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Zhang W, Li R, Lu D, Wang X, Wang Q, Feng X, Qi S, Zhang X. Phospholipids and peroxisomes in ferroptosis: the therapeutic target of acupuncture regulating vascular cognitive impairment and dementia. Front Aging Neurosci 2025; 17:1512980. [PMID: 40365351 PMCID: PMC12070441 DOI: 10.3389/fnagi.2025.1512980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 03/26/2025] [Indexed: 05/15/2025] Open
Abstract
Ferroptosis, since its conceptualization in 2012, has witnessed an exponential growth in research interest over recent years. It is regulated by various cellular metabolic pathways during chronic cerebral ischemia and hypoxia, including reactive oxygen species (ROS) generation, iron accumulation, abnormalities in glutathione metabolism, and disruptions in lipid and glucose metabolism. With the deepening and widespread research, ferroptosis has emerged as a critical pathway in the pathogenesis of vascular cognitive impairment and dementia (VCID). This unique cell death pathway caused by iron-dependent phospholipid peroxidation is strongly related to VICD. We examine the impact of phospholipid composition on neuronal susceptibility to ferroptosis, with a particular focus on the critical role of polyunsaturated fatty acids (PUFAs) in this process. Intriguingly, peroxisomes, as key regulators of lipid metabolism and oxidative stress, influence the susceptibility of neuronal cells to ferroptosis through the synthesis of plasmalogens and other lipid species. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of acupuncture for ferroptosis, the potential functions of acupuncture in peroxisomal functions and phospholipid metabolism, and its neuroprotective effects in VCID, together with a potential for therapeutic targeting. As such, this highlights the theoretical basis for the application of acupuncture in VCID through multi-target regulation of ferroptosis. This review underscores the potential of acupuncture as a non-pharmacological therapeutic approach in VCID, offering new insights into its role in modulating ferroptosis and associated metabolic pathways for neuroprotection.
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Affiliation(s)
- Wenyu Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ruiyu Li
- Beijing University of Chinese Medicine Shenzhen Hospital (Longgang), Shenzhen, China
| | - Donglei Lu
- Sports Training Academy of Tianjin University of Sport, Tianjin, China
| | - Xinliang Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qiuxuan Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xuyang Feng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Sai Qi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xuezhu Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Zhuo B, Qin C, Deng S, Jiang H, Si S, Tao F, Cai F, Meng Z. The role of ACSL4 in stroke: mechanisms and potential therapeutic target. Mol Cell Biochem 2025; 480:2223-2246. [PMID: 39496916 PMCID: PMC11961533 DOI: 10.1007/s11010-024-05150-6] [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: 07/11/2024] [Accepted: 10/24/2024] [Indexed: 11/06/2024]
Abstract
Stroke, as a neurological disorder with a poor overall prognosis, has long plagued the patients. Current stroke therapy lacks effective treatments. Ferroptosis has emerged as a prominent subject of discourse across various maladies in recent years. As an emerging therapeutic target, notwithstanding its initial identification in tumor cells associated with brain diseases, it has lately been recognized as a pivotal factor in the pathological progression of stroke. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a potential target and biomarker of catalytic unsaturated fatty acids mediating ferroptosis in stroke. Specifically, the upregulation of ACSL4 leads to heightened accumulation of lipid peroxidation products and reactive oxygen species (ROS), thereby exacerbating the progression of ferroptosis in neuronal cells. ACSL4 is present in various tissues and involved in multiple pathways of ferroptosis. At present, the pharmacological mechanisms of targeting ACSL4 to inhibit ferroptosis have been found in many drugs, but the molecular mechanisms of targeting ACSL4 are still in the exploratory stage. This paper introduces the physiopathological mechanism of ACSL4 and the current status of the research involved in ferroptosis crosstalk and epigenetics, and summarizes the application status of ACSL4 in modern pharmacology research, and discusses the potential application value of ACSL4 in the field of stroke.
