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Shao N, Cai K, Hong Y, Wu L, Luo Q. USP9X suppresses ferroptosis in diabetic kidney disease by deubiquitinating Nrf2 in vitro. Ren Fail 2025; 47:2458761. [PMID: 39967230 PMCID: PMC11841168 DOI: 10.1080/0886022x.2025.2458761] [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: 08/21/2024] [Revised: 12/22/2024] [Accepted: 01/21/2025] [Indexed: 02/20/2025] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates many critical genes associated with iron storage and transportation, the activity of which is influenced by E3 ligase-mediated ubiquitination. We wondered whether there is a deubiquitinase that mediates the deubiquitination of Nrf2 to stabilize Nrf2 expression and further prevent diabetic kidney disease (DKD). High glucose (HG) was applied to induce an in vitro model of DKD. The effects of HG on HK-2 cell viability, apoptosis, Fe2+ level, Nrf2, and ubiquitin-specific protease 9X (USP9X) were assessed by cell counting kit-8 (CCK-8) assay, flow cytometry, iron assay, and Western blot. The direct interaction between Nrf2 and USP9X was analyzed using co-immunoprecipitation and ubiquitination assay. After transfection and ferrostatin-1 (Fer-1) intervention, Nrf2 and USP9X levels, cell viability, apoptosis, and Fe2+ level were tested again. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) contents, and ferroptosis-related markers were assessed by ROS assay kit, ELISA, and Western blot. HG reduced cell viability and levels of USP9X and Nrf2, while elevating apoptosis and Fe2+ level. An interaction between USP9X and Nrf2 has been verified and USP9X deubiquitinated Nrf2. Nrf2 up-regulation augmented the viability, GSH content, and ferroptosis-related protein expressions, while suppressing the apoptosis, Fe2+ level, MDA, and ROS content in HG-mediated HK-2 cells, which was reversed by USP9X silencing. Fer-1 offset the combined modulation of Nrf2 and siUSP9X on HG-induced HK-2 cells. USP9X mediates Nrf2 deubiquitinase to hamper the ferroptosis in DKD in vitro.
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Affiliation(s)
- Ningjun Shao
- Department of Nephrology, Ningbo No.2 Hospital, Ningbo, China
| | - Kedan Cai
- Department of Nephrology, Ningbo No.2 Hospital, Ningbo, China
| | - Yue Hong
- Department of Nephrology, Ningbo No.2 Hospital, Ningbo, China
| | - Lingping Wu
- Department of Nephrology, Ningbo No.2 Hospital, Ningbo, China
| | - Qun Luo
- Department of Nephrology, Ningbo No.2 Hospital, Ningbo, China
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Liu X, Zhai X, Wang X, Zhu X, Wang Z, Jiang Z, Bao H, Chen Z. Nuclear Factor Erythroid 2-Related Factor 2 Activator DDO-1039 Ameliorates Podocyte Injury in Diabetic Kidney Disease via Suppressing Oxidative Stress, Inflammation, and Ferroptosis. Antioxid Redox Signal 2025; 42:787-806. [PMID: 39723566 DOI: 10.1089/ars.2024.0653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
Aims: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and podocyte injury is one of the major contributors to DKD. As a crucial transcriptional factor that regulates cellular response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is an attractive therapeutic target for DKD. In this study, we evaluated the therapeutic potential of DDO-1039, a novel small-molecule Nrf2 activator developed with protein-protein interaction strategy, on podocyte injury in DKD. Results: DDO-1039 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, thereby upregulating Nrf2 target genes [heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase modifier, and tyrosine-protein kinase receptor] both in vitro and in vivo. DDO-1039 attenuated glomerular sclerosis and podocyte injury in the high-fat diet/streptozotocin-induced (HFD/STZ) diabetic mice and db/db diabetic mice. It also significantly improved hyperglycemia in both diabetic mice and mitigated proteinuria in HFD/STZ mice. Meanwhile, DDO-1039 attenuated oxidative stress and inflammation as well as apoptosis in vivo and in podocytes stimulated with palmitic acid and high glucose. Interestingly, we identified podocyte protective factor Tyro3 as a novel Nrf2-regulated gene. In addition, podocyte ferroptosis is reduced via activation of glutathione peroxidase 4 by the novel Nrf2 activator. Innovation and conclusion: DDO-1039 activates the Nrf2-based cytoprotective system to mitigate podocyte injury in the context of diabetes, suggesting the potential of DDO-1039 in the treatment of DKD. Antioxid. Redox Signal. 42, 787-806.
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Affiliation(s)
- Xing Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
- Clinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiuwen Zhai
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaoyu Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaodong Zhu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Ziyue Wang
- Nanjing University School of Medicine, Nanjing, China
| | - Zhengyu Jiang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
| | - Hao Bao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
- Nanjing University School of Medicine, Nanjing, China
| | - ZhaoHong Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
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Li Q, Shang J, Inagi R. Control of Mitochondrial Quality: A Promising Target for Diabetic Kidney Disease Treatment. Kidney Int Rep 2025; 10:994-1010. [PMID: 40303215 PMCID: PMC12034889 DOI: 10.1016/j.ekir.2024.12.029] [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: 07/29/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 05/02/2025] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.
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Affiliation(s)
- Qi Li
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Jin Shang
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Reiko Inagi
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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Mu F, Luo P, Zhu Y, Nie P, Li B, Bai X. Iron Metabolism and Ferroptosis in Diabetic Kidney Disease. Cell Biochem Funct 2025; 43:e70067. [PMID: 40166850 DOI: 10.1002/cbf.70067] [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: 09/15/2024] [Revised: 02/20/2025] [Accepted: 03/04/2025] [Indexed: 04/02/2025]
Abstract
Diabetic kidney disease (DKD) is a major diabetic microvascular complication that still lacks effective therapeutic drugs. Ferroptosis is a recently identified form of programmed cell death that is triggered by iron overload. It is characterized by unrestricted lipid peroxidation and subsequent membrane damage and is found in various diseases. Accumulating evidence has highlighted the crucial roles of iron overload and ferroptosis in DKD. Here, we review iron metabolism and the biology of ferroptosis. The role of aberrant ferroptosis in inducing diverse renal intrinsic cell death, oxidative stress, and renal fibrosis in DKD is summarized, and we elaborate on critical regulatory factors related to ferroptosis in DKD. Finally, we focused on the significance of ferroptosis in the treatment of DKD and highlight recent data regarding the novel activities of some drugs as ferroptosis inhibitors in DKD, aiming to provide new research targets and treatment strategies on DKD.
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Affiliation(s)
- Fangxin Mu
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Ping Luo
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Yuexin Zhu
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Ping Nie
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Bing Li
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Xue Bai
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
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Hu Y, Tang J, Hong H, Chen Y, Ye B, Gao Z, Zhu G, Wang L, Liu W, Wang Y. Ferroptosis in kidney disease: a bibliometric analysis from 2012 to 2024. Front Pharmacol 2025; 15:1507574. [PMID: 39872050 PMCID: PMC11769937 DOI: 10.3389/fphar.2024.1507574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/27/2024] [Indexed: 01/29/2025] Open
Abstract
Background and aims Ferroptosis, a novel concept of programmed cell death proposed in 2012, in kidney disease, has garnered significant attention based on evidence of abnormal iron deposition and lipid peroxidation damage in the kidney. Our study aim to examine the trends and future research directions in the field of ferroptosis in kidney disease, so as to further explore the target or treatment strategy for clinical treatment of kidney disease. Material and Methods A thorough survey using the Web of Science Core Collection, focusing on literature published between 2012 and 2024 examining the interaction between kidney disease and ferroptosis was conducted. VOSviewer, CiteSpace, and Biblioshiny were used for in-depth scientometric and visualized analyses. Results From 2012 to 2024, a total of 2,244 articles met the inclusion criteria for final analysis. The number of annual publications in this area of study showed a steady pattern at the beginning of the decade. The top 3 journals with the highest publication output were Renal Failure, Oxidative Medicine And Cellular Longevity, and Biomedicine & Pharmacotherapy. China and the United States had the highest number of publications. Central South University and Guangzhou Medical University as the most active and influential institutions. Documents and citation analysis suggested that Andreas Linkermann, Jolanta Malyszko, and Alberto Ortiz are active researchers, and the research by Scott J. Dixon and Jose Pedro Friedmann Angeli, as the most cited article, are more important drivers in the development of the field. Keywords associated with glutathione, lipid peroxidation, and nitric oxide had high frequency in the early studies. In recent years, however, there has been a shift towards biomarkers, inflammation and necrosis, which indicate current and future research directions in this area. Conclusion The global landscape of the ferroptosis research in kidney disease from 2012 to 2024 was presented. Basic research and mechanism exploration for renal fibrosis and chronic kidney disease may be a hot spot in the future.
