Zhu
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 518104, China.
| | - Weihong Kuang
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Key Laboratory of Research and Development of New Medical Materials of Guangdong Medical University, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China.
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Chen S, Zhu JY, Zang X, Zhai YZ. The Emerging Role of Ferroptosis in Liver Diseases. Front Cell Dev Biol 2022; 9:801365. [PMID: 34970553 PMCID: PMC8713249 DOI: 10.3389/fcell.2021.801365] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/22/2021] [Indexed: 12/23/2022] Open
Abstract
Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.
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Affiliation(s)
- Si Chen
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jun-Yao Zhu
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xin Zang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yong-Zhen Zhai
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
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Wojtusik J, Curry E, Roth TL. Rhinoceros Serum microRNAs: Identification, Characterization, and Evaluation of Potential Iron Overload Biomarkers. Front Vet Sci 2021; 8:711576. [PMID: 34977204 PMCID: PMC8716540 DOI: 10.3389/fvets.2021.711576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 11/17/2021] [Indexed: 11/13/2022] Open
Abstract
Iron overload disorder (IOD) in critically endangered Sumatran (Dicerorhinus sumatrensis) and black (Diceros bicornis) rhinoceros is an over-accumulation of iron in organs which may exacerbate other diseases and indicate metabolic disturbances. IOD in rhinos is not well understood and diagnostics and therapeutics are limited in effectiveness. MicroRNAs (miRNAs) are small non-coding RNAs capable of altering protein synthesis. miRNA expression responds to physiological states and could serve as the basis for development of diagnostics and therapeutics. This study aimed to identify miRNAs differentially expressed among healthy rhinos and those afflicted with IOD or other diseases ("unhealthy"), and assess expression of select miRNAs to evaluate their potential as biomarkers of IOD. miRNAs in serum of black (n = 11 samples; five individuals) and Sumatran (n = 7 samples; four individuals) rhinos, representing individuals categorized as healthy (n = 9), unhealthy (n = 5), and afflicted by IOD (n = 3) were sequenced. In total, 715 miRNAs were identified, of which 160 were novel, 131 were specific to black rhinos, and 108 were specific to Sumatran rhinos. Additionally, 95 miRNAs were specific to healthy individuals, 31 specific to unhealthy, and 63 were specific to IOD individuals. Among healthy, unhealthy, and IOD states, 21 miRNAs were differentially expressed (P ≤ 0.01). Five known miRNAs (let-7g, miR-16b, miR-30e, miR-143, and miR-146a) were selected for further assessment via RT-qPCR in serum from black (n = 61 samples; seven individuals) and Sumatran (n = 38 samples; five individuals) rhinos. let-7g, miR-30e, and miR-143 all showed significant increased expression (P ≤ 0.05) during IOD (between 1 and 2 years prior to death) and late IOD (within 1 year of death) compared to healthy and unhealthy individuals. miR-16b expression increased (P ≤ 0.05) in late IOD, but was not different among IOD, healthy, and unhealthy states (P > 0.05). Expression of miR-146a increased in IOD and late IOD as compared to unhealthy samples (P ≤ 0.05) but was not different from the healthy state (P > 0.05). Selected serum miRNAs of black and Sumatran rhinos, in particular let-7g, miR-30e, and miR-143, could therefore provide a tool for advancing rhino IOD diagnostics that should be further investigated.