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Affiliation(s)
- Bifang Zhuo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chenyang Qin
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shizhe Deng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hailun Jiang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shangkun Si
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Feng Tao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Fei Cai
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
| | - Zhihong Meng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
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Li Q, Yang X, Li T. Natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in central nervous system diseases: current preclinical evidence and future perspectives. Front Pharmacol 2025; 16:1570069. [PMID: 40196367 PMCID: PMC11973303 DOI: 10.3389/fphar.2025.1570069] [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: 02/02/2025] [Accepted: 02/24/2025] [Indexed: 04/09/2025] Open
Abstract
Flavonoids are a class of important polyphenolic compounds, renowned for their antioxidant properties. However, recent studies have uncovered an additional function of these natural flavonoids: their ability to inhibit ferroptosis. Ferroptosis is a key mechanism driving cell death in central nervous system (CNS) diseases, including both acute injuries and chronic neurodegenerative disorders, characterized by iron overload-induced lipid peroxidation and dysfunction of the antioxidant defense system. This review discusses the therapeutic potential of natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in CNS diseases, focusing on their molecular mechanisms, summarizing findings from preclinical animal models, and providing insights for clinical translation. We specifically highlight natural flavonoids such as Baicalin, Baicalein, Chrysin, Vitexin, Galangin, Quercetin, Isoquercetin, Eriodictyol, Proanthocyanidin, (-)-epigallocatechin-3-gallate, Dihydromyricetin, Soybean Isoflavones, Calycosin, Icariside II, and Safflower Yellow, which have shown promising results in animal models of acute CNS injuries, including ischemic stroke, cerebral ischemia-reperfusion injury, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury. Among these, Baicalin and its precursor Baicalein stand out due to extensive research and favorable outcomes in acute injury models. Mechanistically, these flavonoids not only regulate the Nrf2/ARE pathway and activate GPX4/GSH-related antioxidant pathways but also modulate iron metabolism proteins, thereby alleviating iron overload and inhibiting ferroptosis. While flavonoids show promise as ferroptosis inhibitors for CNS diseases, especially in acute injury settings, further studies are needed to evaluate their efficacy, safety, pharmacokinetics, and blood-brain barrier penetration for clinical application.
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Affiliation(s)
- Qiuhe Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaohang Yang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Tiegang Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China
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Xu DJ, Wang GT, Zhong Q. Extracellular matrix gene set and microRNA network in intestinal ischemia-reperfusion injury: Insights from RNA sequencing for diagnosis and therapy. World J Gastrointest Surg 2025; 17:100034. [DOI: 10.4240/wjgs.v17.i2.100034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/26/2024] [Accepted: 12/06/2024] [Indexed: 01/22/2025] Open
Abstract
Intestinal ischemia-reperfusion injury (IIRI) is a complex and severe pathophysiological process characterized by oxidative stress, inflammation, and apoptosis. In recent years, the critical roles of extracellular matrix (ECM) genes and microRNAs (miRNAs) in IIRI have garnered widespread attention. This review aims to systematically summarize the diagnostic and therapeutic potential of ECM gene sets and miRNA regulatory networks in IIRI. First, we review the molecular mechanisms of IIRI, focusing on the dual role of the ECM in tissue injury and repair processes. The expression changes and functions of ECM components such as collagen, elastin, and matrix metalloproteinases during IIRI progression are deeply analyzed. Second, we systematically summarize the regulatory roles of miRNAs in IIRI, particularly the mechanisms and functions of miRNAs such as miR-125b and miR-200a in regulating inflammation, apoptosis, and ECM remodeling. Additionally, this review discusses potential diagnostic biomarkers and treatment strategies based on ECM genes and miRNAs. We extensively evaluate the prospects of miRNA-targeted therapy and ECM component modulation in preventing and treating IIRI, emphasizing the clinical translational potential of these emerging therapies. In conclusion, the diagnostic and therapeutic potential of ECM gene sets and miRNA regulatory networks in IIRI provides new directions for further research, necessitating additional clinical and basic studies to validate and expand these findings for improving clinical outcomes in IIRI patients.