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Affiliation(s)
- Yuxin Hu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Hanzhang Hong
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yexin Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Beibei Ye
- Beijing University of Chinese Medicine, Beijing, China
| | - Ziheng Gao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | | | - Lin Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Weijing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yaoxian Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Henan University of Chinese Medicine, Zhengzhou, Henan, China
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Wu Q, Huang F. Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy. Ann Med 2024; 56:2346543. [PMID: 38657163 PMCID: PMC11044758 DOI: 10.1080/07853890.2024.2346543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 04/09/2024] [Indexed: 04/26/2024] Open
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are limited drugs targeting the treatment of DN. Owing to this, it is highly crucial to investigate the pathogenesis and potential therapeutic targets of DN. The process of ferroptosis is a type of regulated cell death (RCD) involving the presence of iron, distinct from autophagy, apoptosis, and pyroptosis. A primary mechanism of ferroptosis is associated with iron metabolism, lipid metabolism, and the accumulation of ROS. Recently, many studies testified to the significance of ferroptosis in kidney tissue under diabetic conditions and explored the drugs targeting ferroptosis in DN therapy. Our review summarized the most current studies between ferroptosis and DN, along with investigating the significant processes of ferroptosis in different kidney cells, providing a novel target treatment option for DN.
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Affiliation(s)
- Qinrui Wu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fengjuan Huang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Jiang M, Wu S, Xie K, Zhou G, Zhou W, Bao P. The significance of ferroptosis in renal diseases and its therapeutic potential. Heliyon 2024; 10:e35882. [PMID: 39220983 PMCID: PMC11363859 DOI: 10.1016/j.heliyon.2024.e35882] [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: 01/13/2024] [Revised: 04/04/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Kidney diseases are significant global public health concern, with increasing prevalence and substantial economic impact. Developing novel therapeutic approaches are essential for delaying disease progression and improving patient quality of life. Cell death signifying the termination of cellular life, could facilitate appropriate bodily development and internal homeostasis. Recently, regulated cell death (RCD) forms such as ferroptosis, characterized by iron-dependent lipid peroxidation, has garnered attention in diverse renal diseases and other pathological conditions. This review offers a comprehensive examination of ferroptosis, encompassing an analysis of the involvement of iron and lipid metabolism, the System Xc - /glutathione/glutathione peroxidase 4 signaling, and additional associated pathways. Meanwhile, the review delves into the potential of targeting ferroptosis as a therapeutic approach in the management of acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy, and renal tumors. Furthermore, it emphasizes the significance of ferroptosis in the transition from AKI to CKD and further accentuates the potential for repurposing drug and utilizing traditional medicine in targeting ferroptosis-related pathways for clinical applications. The integrated review provides valuable insights into the role of ferroptosis in kidney diseases and highlights the potential for targeting ferroptosis as a therapeutic strategy.
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Affiliation(s)
- Mingzhu Jiang
- The Yangzhou Clinical Medical College of Xuzhou Medical University, Yangzhou, China
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Shujun Wu
- The Yangzhou School of Clinical Medicine of Dalian Medical University, Yangzhou, China
| | - Kun Xie
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Gang Zhou
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Wei Zhou
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
| | - Ping Bao
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
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Long Z, Luo Y, Yu M, Wang X, Zeng L, Yang K. Targeting ferroptosis: a new therapeutic opportunity for kidney diseases. Front Immunol 2024; 15:1435139. [PMID: 39021564 PMCID: PMC11251909 DOI: 10.3389/fimmu.2024.1435139] [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: 05/19/2024] [Accepted: 06/10/2024] [Indexed: 07/20/2024] Open
Abstract
Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and is characterized by the accumulation of lipid peroxides to lethal levels. Ferroptosis involves multiple pathways including redox balance, iron regulation, mitochondrial function, and amino acid, lipid, and glycometabolism. Furthermore, various disease-related signaling pathways also play a role in regulating the process of iron oxidation. In recent years, with the emergence of the concept of ferroptosis and the in-depth study of its mechanisms, ferroptosis is closely associated with various biological conditions related to kidney diseases, including kidney organ development, aging, immunity, and cancer. This article reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, and MBOAT1/2 pathways), and the latest research progress on its involvement in kidney diseases. It summarizes research on ferroptosis in kidney diseases within the frameworks of metabolism, reactive oxygen biology, and iron biology. The article introduces key regulatory factors and mechanisms of ferroptosis in kidney diseases, as well as important concepts and major open questions in ferroptosis and related natural compounds. It is hoped that in future research, further breakthroughs can be made in understanding the regulation mechanism of ferroptosis and utilizing ferroptosis to promote treatments for kidney diseases, such as acute kidney injury(AKI), chronic kidney disease (CKD), diabetic nephropathy(DN), and renal cell carcinoma. This paves the way for a new approach to research, prevent, and treat clinical kidney diseases.
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Affiliation(s)
- Zhiyong Long
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yanfang Luo
- Department of Nephrology, The Central Hospital of Shaoyang, Shaoyang, Hunan, China
| | - Min Yu
- Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Wang
- Department of Nephrology, The Central Hospital of Shaoyang, Shaoyang, Hunan, China
| | - Liuting Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Kailin Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
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Albayrak B, Guneyin EA, Celik M. Relationship between salusin beta levels and the severity of acute pancreatitis in patients. Medicine (Baltimore) 2024; 103:e38685. [PMID: 38905397 PMCID: PMC11191942 DOI: 10.1097/md.0000000000038685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 05/31/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND This study aimed to evaluate the significance of serum salusin beta (SAL-β) levels in predicting the severity of acute pancreatitis (AP) in patients diagnosed with this condition and to assess its relationship with disease and prognosis. METHODS Sixty-four patients between 18 and 100 years of age diagnosed with AP, were included in the study. Patients were categorized into 3 groups based on the Revised Atlanta Classification: mild, moderate, and severe AP. Eighteen healthy adults were included as the control group. Sex, age, height, weight, presence of additional diseases, laboratory results, imaging findings, levels of white blood cells, neutrophil-lymphocyte ratio, mean platelet volume, amylase, lipase, sensitive C-reactive protein, sedimentation, and serum SAL-β were measured and recorded. SAL-β levels were reevaluated on the third day of hospitalization. RESULTS The average age of the patients included in the study was 62.66 ± 17.67. Gallstones were present in 64.1% of the patients. The difference in the SAL-β averages on the 1st and 3rd days was statistically significant (P < .05). On the first day, the SAL-β averages of those with severe Atlanta scores were higher than those with mild and moderate Atlanta severity. Similarly, on the third day, the SAL-β averages of those with severe Atlanta scores were higher than those with mild and moderate Atlanta severity. According to receiver operating characteristic analysis using the Youden index, the cutoff value for SAL-β for severe pancreatitis was 178.8 pg/mL on the 1st day and 207.5 pg/mL on the 3rd day. CONCLUSION SAL-β can be used to detect and monitor severe pancreatitis. Further extensive clinical studies with larger case series are needed.