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Affiliation(s)
- Jessye Wojtusik
- Center for Conservation and Research of Endangered Wildlife (CREW), Cincinnati Zoo and Botanical Garden, Cincinnati, OH, United States
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40
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Ji Y, Si W, Zeng J, Huang L, Huang Z, Zhao L, Liu J, Zhu M, Kuang W. Niujiaodihuang Detoxify Decoction inhibits ferroptosis by enhancing glutathione synthesis in acute liver failure models. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114305. [PMID: 34129898 DOI: 10.1016/j.jep.2021.114305] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Niujiaodihuang Detoxify Decoction (NDD) is an integrated traditional Chinese medicine prescription that has been used as a therapeutic agent for the treatment of acute liver failure (ALF). However, the mechanisms underlying its action remain unclear. AIM OF THE STUDY To determine the protective effect of NDD on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF and explore the underlying mechanisms. MATERIALS AND METHODS We characterized the NDD fingerprint by HPLC and established D-GalN/LPS-induced ALF models in Sprague-Dawley rats and LO2 cells. Next, we measured the protective and antiferroptotic effects of NDD in vivo and in vitro. To further investigate the molecular mechanisms underlying the effects of NDD, we performed metabolomic analysis of the liver tissue using LC-MS/MS. RESULTS Results of serum biochemical analysis, liver histopathology, and cell viability showed that NDD effectively relieved the liver injury. It reduced the accumulation of labile iron and alleviated lipid peroxidation by enhancing GPX4 activity. The mitochondrial morphology indicated that NDD exerted its hepatoprotective effect through an antiferroptotic activity. Metabolomic analysis showed that NDD treatment increased the levels of cysteine, decreased those of glutamate, and ameliorated the D-GalN/LPS-induced reduction in the levels of glutathione (GSH). The results for intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were consistent with those of metabolomic analysis. CONCLUSION Our findings indicate that NDD exerts hepatoprotective activity by evoking the reprogramming of GSH metabolism, and thereby, inhibiting ferroptosis.
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Affiliation(s)
- Yichun Ji
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518133, China.
| | - Wenwen Si
- Shenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, China
| | - Juan Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Liqiao Huang
- School of Pharmacy, Guangdong Medical University, Dongguan, 524023, China
| | - Zifeng Huang
- Shenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, China
| | - Lijun Zhao
- Shenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, China
| | - Jiahui Liu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510405, China
| | - Meiling Zhu
- Shenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, China.
| | - Weihong Kuang
- School of Pharmacy, Guangdong Medical University, Dongguan, 524023, China.
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Li JY, Ren C, Wang LX, Yao RQ, Dong N, Wu Y, Tian YP, Yao YM. Sestrin2 protects dendrite cells against ferroptosis induced by sepsis. Cell Death Dis 2021; 12:834. [PMID: 34482365 PMCID: PMC8418614 DOI: 10.1038/s41419-021-04122-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 12/24/2022]
Abstract
Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 μg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2-/-) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.
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Affiliation(s)
- Jing-Yan Li
- Department of Emergency, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China
| | - Chao Ren
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Li-Xue Wang
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Ren-Qi Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Ning Dong
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Yao Wu
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Ying-Ping Tian
- Department of Emergency, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China.
| | - Yong-Ming Yao
- Department of Emergency, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China.
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, People's Republic of China.
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Zhao J, Xu B, Xiong Q, Feng Y, Du H. Erastin‑induced ferroptosis causes physiological and pathological changes in healthy tissues of mice. Mol Med Rep 2021; 24:713. [PMID: 34396451 PMCID: PMC8383038 DOI: 10.3892/mmr.2021.12352] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 07/20/2021] [Indexed: 12/25/2022] Open
Abstract
Ferroptosis is a non-apoptotic form of cell death that relies on iron and lipid peroxidation, which is associated with multiple pathological processes in several diseases. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells, which has shown great potential for cancer therapy. However, the physiological and pathological role of erastin-induced ferroptosis on healthy tissues has not been well characterized. The present study intraperitoneally injected erastin into healthy mice to detect the metabolic changes of several tissues of mice. Erastin injection induced typical characteristics of ferroptosis with higher level of serum iron and malondialdehyde and lower level of glutathione and glutathione peroxidase 4 protein. Erastin injection enhanced iron deposition in the brain, duodenum, kidney and spleen of mice. Erastin-induced ferroptosis altered the blood index values, causing mild cerebral infarction of brain and enlarged glomerular volume of kidney. It also promoted the growth of duodenal epithelium with thicker, longer and denser villi in erastin-treated mice. The findings provided evidence that erastin induced ferroptosis and caused pathological changes in healthy tissues of mice. This suggested that the anti-tumor drug erastin was somewhat toxic to healthy tissues.