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Affiliation(s)
- Dao-Jian Xu
- Department of Emergency Medicine, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang Province, China
| | - Guo-Tao Wang
- Department of Emergency Medicine, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang Province, China
| | - Qiang Zhong
- Department of Emergency Medicine, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang Province, China
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Gowtham A, Chauhan C, Rahi V, Kaundal RK. An update on the role of ferroptosis in ischemic stroke: from molecular pathways to Neuroprotection. Expert Opin Ther Targets 2024; 28:1149-1175. [PMID: 39710973 DOI: 10.1080/14728222.2024.2446319] [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: 06/07/2024] [Revised: 11/29/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION Ischemic stroke (IS), a major cause of mortality and disability worldwide, remains a significant healthcare challenge due to limited therapeutic options. Ferroptosis, a distinct iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress, has emerged as a crucial mechanism in IS pathophysiology. This review explores the role of ferroptosis in IS and its potential for driving innovative therapeutic strategies. AREA COVERED This review delves into the practical implications of ferroptosis in IS, focusing on molecular mechanisms like lipid peroxidation, iron accumulation, and their interplay with inflammation, reactive oxygen species (ROS), and the Nrf2-ARE antioxidant system. It highlights ferroptotic proteins, small-molecule inhibitors, and non-coding RNA modulators as emerging therapeutic targets to mitigate neuroinflammation and neuronal cell death. Studies from PubMed (1982-2024) were identified using MeSH terms such as 'Ferroptosis' and 'Ischemic Stroke,' and only rigorously screened articles were included. EXPERT OPINION Despite preclinical evidence supporting the neuroprotective effects of ferroptosis inhibitors, clinical translation faces hurdles such as suboptimal pharmacokinetics and safety concerns. Advances in drug delivery systems, bioinformatics, and AI-driven drug discovery may optimize ferroptosis-targeting strategies, develop biomarkers, and improve therapeutic outcomes for IS patients.
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Affiliation(s)
- A Gowtham
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Lucknow, India
| | - Chandan Chauhan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Lucknow, India
| | - Vikrant Rahi
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Lucknow, India
| | - Ravinder K Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Lucknow, India
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Tan Y, Yu Y, Niu H, Wang C, Mo P, Li D, Zhang Q, Feng D, Liu C. Profile of miRNA expression in the hippocampus of epileptic mice and the prediction of potential therapeutic targets. Mol Biol Rep 2024; 51:929. [PMID: 39172288 DOI: 10.1007/s11033-024-09861-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024]
Abstract
Epilepsy is a common neurological disease. Increasing evidence has highlighted the role of miRNAs in the molecular mechanisms underlying the development of neurological diseases such as epilepsy. In this study, we established a lithium chloride-pilocarpine epilepsy mouse model, performed miRNA sequencing of hippocampal tissue samples, and compared the obtained miRNA expression profile with that of normal control mice to determine differences in expression levels. We found that 55 miRNAs were differentially expressed in status epilepticus mice compared with normal control mice, with 38 upregulated and 17 downregulated miRNAs. Through subsequent analysis of the five downregulated miRNAs (mmu-let-7a-1-3p, mmu-let-7a-2-3p, mmu-let-7c-5p, mmu-let-7d-5p, and mmu-let-7e-5p) with the most significant differences in expression, the key pathways involved included the MAPK signaling pathway and focal adhesion, among others. Therefore, we believe that let-7 family miRNAs may be potential therapeutic targets for epilepsy.
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Affiliation(s)
- Yafu Tan
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yongjia Yu
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Haodong Niu
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Chunxi Wang
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Panlin Mo
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Dongqiao Li
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Qing Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Daqin Feng
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
- State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning, Guangxi, 530021, China.
| | - Chang Liu
- Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
- State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning, Guangxi, 530021, China.