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Affiliation(s)
- Bulent Albayrak
- Department of Gastroenterology, Ataturk University, Erzurum, Turkey
| | | | - Muhammet Celik
- Department of Biochemistry, Ataturk University, Erzurum, Turkey
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Lv S, Fan L, Chen X, Su X, Dong L, Wang Q, Wang Y, Zhang H, Cui H, Zhang S, Wang L. Jian-Pi-Gu-Shen-Hua-Yu Decoction Alleviated Diabetic Nephropathy in Mice through Reducing Ferroptosis. J Diabetes Res 2024; 2024:9990304. [PMID: 38523631 PMCID: PMC10960652 DOI: 10.1155/2024/9990304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 02/06/2024] [Accepted: 02/22/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN), one of the most frequent complications of diabetes mellitus, is a leading cause of end-stage renal disease. However, the current treatment methods still cannot effectively halt the progression of DN. Jian-Pi-Gu-Shen-Hua-Yu (JPGS) decoction can be used for the treatment of chronic kidney diseases such as DN, but the specific mechanism of action has not been fully elucidated yet. PURPOSE The aim of this study is to clarify whether JPGS alleviates the progression of diabetic nephropathy by inhibiting ferroptosis. MATERIALS AND METHODS We established a DN mouse model to investigate the therapeutic effect of JPGS in a DN mouse model. Subsequently, we examined the effects of JPGS on ferroptosis- and glutathione peroxidase 4 (GPX4) pathway-related indices. Finally, we validated whether JPGS inhibited ferroptosis in DN mice via the GPX4 pathway using GPX4 inhibitor and ferroptosis inhibitors. RESULTS The results indicate that JPGS has a therapeutic effect on DN mice by improving kidney function and reducing inflammation. Additionally, JPGS treatment decreased iron overload and oxidative stress levels while upregulating the expression of GPX4 pathway-related proteins. Moreover, JPGS demonstrated a similar therapeutic effect as Fer-1 in the context of DN treatment, and RSL3 was able to counteract the therapeutic effect of JPGS and antiferroptotic effect. CONCLUSION JPGS has significant therapeutic and anti-inflammatory effects on DN mice, and its mechanism is mainly achieved by upregulating the expression of GPX4 pathway-related proteins, thereby alleviating iron overload and ultimately reducing ferroptosis.
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Affiliation(s)
- Shuquan Lv
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Lirong Fan
- Botou Hospital of Traditional Chinese Medicine, Botou 062154, Hebei, China
| | - Xiaoting Chen
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Xiuhai Su
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Li Dong
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Qinghai Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Yuansong Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Hui Zhang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Huantian Cui
- Yunnan University of Chinese Medicine, Kunming 650500, Yunnan, China
| | - Shufang Zhang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
| | - Lixin Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Cangzhou 061012, Hebei, China
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11
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Li S, Han Q, Liu C, Wang Y, Liu F, Pan S, Zuo L, Gao D, Chen K, Feng Q, Liu Z, Liu D. Role of ferroptosis in chronic kidney disease. Cell Commun Signal 2024; 22:113. [PMID: 38347570 PMCID: PMC10860320 DOI: 10.1186/s12964-023-01422-8] [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: 08/14/2023] [Accepted: 12/03/2023] [Indexed: 02/15/2024] Open
Abstract
Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with the gradual loss of renal function, the incidence of various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection and stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt the progression of kidney injury in CKD, emphasizing the urgent need to delve into the precise molecular mechanisms governing the occurrence and development of CKD while identifying novel therapeutic targets. Renal fibrosis, a typical pathological feature of CKD, plays a pivotal role in disrupting normal renal structures and the loss of renal function. Ferroptosis is a recently discovered iron-dependent form of cell death characterized by lipid peroxide accumulation. Ferroptosis has emerged as a potential key player in various diseases and the initiation of organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute to the intricate interplay between CKD and its progression. This review comprehensively outlines the intricate relationship between CKD and ferroptosis in terms of iron metabolism and lipid peroxidation, and discusses the current landscape of pharmacological research on ferroptosis, shedding light on promising avenues for intervention. It further illustrates recent breakthroughs in ferroptosis-related regulatory mechanisms implicated in the progression of CKD, thereby providing new insights for CKD treatment. Video Abstract.
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Affiliation(s)
- Shiyang Li
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China
| | - Qiuxia Han
- Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People's Republic of China
| | - Chang Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China
| | - Yixue Wang
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China
| | - Fengxun Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China
| | - Shaokang Pan
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China
| | - Lihua Zuo
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Dan Gao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China
| | - Kai Chen
- Kaifeng Renmin Hospital, Kaifeng, 475000, Henan, People's Republic of China
| | - Qi Feng
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China.
| | - Zhangsuo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China.
| | - Dongwei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, Henan, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, Henan, People's Republic of China.
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Xu A, Wang L, Luo M, Zhang H, Ning M, Pan J, Duan X, Wang Y, Liu X. Overexpression of salusin‑β downregulates adipoR1 expression to prevent fatty acid oxidation in HepG2 cells. Mol Med Rep 2024; 29:18. [PMID: 38063230 PMCID: PMC10784734 DOI: 10.3892/mmr.2023.13141] [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: 08/01/2023] [Accepted: 11/07/2023] [Indexed: 12/18/2023] Open
Abstract
Salusin‑β and adiponectin receptor 1 (adipoR1) serve important roles in the development of certain cardiovascular diseases and lipid metabolism. However, to the best of our knowledge, the relationship between salusin‑β and adipoR1, and their underlying mechanisms of action, currently remain unclear. In the present study, lentiviral vectors designed to overexpress salusin‑β or knock down salusin‑β expression were used in 293T and HepG2 cells. Semi‑quantitative PCR was performed to investigate the relationship between salusin‑β and adipoR1 mRNA expression in 293T cells. Western blotting was used to assess the protein expression levels of adipoR1, adenosine monophosphate‑activated protein kinase (AMPK), acetyl‑CoA carboxylase (ACC) and carnitine palmitoyl transferase 1A (CPT‑1A) in transfected HepG2 cells. Simultaneously, HepG2 cells were treated with an adipoR1 inhibitor (thapsigargin) or agonist (AdipoRon) and the resultant changes in the expression levels of the aforementioned proteins were observed. Oil Red O staining and measurements of cellular triglyceride levels were performed to assess the extent of lipid accumulation in HepG2 cells. The results demonstrated that salusin‑β overexpression downregulated adipoR1 expression and inhibited the phosphorylation of AMPK and ACC, which led to decreased CPT‑1A protein expression. By contrast, salusin‑β knockdown increased adipoR1 expression and promoted the phosphorylation of AMPK and ACC, which conversely enhanced CPT‑1A protein expression. Treatment with adipoR1 agonist, AdipoRon, reversed the effects of salusin‑β overexpression. In addition, salusin‑β overexpression enhanced intracellular lipid accumulation in HepG2 cells induced by free fatty acid treatment. These findings highlighted the potential regulatory role of salusin‑β in adipoR1‑mediated signaling pathways. To conclude, the present study provided insights into the regulation of fatty acid metabolism by the liver. In particular, salusin‑β may serve as a potential target for the therapeutic intervention of metabolic disorders of lipids.