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Affiliation(s)
- Jing Zhao
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Ben Xu
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Qingqing Xiong
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Yunfei Feng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Huahua Du
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
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Duan JY, Lin X, Xu F, Shan SK, Guo B, Li FXZ, Wang Y, Zheng MH, Xu QS, Lei LM, Ou-Yang WL, Wu YY, Tang KX, Yuan LQ. Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization? Front Cell Dev Biol 2021; 9:701788. [PMID: 34307381 PMCID: PMC8299754 DOI: 10.3389/fcell.2021.701788] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022] Open
Abstract
Ferroptosis is classified as an iron-dependent form of regulated cell death (RCD) attributed to the accumulation of lipid hydroperoxides and redox imbalance. In recent years, accumulating researches have suggested that ferroptosis may play a vital role in the development of diverse metabolic diseases, for example, diabetes and its complications (e.g., diabetic nephropathy, diabetic cardiomyopathy, diabetic myocardial ischemia/reperfusion injury and atherosclerosis [AS]), metabolic bone disease and adrenal injury. However, the specific physiopathological mechanism and precise therapeutic effect is still not clear. In this review, we summarized recent advances about the development of ferroptosis, focused on its potential character as the therapeutic target in metabolic diseases, and put forward our insights on this topic, largely to offer some help to forecast further directions.
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Affiliation(s)
- Jia-Yue Duan
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fu-Xing-Zi Li
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Wang
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Lu Ou-Yang
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yun-Yun Wu
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ke-Xin Tang
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- National Clinical Research Center for Metabolic Disease, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
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Ajoolabady A, Aslkhodapasandhokmabad H, Libby P, Tuomilehto J, Lip GYH, Penninger JM, Richardson DR, Tang D, Zhou H, Wang S, Klionsky DJ, Kroemer G, Ren J. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol Metab 2021; 32:444-462. [PMID: 34006412 DOI: 10.1016/j.tem.2021.04.010] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/07/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Ferroptosis is a form of regulated cell death modality associated with disturbed iron-homeostasis and unrestricted lipid peroxidation. Ample evidence has depicted an essential role for ferroptosis as either the cause or consequence for human diseases, denoting the likely therapeutic promises for targeting ferroptosis in the preservation of human health. Ferritinophagy, a selective form of autophagy, contributes to the initiation of ferroptosis through degradation of ferritin, which triggers labile iron overload (IO), lipid peroxidation, membrane damage, and cell death. In this review, we will delineate the role of ferritinophagy in ferroptosis, and its underlying regulatory mechanisms, to unveil the therapeutic value of ferritinophagy as a target in the combat of ferroptosis to manage metabolic diseases.
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Affiliation(s)
- Amir Ajoolabady
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
| | | | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jaakko Tuomilehto
- Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Gregory Y H Lip
- University of Liverpool Institute of Ageing and Chronic Disease, Liverpool Centre for Cardiovascular Science, Liverpool, UK
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales 2006, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hao Zhou
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China
| | - Shuyi Wang
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; School of Medicine Shanghai University, Shanghai 200444, China.