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Fan B, Zhang Y, Luo Q, Hao C, Liao W. Physical and social environmental enrichment alleviate ferroptosis and inflammation with inhibition of TLR4/MyD88/p38MAPK pathway in chronic cerebral hypoperfusion rats. Brain Res Bull 2024; 208:110897. [PMID: 38340777 DOI: 10.1016/j.brainresbull.2024.110897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/30/2024] [Accepted: 02/06/2024] [Indexed: 02/12/2024]
Abstract
A typical enriched environment (EE), which combines physical activity and social interaction, has been proven to mitigate cognitive impairment caused by chronic cerebral hypoperfusion (CCH). However, it remains unclear how the different components of EE promote cognitive recovery after CCH. This study stripped out the different components of EE into physical environmental enrichment (PE) and social environmental enrichment (SE), and compared the neuroprotective effects of PE, SE and typical EE (PSE) in CCH. The results of novel object recognition and Morris water maze tests showed that PE, SE, and PSE improved cognitive function in CCH rats. Additionally, Nissl and TUNEL staining revealed that three EEs reduced neuronal loss in the hippocampus. PSE exhibited superior neuroprotective and functional improvement effects compared to PE and SE, while there was no significant difference between PE and SE. Furthermore, three EEs reduced lipid peroxidation in the hippocampus with decreasing the levels of MDA and increasing the activities of SOD and GSH. The expression of SLC7A11 and GPX4 was increased, while the level of p53 was reduced in three EEs. This suggested that three EEs inhibited ferroptosis by maintaining the redox homeostasis in the hippocampus. Three EEs reduced the levels of IL-β, TNF-α, and IL-6, thereby inhibiting neuroinflammation. Additionally, Western blotting and immunofluorescence results indicated that three EEs also inhibited the TLR4/MyD88/p38MAPK signaling pathway. These findings collectively demonstrated that the three EEs alleviated hippocampal ferroptosis and neuroinflammation in CCH rats, thereby reducing neuronal loss, which might be associated with the inhibition of the TLR4/MyD88/p38MAPK signaling pathway. Moreover, the study results supported that it is only through the combination of physical exercise and social interaction that the optimal neuroprotective effects can be achieved. These findings provided valuable insights for the prevention and treatment of vascular cognitive impairment.
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Affiliation(s)
- Bin Fan
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ying Zhang
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qihang Luo
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chizi Hao
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Weijing Liao
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
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Tian X, Li X, Pan M, Yang LZ, Li Y, Fang W. Progress of Ferroptosis in Ischemic Stroke and Therapeutic Targets. Cell Mol Neurobiol 2024; 44:25. [PMID: 38393376 PMCID: PMC10891262 DOI: 10.1007/s10571-024-01457-6] [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: 11/28/2023] [Accepted: 01/24/2024] [Indexed: 02/25/2024]
Abstract
Ferroptosis is an iron-dependent form of programmed cell death (PCD) and ischemic stroke (IS) has been confirmed to be closely related to ferroptosis. The mechanisms of ferroptosis were summarized into three interrelated aspects: iron metabolism, lipid peroxide metabolism, as well as glutathione and amino acid metabolism. What's more, the causal relationship between ferroptosis and IS has been elucidated by several processes. The disruption of the blood-brain barrier, the release of excitatory amino acids, and the inflammatory response after ischemic stroke all lead to the disorder of iron metabolism and the antioxidant system. Based on these statements, we reviewed the reported effects of compounds and drugs treating IS by modulating key molecules in ferroptosis. Through detailed analysis of the roles of these key molecules, we have also more clearly demonstrated the essential effect of ferroptosis in the occurrence of IS so as to provide new targets and ideas for the therapeutic targets of IS.
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Affiliation(s)
- Xinjuan Tian
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Xiang Li
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Mengtian Pan
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Lele Zixin Yang
- The Pennsylvania State University, State College, PA, 16801, USA
| | - Yunman Li
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People's Republic of China.
| | - Weirong Fang
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People's Republic of China.
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Chavoshinezhad S, Beirami E, Izadpanah E, Feligioni M, Hassanzadeh K. Molecular mechanism and potential therapeutic targets of necroptosis and ferroptosis in Alzheimer's disease. Biomed Pharmacother 2023; 168:115656. [PMID: 37844354 DOI: 10.1016/j.biopha.2023.115656] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/01/2023] [Accepted: 10/04/2023] [Indexed: 10/18/2023] Open
Abstract
Alzheimer's disease (AD), a neurodegenerative condition, is defined by neurofibrillary tangles, amyloid plaques, and gradual cognitive decline. Regardless of the advances in understanding AD's pathogenesis and progression, its causes are still contested, and there are currently no efficient therapies for the illness. The post-mortem analyses revealed widespread neuronal loss in multiple brain regions in AD, evidenced by a decrease in neuronal density and correlated with the disease's progression and cognitive deterioration. AD's neurodegeneration is complicated, and different types of neuronal cell death, alone or in combination, play crucial roles in this process. Recently, the involvement of non-apoptotic programmed cell death in the neurodegenerative mechanisms of AD has received a lot of attention. Aberrant activation of necroptosis and ferroptosis, two newly discovered forms of regulated non-apoptotic cell death, is thought to contribute to neuronal cell death in AD. In this review, we first address the main features of necroptosis and ferroptosis, cellular signaling cascades, and the mechanisms involved in AD pathology. Then, we discuss the latest therapies targeting necroptosis and ferroptosis in AD animal/cell models and human research to provide vital information for AD treatment.