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Affiliation(s)
- Aohong Xu
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Lei Wang
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Min Luo
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Huan Zhang
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Meiwei Ning
- Jiamusi College, Heilongjiang University of Chinese Medicine, Jiamusi, Heilongjiang 154007, P.R. China
| | - Jintong Pan
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Xiuqun Duan
- Clinical Laboratory, Ezhou Central Hospital, Ezhou, Hubei 436000, P.R. China
| | - Yuxue Wang
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Xiang Liu
- Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
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Hou B, Ma P, Yang X, Zhao X, Zhang L, Zhao Y, He P, Zhang L, Du G, Qiang G. In silico prediction and experimental validation to reveal the protective mechanism of Puerarin against excessive extracellular matrix accumulation through inhibiting ferroptosis in diabetic nephropathy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117281. [PMID: 37797872 DOI: 10.1016/j.jep.2023.117281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/16/2023] [Accepted: 10/03/2023] [Indexed: 10/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Puerarin (PUR) isolated from the root of Pueraria lobata (Willd.) Ohwi is considered as one of the main medicines to alleviate asthenic splenonephro-yang of diabetic nephropathy (DN). Whereas, the exact mechanism of Puerarin on diabetic nephropathy is still unclear. AIM OF STUDY In this study, we aimed to investigate the protective effects of PUR on type 2 diabetic nephropathy in vivo, in silico and in vitro, as well as unveil the underlying mechanism through inhibiting ferroptosis. MATERIALS AND METHODS In vivo, blood glucose and lipid, renal function, kidney histology and immunohistochemistry analysis were used to vindicate the protective effects of PUR on diabetic nephropathy in type 2 DN rat model. In silico, pharmacophore matching and enrichment analysis were adopted to predict the potential mechanism of PUR on DN. In vitro, we utilized high glucose stress to induce impairment in glomerular mesangial cells (GMCs) as diabetic nephropathy cell model. Cell count kit-8 (CCK-8) was used to observe cell viability. qPCR, Western blot, immunofluorescence staining and flow cytometry were used to evaluate the effect of PUR on the generation of extracellular matrix (ECM), ferroptosis and iron homeostasis in vitro and in vivo. RESULTS PUR markedly improved glucose and lipid metabolism, as well as alleviated renal dysfunction in diabetic nephropathy rats. Pharmacophore matching and enrichment analysis predicted the anti-DN effect of PUR may correlate with ECM. Experimental validation suggested that PUR treatment could inhibit the generation of ECM to alleviate high-glucose-induced cell impairments, suppressing ROS production and excessive collagen fiber accumulation in GMSs, and reduce mesangial matrix expansion and renal fibrosis in type 2 DN rats. Further study suggested that PUR protected GMCs against ferroptosis via reducing LDH release and GSH disruption, suppressing key regulators of two pathways for ferroptosis execution. Moreover, PUR also maintained iron metabolism hemostasis by regulating iron transportation proteins, iron exporter proteins, and iron storage proteins and reducing intracellular iron in type 2 DN rats. CONCLUSION PUR inhibited excessive ECM accumulation to protect against type 2 diabetic nephropathy, which meditated by regulating iron homeostasis and mitigating ferroptosis. This study provides promising therapeutics for diabetic nephropathy treatment.
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Affiliation(s)
- Biyu Hou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Peng Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Xinyu Yang
- Faculty of Biology, Medicine and Health Sciences, The University of Manchester Oxford Road, Manchester, M13 9PL, United Kingdom
| | - Xiaoyue Zhao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China; Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Medical Science Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Li Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China; Inner Mongolia Clinical College, Inner Mongolia Medical University, Hohhot, 010110, China
| | - Yuerong Zhao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Ping He
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Li Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Guanhua Du
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China.
| | - Guifen Qiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China.
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14
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Liu C, Wang W, Gu J. Targeting ferroptosis: New perspectives of Chinese herbal medicine in the treatment of diabetes and its complications. Heliyon 2023; 9:e22250. [PMID: 38076182 PMCID: PMC10709212 DOI: 10.1016/j.heliyon.2023.e22250] [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: 06/03/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 12/28/2024] Open
Abstract
Ferroptosis is a non-apoptotic mode of cell death. A large number of studies have confirmed that ferroptosis plays a vital role in the occurrence and development of diabetes and diabetic complications. Previous studies have found that Chinese herbal medicines have very promising results in the prevention and treatment of diabetes and diabetic complications, and some of these herbs or herbal natural compounds may act via the inhibition of ferroptosis. In this review, we summarized the relationship between ferroptosis and diabetes and diabetic complications, and discussed its molecular mechanisms. We also reviewed the published studies of herbal medicines or herbal natural compounds that improved diabetes or diabetic complications via the ferroptosis pathway. In addition, we are trying to provide new insights for better treatment of diabetes and diabetic complications with Chinese herbal medicine and its herbal compounds.
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Affiliation(s)
- Cuiping Liu
- Department of Endocrinology, The Second People's Hospital of Yibin City-West China Yibin Hospital, Sichuan University, Yibin, Sichuan, PR China
- Clinical Research and Translation Center, Second People's Hospital of Yibin City-West China Yibin Hospital, Sichuan University, Yibin, Sichuan, PR China
| | - Wuxi Wang
- Community Health Service Center of Tongyuanju, Chongqing, PR China
| | - Junling Gu
- Department of Endocrinology, The Second People's Hospital of Yibin City-West China Yibin Hospital, Sichuan University, Yibin, Sichuan, PR China
- Clinical Research and Translation Center, Second People's Hospital of Yibin City-West China Yibin Hospital, Sichuan University, Yibin, Sichuan, PR China
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Kim M, Bae JY, Yoo S, Kim HW, Lee SA, Kim ET, Koh G. 2-Deoxy-d-ribose induces ferroptosis in renal tubular epithelial cells via ubiquitin-proteasome system-mediated xCT protein degradation. Free Radic Biol Med 2023; 208:384-393. [PMID: 37659699 DOI: 10.1016/j.freeradbiomed.2023.08.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/04/2023]
Abstract
Ferroptosis is a novel form of cell death triggered by iron-dependent lipid peroxidation. Recent findings suggest that inhibiting system χc-induces ferroptosis by reducing intracellular cystine levels, and that ferroptosis in renal tubular epithelial cells (RTECs) contributes to acute kidney injury (AKI) and diabetic nephropathy. Moreover, 2-deoxy-d-ribose (dRib) has been shown to inhibit cystine uptake through xCT, the functional unit of system χc-, in β-cells. This study aimed to investigate if dRib induces ferroptosis in RTECs and identify the underlying mechanisms. dRib treatment reduced cystine uptake and glutathione (GSH) content, and increased intracellular levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), lipid reactive oxygen species (ROS), and cell death in both NRK-52E cells and primary cultured RTECs. However, treatment with inhibitors of ferroptosis, such as deferoxamine (DFO), ferrostatin-1 (Fer-1), and liproxstatin-1 (Lip-1), counteracted the effects of dRib on GSH, MDA, 4-HNE, and lipid ROS levels, as well as cell death. Additionally, 2-mercaptoethanol (2-ME) treatment or xCT gene overexpression protected against dRib-induced changes. Moreover, transmission electron microscopy revealed dRib-induced mitochondrial shrinkage, decrease in cristae number, and outer membrane rupture. Furthermore, dRib treatment upregulated the expression of genes associated with ferroptosis, and downregulated xCT protein expression. The decrease in xCT protein caused by dRib was consistently observed even when treated with the protein synthesis inhibitor cycloheximide. However, treatment with the proteasome inhibitor MG132 reversed the dRib-induced decrease in xCT protein expression. Additionally, dRib increased xCT protein ubiquitination. Overall, dRib induces ferroptosis in RTECs by degrading xCT protein through ubiquitin-proteasome system (UPS), resulting in reduced intracellular cystine uptake. Therefore, targeting the regulation of system χc-through UPS could be a potential therapeutic approach for AKI and diabetic nephropathy.