| | - Daniel J Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
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Sun D, Yang L, Zheng W, Cao H, Wu L, Song H. Protective Effects of Bone Marrow Mesenchymal Stem Cells (BMMSCS) Combined with Normothermic Machine Perfusion on Liver Grafts Donated After Circulatory Death via Reducing the Ferroptosis of Hepatocytes. Med Sci Monit 2021; 27:e930258. [PMID: 34112750 PMCID: PMC8204680 DOI: 10.12659/msm.930258] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To improve the quality of liver grafts from extended-criteria donors donated after circulatory death (DCD), this study explored whether bone marrow mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP) have protective effects on DCD donor livers and the effects of ferroptosis in this procedure. MATERIAL AND METHODS Twenty-four male rat DCD donor livers were randomly and averagely divided into normal, static cold storage (SCS), NMP, and NMP combined with BMMSCs groups. Liver function, bile secretion, and pathological features of DCD donor livers were detected to evaluate the protective effects of NMP and BMMSCs on DCD donor livers. Hydrogen peroxide was used to induce an oxidative stress model of hepatocyte IAR-20 cells to evaluate the protective effects of BMMSCs in vitro. RESULTS Livers treated with NMP combined with BMMSCs showed better liver function, relieved histopathological damage, reduced oxidative stress injury and ferroptosis, and the mechanism of reduction was associated with downregulation of intracellular reactive oxygen species (ROS) and free Fe²⁺ levels. BMMSCs showed significant protective effects on the ultrastructure of DCD donor livers and ROS-induced injury to IAR-20 cells under electron microscopy. BMMSCs also significantly improved the expression level of microtubule-associated protein 1 light chain 3 (LC3)-II in both DCD donor livers and ROS-induced injured IAR-20 cells, including upregulating the expression of ferritin. CONCLUSIONS BMMSCs combined with NMP could reduce the level of ROS and free Fe²⁺ in oxidative stress damaged rat DCD donor livers, potentially reduce the ferroptosis in hepatocytes, and repair both morphology and function of DCD donor livers.
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Affiliation(s)
- Dong Sun
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, China (mainland)
| | - Liu Yang
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, China (mainland)
| | - Weiping Zheng
- Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China (mainland).,Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China (mainland)
| | - Huan Cao
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, China (mainland).,NHC Key Laboratory of Critical Care Medicine, Tianjin, China (mainland)
| | - Longlong Wu
- School of Medicine, Nankai University, Tianjin, China (mainland)
| | - Hongli Song
- Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China (mainland).,Tianjin Key Laboratory of Organ Transplantation, Tianjin, China (mainland)
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Shi Z, Zhang L, Zheng J, Sun H, Shao C. Ferroptosis: Biochemistry and Biology in Cancers. Front Oncol 2021; 11:579286. [PMID: 33868986 PMCID: PMC8047310 DOI: 10.3389/fonc.2021.579286] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 03/15/2021] [Indexed: 12/21/2022] Open
Abstract
The challenge of eradicating cancer is that cancer cells possess diverse mechanisms to protect themselves from clinical strategies. Recently, ferroptosis has been shown to exhibit appreciable anti-tumor activity that could be harnessed for cancer therapy in the future. Ferroptosis is an iron-dependent form of regulated cell death that is characterized by the oxidization of polyunsaturated fatty acids (PUFAs) and accumulation of lipid peroxides. Ferroptosis has been closely correlated with numerous biological processes, such as amino acid metabolism, glutathione metabolism, iron metabolism, and lipid metabolism, as well as key regulators including GPX4, FSP1, NRF2, and p53. Although ferroptosis could be involved in killing various cancer cells, multiple aspects of this phenomenon remain unresolved. In this review, we summarize the biochemistry and biology of ferroptosis in diverse cancers and discuss the potential mechanisms of ferroptosis, which might pave the way for guiding cancer therapeutics.
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Affiliation(s)
- Zhiyuan Shi
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Lei Zhang
- School of Public Health, Xiamen Univerisity, Xiamen, China
| | - Jianzhong Zheng
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Huimin Sun
- Clinical Central Research Core, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Chen Shao
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, China
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Wang B J, Wang S, Xiao M, Zhang J, Wang A J, Guo Y, Tang Y, Gu J. Regulatory mechanisms of Sesn2 and its role in multi-organ diseases. Pharmacol Res 2020; 164:105331. [PMID: 33285232 DOI: 10.1016/j.phrs.2020.105331] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/20/2020] [Accepted: 11/21/2020] [Indexed: 02/07/2023]
Abstract
Sestrin2 (Sesn2) is a powerful anti-oxidant that can prevent acute and chronic diseases. The role of Sesn2 has been thoroughly reviewed in liver, nervous system, and immune system diseases. However, there is a limited number of reviews that have summarized the effects of Sesn2 in heart and vascular diseases, and very less literature-based information is available on involvement of Sesn2 in renal and respiratory pathologies. This review summarizes the latest research on Sesn2 in multi-organ stress responses, with a particular focus on the protective role of Sesn2 in cardiovascular, respiratory, and renal diseases, emphasizing the potential therapeutic benefit of targeting Sesn2 in stress-related diseases.