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Affiliation(s)
- Sara Chavoshinezhad
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Elmira Beirami
- Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Esmael Izadpanah
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Marco Feligioni
- Laboratory of Neuronal Cell Signaling, EBRI Rita Levi-Montalcini Foundation, 00161 Rome, Italy; Department of Neurorehabilitation Sciences, Casa di Cura del Policlinico, 20144 Milan, Italy.
| | - Kambiz Hassanzadeh
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
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Ding K, Liu C, Li L, Yang M, Jiang N, Luo S, Sun L. Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism. Chin Med J (Engl) 2023; 136:2521-2537. [PMID: 37442770 PMCID: PMC10617883 DOI: 10.1097/cm9.0000000000002533] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Indexed: 07/15/2023] Open
Abstract
ABSTRACT Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4) is an enzyme that esterifies CoA into specific polyunsaturated fatty acids, such as arachidonic acid and adrenic acid. Based on accumulated evidence, the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation. Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids; ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis, respectively. In addition, ACSL4 is an essential regulator of fatty acid (FA) metabolism. ACSL4 remodels the phospholipid composition of cell membranes, regulates steroidogenesis, and balances eicosanoid biosynthesis. In addition, ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology. Because it facilitates the cross-talk between ferroptosis and FA metabolism, ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries. In this review, we focus on the structure, biological function, and unique role of ASCL4 in various human diseases. Finally, we propose that ACSL4 might be a potential therapeutic target.
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Affiliation(s)
- Kaiyue Ding
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
| | - Chongbin Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
| | - Li Li
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
| | - Na Jiang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410000, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410000, China
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Zhang J, Cai W, Wei X, Shi Y, Zhang K, Hu C, Wan J, Luo K, Shen W. Moxibustion ameliorates cerebral ischemia-reperfusion injury by regulating ferroptosis in rats. Clin Exp Pharmacol Physiol 2023; 50:779-788. [PMID: 37417429 DOI: 10.1111/1440-1681.13801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/25/2023] [Accepted: 05/29/2023] [Indexed: 07/08/2023]
Abstract
Moxibustion is an effective treatment for the clinical management of acute cerebral infarction. However, its exact mechanism of action is still not fully understood. This study aimed to investigate the protective effect of moxibustion on cerebral ischemia-reperfusion injury (CIRI) in rats. Middle cerebral artery occlusion/reperfusion (MCAO/R) was used to construct a CIRI rat model, all animals were randomly divided into four groups including sham operation group, MCAO/R group (MCAO/R), moxibustion therapy + MCAO/R (Moxi) and ferrostatin-1 + MCAO/R (Fer-1) group. In the Moxi group, moxibustion treatment was initiated 24 h after modeling, once a day for 30 mins each time for 7 days. Moreover, the Fer-1 group received intraperitoneal injections of Fer-1 12 h after modeling, once a day for a total of 7 days. The results showed that moxibustion could reduce nerve function damage and neuronal death. Additionally, moxibustion could reduce the production of lipid peroxides such as lipid peroxide, malondialchehyche and ACSL4 to regulate lipid metabolism, promote the production of glutathione and glutathione peroxidase 4 and reduce the expression of hepcidin by inhibiting the production of inflammatory factor interleukin-6, therefore, downregulating the expression of SLC40A1, reducing the iron level in the cerebral cortex, reducing the accumulation of reactive oxygen species and inhibiting ferroptosis. Based on our studies, it can be concluded that moxibustion has the ability to inhibit ferroptosis of nerve cells post CIRI and plays a protective role in the brain. This protective role can be attributed to the regulation of iron metabolism of nerve cells, reduction of iron deposition in the hippocampus and lowering the level of lipid peroxidation.