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Affiliation(s)
- Miyeon Kim
- Department of Internal Medicine, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea; Deparment of Internal Medicine, Jeju National University Hospital, 15 Aran 13-gil, Jeju, 63241, Republic of Korea
| | - Ju Young Bae
- Department of Internal Medicine, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea
| | - Soyeon Yoo
- Department of Internal Medicine, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea; Deparment of Internal Medicine, Jeju National University Hospital, 15 Aran 13-gil, Jeju, 63241, Republic of Korea
| | - Hyun Woo Kim
- Department of Internal Medicine, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea; Deparment of Internal Medicine, Jeju National University Hospital, 15 Aran 13-gil, Jeju, 63241, Republic of Korea
| | - Sang Ah Lee
- Department of Internal Medicine, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea; Deparment of Internal Medicine, Jeju National University Hospital, 15 Aran 13-gil, Jeju, 63241, Republic of Korea
| | - Eui Tae Kim
- Department of Microbiology & Immunology, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea
| | - Gwanpyo Koh
- Department of Internal Medicine, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju, 63241, Republic of Korea; Deparment of Internal Medicine, Jeju National University Hospital, 15 Aran 13-gil, Jeju, 63241, Republic of Korea.
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Lv S, Li H, Zhang T, Su X, Sun W, Wang Q, Wang L, Feng N, Zhang S, Wang Y, Cui H. San-Huang-Yi-Shen capsule ameliorates diabetic nephropathy in mice through inhibiting ferroptosis. Biomed Pharmacother 2023; 165:115086. [PMID: 37418978 DOI: 10.1016/j.biopha.2023.115086] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/09/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the main complications of diabetes. However, effective therapy to block or slow down the progression of DN is still lacking. San-Huang-Yi-Shen capsule (SHYS) has been shown to significantly improve renal function and delay the progression of DN. However, the mechanism of SHYS on DN is still unclear. In this study, we established a mouse model of DN. Then, we investigated the anti-ferroptotic effects of SHYS including the reduction of iron overload and the activation of cystine/GSH/GPX4 axis. Finally, we used a GPX4 inhibitor (RSL3) and ferroptosis inhibitor (ferrostatin-1) to determine whether SHYS ameliorates DN through inhibiting ferroptosis. The results showed that SHYS treatment was effective for mice with DN in terms of improving renal function, and reducing inflammation and oxidative stress. Besides, SHYS treatment reduced iron overload and upregulated the expression of cystine/GSH/GPX4 axis-related factors in kidney. Moreover, SHYS exhibited similar therapeutic effect on DN as ferrostatin-1, RSL3 could abolish the therapeutic and anti- ferroptotic effects of SHYS on DN. In conclusion, SHYS can be used to treat mice with DN. Furthermore, SHYS could inhibit ferroptosis in DN through reducing iron overload and upregulating the expression of cystine/GSH/GPX4 axis.
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Affiliation(s)
- Shuquan Lv
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China; Hebei University of Traditional Chinese Medicine, Hebei, China
| | - Huajun Li
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Tianyu Zhang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Xiuhai Su
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Wenjuan Sun
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Qinghai Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Lixin Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Nana Feng
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China
| | - Shufang Zhang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China.
| | - Yuansong Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei, Hebei, China.
| | - Huantian Cui
- Yunnan University of Chinese Medicine, Yunnan, China; Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Shandong, China.
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17
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Fang X, Song J, Chen Y, Zhu S, Tu W, Ke B, Wu L. LncRNA SNHG1 knockdown inhibits hyperglycemia induced ferroptosis via miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy. J Diabetes Investig 2023; 14:1056-1069. [PMID: 37315165 PMCID: PMC10445199 DOI: 10.1111/jdi.14036] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/26/2023] [Accepted: 05/18/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Hyperglycemia accelerates the development of diabetic nephropathy (DN) by inducing renal tubular injury. Nevertheless, the mechanism has not been elaborated fully. Here, the pathogenesis of DN was investigated to seek novel treatment strategies. METHODS A model of diabetic nephropathy was established in vivo, the levels of blood glucose, urine albumin creatinine ratio (ACR), creatinine, blood urea nitrogen (BUN), malondialdehyde (MDA), glutathione (GSH), and iron were measured. The expression levels were detected by qRT-PCR and Western blotting. H&E, Masson, and PAS staining were used to assess kidney tissue injury. The mitochondria morphology was observed by transmission electron microscopy (TEM). The molecular interaction was analyzed using a dual luciferase reporter assay. RESULTS SNHG1 and ACSL4 were increased in kidney tissues of DN mice, but miR-16-5p was decreased. Ferrostatin-1 treatment or SNHG1 knockdown inhibited ferroptosis in high glucose (HG)-treated HK-2 cells and in db/db mice. Subsequently, miR-16-5p was confirmed to be a target for SNHG1, and directly targeted to ACSL4. Overexpression of ACSL4 greatly reversed the protective roles of SNHG1 knockdown in HG-induced ferroptosis of HK-2 cells. CONCLUSIONS SNHG1 knockdown inhibited ferroptosis via the miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy, which provided some new insights for the novel treatment of diabetic nephropathy.
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Affiliation(s)
- Xiangdong Fang
- Department of NephrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Jianling Song
- Department of NephrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Yanxia Chen
- Department of NephrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Shuying Zhu
- Department of NephrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Weiping Tu
- Department of NephrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Ben Ke
- Department of NephrologyThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
| | - Lidong Wu
- Emergency DepartmentThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina
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18
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Zhou C, Wu M, Liu G, Zhou L. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy. Open Life Sci 2023; 18:20220678. [PMID: 37589000 PMCID: PMC10426721 DOI: 10.1515/biol-2022-0678] [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: 04/17/2023] [Revised: 06/14/2023] [Accepted: 07/18/2023] [Indexed: 08/18/2023] Open
Abstract
The aim of this study was to investigate the role of ferroptosis in diabetic nephropathy (DN) and the mechanism of its regulatory genes. HK-2 cells were cultured with high glucose and mice were intraperitoneally injected with streptozotocin to establish DN models. GSE111154 was analyzed to identify the abnormal expression of genes associated with DN. Cell injury was evaluated through CCK-8 assay and 4',6-diamidino-2-phenylindole/phenylindole double staining. The levels of iron, glutathione, malondialdehyde, urinary albumin, and urinary creatinine were determined by ELISA. Furthermore, western blot and RT-qPCR were used to detect protein and mRNA levels, respectively. Our data showed that heterochromatin protein 1 is an abnormally elevated gene related to DN and is further elevated by ferroptosis activators. Inhibition of HP1 significantly inhibited ferroptosis but promoted cell viability. In addition, nuclear factor erythroid2-related factor2 (NRF2) was decreased in DN cell model, but increased under the action of ferroptosis activators. NRF2 silencing reversed the protective effects of HP1 inhibition on HK-2 cells. Additionally, HP1 silencing also alleviated kidney damage in DN mice. Collectively, these findings suggest that inhibiting HP1 inhibits ferroptosis via NRF2 pathway, thereby protecting renal tubular epithelial cells from damage.