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Affiliation(s)
- Jie Wang B
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shudong Wang
- Department of Cardiology at the First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Mengjie Xiao
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jingjing Zhang
- Department of Cardiology at the First Hospital of China Medical University, Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang, Liaoning, 110016, China
| | - Jie Wang A
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yuanfang Guo
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yufeng Tang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China
| | - Junlian Gu
- School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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48
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Yu J, Wang JQ. Research mechanisms of and pharmaceutical treatments for ferroptosis in liver diseases. Biochimie 2020; 180:149-157. [PMID: 33166595 DOI: 10.1016/j.biochi.2020.11.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022]
Abstract
Regulated cell death (RCD) is a universal process in living organisms that is essential for tissue homeostasis or to the restoration of biological equilibrium following stress. Ferroptosis is a specific nonapoptotic cell death that is dependent on iron and is very different from other forms of RCD. Ferroptosis can affect the development of liver diseases such as drug-induced liver injury (DILI), liver fibrosis, and hepatocellular carcinoma (HCC) by regulating the level of intracellular iron, the production of intracellular reactive oxygen species, and lipid peroxides. In this review, we summarize the current knowledge of ferroptosis, in terms of discovery, history, characteristics, mechanism, and the factors regulating liver diseases. We discuss how these factors and signaling pathways change in the context of liver disease. Furthermore, we focus on delineating the roles of effective therapeutic drugs or compounds in liver disease. In summary, we discuss the role of ferroptosis in liver disease, providing a strategy and new ideas for preventing liver disease, finding new therapeutic targets, and reducing liver damage.
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Affiliation(s)
- Jun Yu
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
| | - Jian-Qing Wang
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.
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Abstract
Sestrins are a family of proteins that respond to a variety of environmental stresses, including genotoxic, oxidative, and nutritional stresses. Sestrins affect multiple signaling pathways: AMP-activated protein kinase, mammalian target of rapamycin complexes, insulin-AKT, and redox signaling pathways. By regulating these pathways, Sestrins are thought to help adapt to stressful environments and subsequently restore cell and tissue homeostasis. In this review, we describe how Sestrins mediate physiological stress responses in the context of nutritional and chemical stresses (liver), physical movement and exercise (skeletal muscle), and chemical, physical, and inflammatory injuries (heart). These findings also support the idea that Sestrins are a molecular mediator of hormesis, a paradoxical beneficial effect of low- or moderate-level stresses in living organisms.
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Affiliation(s)
- Myungjin Kim
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA; ,
| | - Allison H Kowalsky
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA; ,
| | - Jun Hee Lee
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA; ,
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50
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Kim KM, Cho SS, Ki SH. Emerging roles of ferroptosis in liver pathophysiology. Arch Pharm Res 2020; 43:985-996. [PMID: 33079307 DOI: 10.1007/s12272-020-01273-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/13/2020] [Indexed: 02/08/2023]
Abstract
Ferroptosis is a widely recognized process of regulated cell death linking redox state, metabolism, and human health. It is considered a defense mechanism against extensive lipid peroxidation, a complex process that may disrupt the membrane integrity, eventually leading to toxic cellular injury. Ferroptosis is controlled by iron, reactive oxygen species, and polyunsaturated fatty acids. Accumulating evidence has addressed that ferroptosis plays an unneglectable role in regulating the development and progression of multiple pathologies of the liver, including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatosis, hepatic ischemia-reperfusion injury, and liver failure. This review may increase our understating of the cellular and molecular mechanisms of liver disease progression and establish the foundation of strategies for pharmacological intervention.
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Affiliation(s)
- Kyu Min Kim
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 61452, Republic of Korea
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 61452, Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 61452, Republic of Korea.
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