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Affiliation(s)
- JingRuo Zhang
- Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Acupuncture and Moxibustion, Jiaxing Hospital of TCM, Zhejiang Chinese Medicine University, Jiaxing, China
| | - Wa Cai
- Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xifang Wei
- Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanbo Shi
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Hospital of TCM, Zhejiang Chinese Medicine University, Jiaxing, China
| | - Kun Zhang
- Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chen Hu
- Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Wan
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kaitao Luo
- Department of Acupuncture and Moxibustion, Jiaxing Hospital of TCM, Zhejiang Chinese Medicine University, Jiaxing, China
| | - Weidong Shen
- Department of Acupuncture, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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12
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Chen F, Kang R, Liu J, Tang D. The ACSL4 Network Regulates Cell Death and Autophagy in Diseases. BIOLOGY 2023; 12:864. [PMID: 37372148 DOI: 10.3390/biology12060864] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/05/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023]
Abstract
Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.
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Affiliation(s)
- Fangquan Chen
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiao Liu
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
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13
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Wang Y, Qiu L, Jiang W, Chen M, He Z, Wang Y, Deng S. Genetic variants in the promoters of let-7 are associated with the risk and age at onset of ischemic stroke: A case control study. J Stroke Cerebrovasc Dis 2023; 32:106998. [PMID: 36780761 DOI: 10.1016/j.jstrokecerebrovasdis.2023.106998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 02/13/2023] Open
Abstract
PURPOSE Let-7 family members serve as crucial regulatory molecules in the pathogenesis of ischemic stroke. We predicted that genetic variations in the let-7 family's promoters may be linked to the risk of ischemic stroke. The connection of rs10877887 and rs13293512 in the let-7 family promoters with liability to ischemic stroke was explored in this study. PATIENTS AND METHODS Clinical data and peripheral blood samples were collected from 914 ischemic stroke patients and 836 controls in this case-control study. All statistical analyses were carried out using SPSS. RESULTS Our analysis results reveal that the rs10877887 TC+CC genotype in the dominant model is associated with a lower risk of ischemic stroke than the TT genotype. Individuals with heterozygous TC or homozygous CC genotypes in the male population showed higher odds of ischemic stroke than those with the wild TT genotype in rs13293512 analysis. Furthermore, there existed a multiplicative interaction between the rs10877887 C allele and the rs13293512 T allele. In the presence of the rs13293512 T allele, the effect of the rs10877887 C allele on ischemic stroke risk was increased. Similarly, in the presence of the rs10877887 C allele, the outcome of the rs13293512 T allele on ischemic stroke risk was elevated. In addition, the rs13293512 CC genotype seemed to lead to an earlier onset of ischemic stroke. CONCLUSION Our findings indicated that these two SNPs might have a joint role in IS and could potentially act as risk markers. Detecting let-7 promoter polymorphisms could raise awareness of the risk of IS, which directed individuals with risk alleles to have regular checks at an appropriate frequency to avoid developing the disease.
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Affiliation(s)
- Yuye Wang
- Department of Neurology, China-Japan Friendship Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100029, China; Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Luying Qiu
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Wenjuan Jiang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Meilin Chen
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Zhiyi He
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Yanzhe Wang
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
| | - Shumin Deng
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
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14
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Zan CF, Wei WF, Li JA, Shi MP, Cong L, Gu MY, Chen YH, Wang SY, Li ZH. Circulating exosomal lncRNA contributes to the pathogenesis of spinal cord injury in rats. Neural Regen Res 2023; 18:889-894. [DOI: 10.4103/1673-5374.353504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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15
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Xu Y, Li K, Zhao Y, Zhou L, Liu Y, Zhao J. Role of Ferroptosis in Stroke. Cell Mol Neurobiol 2023; 43:205-222. [PMID: 35102454 PMCID: PMC11415219 DOI: 10.1007/s10571-022-01196-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/18/2022] [Indexed: 01/07/2023]
Abstract