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Affiliation(s)
- Chuanqiang Zhou
- Department of Nephrology, The First People’s Hospital of Longquanyi District, Chengdu & West China Longquan Hospital, Sichuan University, No. 669, Donglang Road, Longquanyi District, Chengdu, Sichuan Province 610100, China
| | - Min Wu
- Department of Nephrology, The First People’s Hospital of Longquanyi District, Chengdu & West China Longquan Hospital, Sichuan University, No. 669, Donglang Road, Longquanyi District, Chengdu, Sichuan Province 610100, China
| | - Gaolun Liu
- Department of Nephrology, The First People’s Hospital of Longquanyi District, Chengdu & West China Longquan Hospital, Sichuan University, No. 669, Donglang Road, Longquanyi District, Chengdu, Sichuan Province 610100, China
| | - Li Zhou
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610100, China
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Li L, Dai Y, Ke D, Liu J, Chen P, Wei D, Wang T, Teng Y, Yuan X, Zhang Z. Ferroptosis: new insight into the mechanisms of diabetic nephropathy and retinopathy. Front Endocrinol (Lausanne) 2023; 14:1215292. [PMID: 37600716 PMCID: PMC10435881 DOI: 10.3389/fendo.2023.1215292] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the most serious and common diabetes-associated complications. DN and DR are all highly prevalent and dangerous global diseases, but the underlying mechanism remains to be elucidated. Ferroptosis, a relatively recently described type of cell death, has been confirmed to be involved in the occurrence and development of various diabetic complications. The disturbance of cellular iron metabolism directly triggers ferroptosis, and abnormal iron metabolism is closely related to diabetes. However, the molecular mechanism underlying the role of ferroptosis in DN and DR is still unclear, and needs further study. In this review article, we summarize and evaluate the mechanism of ferroptosis and its role and progress in DN and DR, it provides new ideas for the diagnosis and treatment of DN and DR.
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Affiliation(s)
- Luxin Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Yucen Dai
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Dan Ke
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Jieting Liu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Peijian Chen
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Dong Wei
- Department of Ophthalmology, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, China
| | - Tongtong Wang
- Department of Endocrinology, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, China
| | - Yanjie Teng
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaohuan Yuan
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Zhen Zhang
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
- School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, China
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Wei M, Liu X, Tan Z, Tian X, Li M, Wei J. Ferroptosis: a new strategy for Chinese herbal medicine treatment of diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:1188003. [PMID: 37361521 PMCID: PMC10289168 DOI: 10.3389/fendo.2023.1188003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. It has become a leading cause of death in patients with diabetes and end-stage renal disease. Ferroptosis is a newly discovered pattern of programmed cell death. Its main manifestation is the excessive accumulation of intracellular iron ion-dependent lipid peroxides. Recent studies have shown that ferroptosis is an important driving factor in the onset and development of DN. Ferroptosis is closely associated with renal intrinsic cell (including renal tubular epithelial cells, podocytes, and mesangial cells) damage in diabetes. Chinese herbal medicine is widely used in the treatment of DN, with a long history and definite curative effect. Accumulating evidence suggests that Chinese herbal medicine can modulate ferroptosis in renal intrinsic cells and show great potential for improving DN. In this review, we outline the key regulators and pathways of ferroptosis in DN and summarize the herbs, mainly monomers and extracts, that target the inhibition of ferroptosis.
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Affiliation(s)
- Maoying Wei
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xingxing Liu
- Department of Emergency, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhijuan Tan
- Department of Traditional Chinese Medicine, The Seventh Hospital of Xingtai, Xingtai, Heibei, China
| | - Xiaochan Tian
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingdi Li
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Song SH, Han D, Park K, Um JE, Kim S, Ku M, Yang J, Yoo TH, Yook JI, Kim NH, Kim HS. Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis. Front Endocrinol (Lausanne) 2023; 14:1172199. [PMID: 37293506 PMCID: PMC10244744 DOI: 10.3389/fendo.2023.1172199] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 05/04/2023] [Indexed: 06/10/2023] Open
Abstract
Background Approximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models. Methods We used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion. Results mPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells. Conclusion BMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.
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Affiliation(s)
- Sang Hyun Song
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Dawool Han
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Kyeonghui Park
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Jo Eun Um
- R&D Center, MET Life Science, Seoul, Republic of Korea
| | - Seonghun Kim
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea
- R&D Center, MET Life Science, Seoul, Republic of Korea
| | - Minhee Ku
- Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Convergence Research Center for Systems Molecular Radiological Science, Yonsei University, Seoul, Republic of Korea
| | - Jaemoon Yang
- Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Convergence Research Center for Systems Molecular Radiological Science, Yonsei University, Seoul, Republic of Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jong In Yook
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Nam Hee Kim
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Hyun Sil Kim
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea
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Tian M, Zhi JY, Pan F, Chen YZ, Wang AZ, Jia HY, Huang R, Zhong WH. Bioinformatics analysis identifies potential ferroptosis key genes in the pathogenesis of diabetic peripheral neuropathy. Front Endocrinol (Lausanne) 2023; 14:1048856. [PMID: 37251674 PMCID: PMC10215986 DOI: 10.3389/fendo.2023.1048856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 04/10/2023] [Indexed: 05/31/2023] Open
Abstract
Background Diabetic peripheral neuropathy (DPN) is a serious complication in Diabetes Mellitus (DM) patients and the underlying mechanism is yet unclear. Ferroptosis has been recently intensively researched as a key process in the pathogenesis of diabetes but there yet has been no related bioinformatics-based studies in the context of DPN. Methods We used data mining and data analysis techniques to screen differentially expressed genes (DEGs) and immune cell content in patients with DPN, DM patients and healthy participants (dataset GSE95849). These DEGs were then intersected with the ferroptosis dataset (FerrDb) to obtain ferroptosis DEGs and the associated key molecules and miRNAs interactions were predicted. Results A total of 33 ferroptosis DEGs were obtained. Functional pathway enrichment analysis revealed 127 significantly related biological processes, 10 cellular components, 3 molecular functions and 30 KEGG signal pathways. The biological processes that were significantly enriched were in response to extracellular stimulus and oxidative stress. Key modules constructed by the protein-protein interaction network analysis led to the confirmation of the following genes of interest: DCAF7, GABARAPL1, ACSL4, SESN2 and RB1. Further miRNA interaction prediction revealed the possible involvement of miRNAs such as miR108b-8p, miR34a-5p, mir15b-5p, miR-5838-5p, miR-192-5p, miR-222-3p and miR-23c. Immune-environment content of samples between DM and DPN patients revealed significant difference in the levels of endothelial cells and fibroblasts, which further speculates their possible involvement in the pathogenesis of DPN. Conclusion Our findings could provide insight for investigations about the role of ferroptosis in the development of DPN.
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Affiliation(s)
- Ming Tian
- Burns Department, Shanghai Jiao Tong University Affiliated Ruijin Hospital, Shanghai, China
| | - Jin Yong Zhi
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fan Pan
- Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yong Zhu Chen
- Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ai Zhong Wang
- Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hui Ying Jia
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People's Republic (PR) China, Shanghai, China
- Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Huang
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen Hui Zhong
- Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Li Q, Meng X, Hua Q. Circ ASAP2 decreased inflammation and ferroptosis in diabetic nephropathy through SOX2/SLC7A11 by miR-770-5p. Acta Diabetol 2023; 60:29-42. [PMID: 36153434 DOI: 10.1007/s00592-022-01961-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/16/2022] [Indexed: 01/07/2023]
Abstract
AIMS Diabetes nephropathy (DN) is one of the major complications in diabetes. With the improvement of people's living standards in China in recent years, the incidence of diabetes has become the main cause of end-stage renal disease. However, how and whether circ ASAP2 could mediate DN remain poorly understood. This study aimed to determine the function and its biological mechanism of circ ASAP2 on inflammation and ferroptosis of DN. METHODS C57BL/6 mice were fed with a high-fat diet and injected with streptozotocin. Human renal glomerular endothelial cells stimulated with 20 mmol/L D-glucose. RESULTS In mice model DN, circular ASAP2 expression level was down-regulated, and miR-770-5p expression level was up-regulated. Moreover, the inhibition of ASAP2 aggravated diabetic nephropathy in mice model. The inhibition of ASAP2 promoted inflammation and oxidative stress to aggravate renal injury in mice model. Circular ASAP2 was reducing inflammation and oxidative stress in vitro model. The inhibition of ASAP2 promoted ferroptosis in model of DN. CASAP2 suppressed miR-770-5p in DN. Additionally, miR-770-5p aggravated diabetic nephropathy in mice model. MiR-770-5p promoted inflammation and oxidative stress to aggravate renal injury in mice model. MiR-770-5p was increasing inflammation and oxidative stress in vitro model. Circular ASAP2 induced SLC7A11 expression in model of DN through SOX2 by miR-770-5p. CONCLUSIONS These results suggest that circ ASAP2 decreased inflammation and ferroptosis in DN through SOX2/SLC7A11 by miR-770-5p, which might serve as a target for improving the role of ferroptosis in DN.
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Affiliation(s)
- Qin Li
- Department of Endocrinology, Yijishan Hospital of Wannan Medical College, No.2 Zheshanxi Road, Wuhu, 241001, Anhui, China
| | - Xiangjian Meng
- Department of Endocrinology, Yijishan Hospital of Wannan Medical College, No.2 Zheshanxi Road, Wuhu, 241001, Anhui, China.
| | - Qiang Hua
- Department of Endocrinology, Yijishan Hospital of Wannan Medical College, No.2 Zheshanxi Road, Wuhu, 241001, Anhui, China.
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Chen J, Ou Z, Gao T, Yang Y, Shu A, Xu H, Chen Y, Lv Z. Ginkgolide B alleviates oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination to improve diabetic nephropathy. Biomed Pharmacother 2022; 156:113953. [DOI: 10.1016/j.biopha.2022.113953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/22/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022] Open
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Jayathirtha M, Neagu AN, Whitham D, Alwine S, Darie CC. Investigation of the effects of downregulation of jumping translocation breakpoint (JTB) protein expression in MCF7 cells for potential use as a biomarker in breast cancer. Am J Cancer Res 2022; 12:4373-4398. [PMID: 36225631 PMCID: PMC9548009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/18/2022] [Indexed: 06/16/2023] Open
Abstract
MCF7 is a commonly used luminal type A non-invasive/poor-invasive human breast cancer cell line that does not usually migrate or invade compared with MDA-MB-231 highly metastatic cells, which emphasize an invasive and migratory behavior. Under special conditions, MCF7 cells might acquire invasive features. The aberration in expression and biological functions of the jumping translocation breackpoint (JTB) protein is associated with malignant transformation of cells, based on mitochondrial dysfunction, inhibition of tumor suppressive function of TGF-β, and involvement in cancer cell cycle. To investigate new putative functions of JTB by cellular proteomics, we analyzed the biological processes and pathways that are associated with the JTB protein downregulation. The results demonstrated that MCF7 cell line developed a more "aggressive" phenotype and behavior. Most of the proteins that were overexpressed in this experiment promoted the actin cytoskeleton reorganization that is involved in growth and metastatic dissemination of cancer cells. Some of these proteins are involved in the epithelial-mesenchymal transition (EMT) process (ACTBL2, TUBA4A, MYH14, CSPG5, PKM, UGDH, HSP90AA2, and MIF), in correlation with the energy metabolism reprogramming (PKM, UGDH), stress-response (HSP10, HSP70A1A, HSP90AA2), and immune and inflammatory response (MIF and ERp57-TAPBP). Almost all upregulated proteins in JTB downregulated condition promote viability, motility, proliferation, invasion, survival into a hostile microenvironment, metabolic reprogramming, and escaping of tumor cells from host immune control, leading to a more invasive phenotype for MCF7 cell line. Due to their downregulated condition, four proteins, such as CREBZF, KMT2B, SELENOS and CACNA1I are also involved in maintenance of the invasive phenotype of cancer cells, promoting cell proliferation, migration, invasion and tumorigenesis. Other downregulated proteins, such as MAZ, PLEKHG2, ENO1, TPI2, TOR2A, and CNNM1, may promote suppression of cancer cell growth, invasion, EMT, tumorigenic abilities, interacting with glucose and lipid metabolism, disrupting nuclear envelope stability, or suppressing apoptosis and developing anti-angiogenetic activities. Therefore, the main biological processes and pathways that may increase the tumorigenic potential of the MCF7 cells in JTB downregulated condition are related to the actin cytoskeleton organization, EMT, mitotic cell cycle, glycolysis and fatty acid metabolism, inflammatory response and macrophage activation, chemotaxis and migration, cellular response to stress condition (oxidative stress and hypoxia), transcription control, histone modification and ion transport.
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Affiliation(s)
- Madhuri Jayathirtha
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Anca-Narcisa Neagu
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of IasiCarol I bvd. No. 22, Iasi 700505, Romania
| | - Danielle Whitham
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Shelby Alwine
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Costel C Darie
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
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Fernández-García V, González-Ramos S, Martín-Sanz P, Castrillo A, Boscá L. Unraveling the interplay between iron homeostasis, ferroptosis and extramedullary hematopoiesis. Pharmacol Res 2022; 183:106386. [PMID: 35933006 DOI: 10.1016/j.phrs.2022.106386] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/25/2022] [Accepted: 08/02/2022] [Indexed: 11/25/2022]
Abstract
Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in health and disease. Indeed, iron is associated with both physiological (e.g., immune cell biology and function and hematopoiesis) and pathological (e.g., inflammatory and infectious diseases, ferroptosis and ferritinophagy) processes, yet few studies have addressed the potential functional link between iron, the aforementioned processes and extramedullary hematopoiesis, despite the obvious benefits that this could bring to clinical practice. Further investigation in this direction will shape the future development of individualized treatments for iron-linked diseases and chronic inflammatory disorders, including extramedullary hematopoiesis, metabolic syndrome, cardiovascular diseases and cancer.
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Affiliation(s)
- Victoria Fernández-García
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Universidad Autónoma de Madrid, Madrid, Spain.
| | - Silvia González-Ramos
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
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Schisandrin A from Schisandra chinensis Attenuates Ferroptosis and NLRP3 Inflammasome-Mediated Pyroptosis in Diabetic Nephropathy through Mitochondrial Damage by AdipoR1 Ubiquitination. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5411462. [PMID: 35996380 PMCID: PMC9391610 DOI: 10.1155/2022/5411462] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/16/2022] [Indexed: 11/18/2022]
Abstract
Schisandra chinensis, as a Chinese functional food, is rich in unsaturated fatty acids, minerals, vitamins, and proteins. Hence, this study was intended to elucidate the effects and biological mechanism of Schisandrin A from Schisandra chinensis in DN. C57BL/6 mice were fed with a high-fat diet and then injected with streptozotocin (STZ). Human renal glomerular endothelial cells were stimulated with 20 mmol/L d-glucose for DN model. Schisandrin A presented acute kidney injury in mice of DN. Schisandrin A reduced oxidative stress and inflammation in model of DN. Schisandrin A reduced high glucose-induced ferroptosis and reactive oxygen species (ROS-)-mediated pyroptosis by mitochondrial damage in model of DN. Schisandrin A directly targeted AdipoR1 protein and reduced LPS+ATP-induced AdipoR1 ubiquitination in vitro model. Schisandrin A activated AdipoR1/AMPK signaling pathway and suppressed TXNIP/NLRP3 signaling pathway in vivo and in vitro model of DN. Conclusively, our study revealed that Schisandrin A from Schisandra chinensis attenuates ferroptosis and NLRP3 inflammasome-mediated pyroptosis in DN by AdipoR1/AMPK-ROS/mitochondrial damage. Schisandrin A is a possible therapeutic option for DN or other diabetes.