Stroke is a common and serious nervous system disease caused by the rupture or blockage of the cardiovascular system. It causes millions of deaths and disabilities every year, which is a huge burden on humanity. It may be induced by thrombosis, hypertension, hyperlipidemia, hyperglycemia, smoking, advanced age and so on. According to different causes, stroke can be generally divided into hemorrhagic stroke and ischemic stroke, whose pathogenesis and treatment are quite different. Ferroptosis is a new type of cell death first defined in 2012, which is characterized by non-apoptotic, iron-dependent, and over-accumulated lipid peroxides. Excess lipid reactive oxygen species produced during ferroptosis eventually leads to oxidative cell death. Ferroptosis has been shown to occur and play an important role in tumors, neurological diseases, kidney injury, and ischemia-reperfusion injury. Ferroptosis is also closely related to the pathogenesis of stroke. Moreover, scientists have successfully intervened in the process of stroke in animal models by regulating ferroptosis, indicating that ferroptosis is a new potential target for the treatment of stroke. This paper systematically summarizes the involvement and role of ferroptosis in the pathogenesis of stroke and predicts the potential of ferroptosis in the treatment of stroke. Ferroptosis in stroke. Stroke induces iron overload and lipid metabolism disorders. Elevated iron catalyzes lipid peroxidation and eventually triggers ferroptosis. Conversely, the GSH/GPX4 pathway, as well as CoQ10, Fer-1, and Lip-1, inhibits lipid peroxidation and, thus, alleviates ferroptosis. GSH glutathione; GPX4 glutathione peroxidase 4; CoQ10 coenzyme Q10; Lip-1 liproxstatin-1; Fer-1 ferostatin-1.
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Affiliation(s)
- Yunfei Xu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, Hunan, China
- China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410008, Hunan, China
| | - Kexin Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, Hunan, China
- China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410008, Hunan, China
| | - Yao Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, Hunan, China
- China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410008, Hunan, China
| | - Lin Zhou
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, Hunan, China
- China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410008, Hunan, China
| | - Ying Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China.
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, Hunan, China.
- China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410008, Hunan, China.
| | - Jie Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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16
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Neri S, Gasparini S, Pascarella A, Santangelo D, Cianci V, Mammì A, Lo Giudice M, Ferlazzo E, Aguglia U. Epilepsy in Cerebrovascular Diseases: A Narrative Review. Curr Neuropharmacol 2023; 21:1634-1645. [PMID: 35794769 PMCID: PMC10514540 DOI: 10.2174/1570159x20666220706113925] [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: 01/14/2022] [Revised: 03/31/2022] [Accepted: 05/31/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Epilepsy is a common comorbidity of cerebrovascular disease and an increasing socioeconomic burden. OBJECTIVE We aimed to provide an updated comprehensive review on the state of the art about seizures and epilepsy in stroke, cerebral haemorrhage, and leukoaraiosis. METHODS We selected English-written articles on epilepsy, stroke, and small vessel disease up until December 2021. We reported the most recent data about epidemiology, pathophysiology, prognosis, and management for each disease. RESULTS The main predictors for both ES and PSE are the severity and extent of stroke, the presence of cortical involvement and hemorrhagic transformation, while PSE is also predicted by younger age at stroke onset. Few data exist on physiopathology and seizure semiology, and no randomized controlled trial has been performed to standardize the therapeutic approach to post-stroke epilepsy. CONCLUSION Some aspects of ES and PSE have been well explored, particularly epidemiology and risk factors. On the contrary, few data exist on physiopathology, and existing evidence is mainly based on studies on animal models. Little is also known about seizure semiology, which may also be difficult to interpret by non-epileptologists. Moreover, the therapeutic approach needs standardization as regards indications and the choice of specific ASMs. Future research may help to better elucidate these aspects.
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Affiliation(s)
- Sabrina Neri
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
| | - Sara Gasparini
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
| | - Angelo Pascarella
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
| | - Domenico Santangelo
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
| | - Vittoria Cianci
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
| | - Anna Mammì
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Michele Lo Giudice
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Edoardo Ferlazzo
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
| | - Umberto Aguglia
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
- Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy
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17
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Wu Z, Sun J, Liao Z, Qiao J, Chen C, Ling C, Wang H. An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases. Front Neurosci 2022; 16:1030512. [PMID: 36507355 PMCID: PMC9731139 DOI: 10.3389/fnins.2022.1030512] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/07/2022] [Indexed: 11/25/2022] Open
Abstract
Long-chain acyl-coenzyme A synthetases (ACSLs) are a family of CoA synthetases that activate fatty acid (FA) with chain lengths of 12-20 carbon atoms by forming the acyl-AMP derivative in an isozyme-specific manner. This family mainly includes five members (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6), which are thought to have specific and different functions in FA metabolism and oxidative stress of mammals. Accumulating evidence shows that the dysfunction of ACSLs is likely to affect cell proliferation and lead to metabolic diseases in multiple organs and systems through different signaling pathways and molecular mechanisms. Hence, a central theme of this review is to emphasize the therapeutic implications of ACSLs in nervous system disorders.