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Wang X, Jiang L, Liu XQ, Huang YB, Zhu W, Zeng HX, Gao L, Ma LJ, Zhang MY, Zhu QJ, Wu YG. Identification of Genes Reveals the Mechanism of Cell Ferroptosis in Diabetic Nephropathy. Front Physiol 2022; 13:890566. [PMID: 35721535 PMCID: PMC9204496 DOI: 10.3389/fphys.2022.890566] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 04/22/2022] [Indexed: 12/12/2022] Open
Abstract
Aims/Introduction: Diabetic nephropathy (DN) is one of the main complications of diabetes. Genomics may reveal the essential pathogenesis of DN. We analyzed datasets to search for key genes to explore pathological mechanisms of DN. Materials and Methods: In this study, weighted gene co-expression network analysis (WGCNA) was used to divide the differential expression genes (DEGs) from GSE142025 into different modules, and enrichment pathway analysis was conducted for each module to find key genes related to cell death pathway. Then, verification was carried out through network and histopathology. Finally, the regulatory mechanisms of key gene expression, including transcription factors (TFs), miRNA and E3 ligases related to ubiquitination, were predicted through website prediction and then miRNA results were validated using GSE51674 dataset. Results: The results of WGCNA and enrichment pathway analysis indicated that ferroptosis had significantly occurred in advanced DN (AND) group. Analysis of DEGs indicated that the occurrence and development of ferroptosis are mainly through ALOX15-mediated lipid metabolism pathway, which was found in all intrinsic cells of the glomerulus detected by IHC and IF staining. Moreover, network predictions were used for searching ALOX15-related TFs and ubiquitination. Meanwhile, the network predictions combining with other dataset furtherly discovered miRNAs which regulated ALOX15 expression. This study showed that the levels of mmu-miR-142-3p increased in DN mice kidney tissues, compared with the NC group. Conclusion: Ferroptosis existed in glomerular intrinsic cells of ADN group and its potential key candidate gene was ALOX15 which may be regulated by miR-142 and miRNA-650, TFs (CREBBP, EP300, HDAC1, MTA1, SPI1, STAT6) and E3 ligases related to ubiquitination (PML, ZMIZ1, MARCHF1, MARCHF3, MARCHF8, MARCHF11).
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Affiliation(s)
- Xian Wang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ling Jiang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xue-Qi Liu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yue-Bo Huang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Zhu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Han-Xu Zeng
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Gao
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li-Juan Ma
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Meng-Ya Zhang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qi-Jin Zhu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yong-Gui Wu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Center for Scientific Research of Anhui Medical University, Hefei, China
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He J, Li Z, Xia P, Shi A, FuChen X, Zhang J, Yu P. Ferroptosis and ferritinophagy in diabetes complications. Mol Metab 2022; 60:101470. [PMID: 35304332 PMCID: PMC8980341 DOI: 10.1016/j.molmet.2022.101470] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND With long-term metabolic malfunction, diabetes can cause serious damage to whole-body tissue and organs, resulting in a variety of complications. Therefore, it is particularly important to further explore the pathogenesis of diabetes complications and develop drugs for prevention and treatment. In recent years, different from apoptosis and necrosis, ferroptosis has been recognized as a new regulatory mode of cell death and involves the regulation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Evidence shows that ferroptosis and ferritinophagy play a significant role in the occurrence and development of diabetes complications. SCOPE OF REVIEW we systematically review the current understanding of ferroptosis and ferritinophagy, focusing on their potential mechanisms, connection, and regulation, discuss their involvement in diabetes complications, and consider emerging therapeutic opportunities and the associated challenges with future prospects. MAJOR CONCLUSIONS In summary, ferroptosis and ferritinophagy are worthy targets for the treatment of diabetes complications, but their complete molecular mechanism and pathophysiological process still require further study.
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Affiliation(s)
- Jiahui He
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Panpan Xia
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Ao Shi
- School of Medicine, St. George University of London, London, UK; School of Medicine, University of Nicosia, Nicosia, Cyprus
| | - Xinxi FuChen
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China
| | - Jing Zhang
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 30006, China.
| | - Peng Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China; Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China.
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Yang XD, Yang YY. Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications. Front Endocrinol (Lausanne) 2022; 13:853822. [PMID: 35422764 PMCID: PMC9001950 DOI: 10.3389/fendo.2022.853822] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/02/2022] [Indexed: 12/19/2022] Open
Abstract
The global diabetes epidemic and its complications are increasing, thereby posing a major threat to public health. A comprehensive understanding of diabetes mellitus (DM) and its complications is necessary for the development of effective treatments. Ferroptosis is a newly identified form of programmed cell death caused by the production of reactive oxygen species and an imbalance in iron homeostasis. Increasing evidence suggests that ferroptosis plays a pivotal role in the pathogenesis of diabetes and diabetes-related complications. In this review, we summarize the potential impact and regulatory mechanisms of ferroptosis on diabetes and its complications, as well as inhibitors of ferroptosis in diabetes and diabetic complications. Therefore, understanding the regulatory mechanisms of ferroptosis and developing drugs or agents that target ferroptosis may provide new treatment strategies for patients with diabetes.
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Affiliation(s)
- Xi-Ding Yang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
- Phase I Clinical Trial Center, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yong-Yu Yang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Provincial Engineering Research Central of Translational Medical and Innovative Drug, The Second Xiangya Hospital of Central South University, Changsha, China
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Ferroptosis, a new target for treatment of renal injury and fibrosis in a 5/6 nephrectomy-induced CKD rat model. Cell Death Dis 2022; 8:127. [PMID: 35318301 PMCID: PMC8941123 DOI: 10.1038/s41420-022-00931-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 03/01/2022] [Indexed: 11/08/2022]
Abstract
Ferroptosis is a non-traditional form of regulated cell death, characterized by iron overload and lipid peroxidation. Exploration of ferroptosis in chronic kidney disease (CKD) has been extremely limited to date. In this study, we established a rat model of CKD by 5/6 nephrectomy, treated CKD rats with the ferroptosis inducer, cisplatin (CDDP), and the ferroptosis inhibitor, deferoxamine mesylate (DFO), and observed the resulting pathologic changes (injury markers and fibrosis) and ferroptotic biochemical indices. Kidney iron deposition, lipid peroxidation, mitochondrial defects, ferroptosis marker induction, and TUNEL staining positivity were detected in CKD group rats. Further, treatment with CDDP or DFO influenced renal injury and fibrosis by affecting ferroptosis, rather than apoptosis, and ferroptosis occurs in the remnant kidney due to disordered iron metabolism. In conclusion, our study shows for the first time that 5/6 nephrectomy induces ferroptosis in the remnant kidney and clarifies the underlying pathogenesis. Moreover, we demonstrate that ferroptosis is involved in CKD progression and represents a therapeutic target in chronic kidney injury and renal fibrosis.
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Ni L, Yuan C, Wu X. Targeting ferroptosis in acute kidney injury. Cell Death Dis 2022; 13:182. [PMID: 35210424 PMCID: PMC8873203 DOI: 10.1038/s41419-022-04628-9] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 01/24/2022] [Accepted: 02/09/2022] [Indexed: 12/17/2022]
Abstract
AbstractAcute kidney injury (AKI) is a major public health problem with high incidence and mortality. As a form of programmed cell death (PCD), ferroptosis could be considered as a process of iron accumulation and enhanced lipid peroxidation. Recently, the fundamental roles of ferroptosis in AKI have attracted much attention. The network mechanism of ferroptosis in AKI and its roles in the AKI to chronic kidney disease (CKD) transition is complicated and multifactorial. Strategies targeting ferroptosis show great potential. Here, we review the research progress on ferroptosis and its participation in AKI. We hope that this work will provide clues for further studies of ferroptosis in AKI.
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