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Affiliation(s)
- Zhimin Wu
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jun Sun
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhi Liao
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jia Qiao
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chuan Chen
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cong Ling
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hui Wang
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China,*Correspondence: Hui Wang,
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18
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Li C, Wu Z, Xue H, Gao Q, Zhang Y, Wang C, Zhao P. Ferroptosis contributes to hypoxic-ischemic brain injury in neonatal rats: Role of the SIRT1/Nrf2/GPx4 signaling pathway. CNS Neurosci Ther 2022; 28:2268-2280. [PMID: 36184790 PMCID: PMC9627393 DOI: 10.1111/cns.13973] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 02/06/2023] Open
Abstract
AIMS Hypoxic-ischemic brain injury (HIBI) often results in cognitive impairments. Herein, we investigated the roles of ferroptosis in HIBI and the underlying signaling pathways. METHODS Ferrostatin-1 (Fer-1) or resveratrol (Res) treatments were administered intracerebroventricularly 30 min before HIBI in 7-day-old rats. Glutathione peroxidase 4 (GPx4) expression, malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, and the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured after HIBI. Additionally, the weight ratio of left/right hemisphere, brain morphology, Nissl staining, and the Morris water maze test were conducted to estimate brain damage. RESULTS At 24-h post-HIBI, GPx4 expression was decreased, and MDA concentration and iron content were increased in the hippocampus. HIBI led to mitochondrial atrophy, brain atrophy/damage, and resultant learning and memory impairments, which were alleviated by Fer-1-mediated inhibition of ferroptosis. Furthermore, Res-mediated SIRT1 upregulation increased Nrf2 and GPx4 expression, thereby attenuating ferroptosis, reducing brain atrophy/damage, and improving learning and memory abilities. CONCLUSION The results demonstrated that during HIBI, ferroptosis occurs via the SIRT1/Nrf2/GPx4 signaling pathway, suggesting it as a potential therapeutic target for inhibiting ferroptosis and ameliorating HIBI-induced cognitive impairments.
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Affiliation(s)
- Chang Li
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Ziyi Wu
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Hang Xue
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Qiushi Gao
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Yahan Zhang
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Changming Wang
- Department of AnesthesiologyPeople's Hospital of China Medical University (Liaoning Provincial People's Hospital)ShenyangLiaoningChina
| | - Ping Zhao
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
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19
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Can U, Marzioglu E, Akdu S. Some miRNA expressions and their targets in ischemic stroke. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2022; 41:1224-1262. [PMID: 35876186 DOI: 10.1080/15257770.2022.2098974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/15/2022] [Accepted: 07/02/2022] [Indexed: 06/15/2023]
Abstract
Ischemic stroke (IS) is a global health challenge leading to life-long disabilities or the deaths of patients. IS is a complex disease where genetic and environmental factors are both concerned with the pathophysiology of the condition. Here, we aimed to investigate various microRNA (miRNA) expressions and their targets in IS. A rapid and accurate diagnosis of acute IS is important to perform appropriate treatment. Therefore, there is a need for a more rapid and simple tool to carry out an acute diagnosis of IS. miRNAs are small RNA molecules serving as precious biomarkers due to their easy detection and stability in blood samples. The present systematic review aimed to summarize previous studies investigating several miRNA expressions and their targets in IS.
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Affiliation(s)
- Ummugulsum Can
- Department of Biochemistry, Konya City Hospital, Konya, Türkiye
| | - Ebru Marzioglu
- Department of Genetics, Konya Training and Research Hospital, Konya, Türkiye
| | - Sadinaz Akdu
- Department of Biochemistry, Fethiye State Hospital, Muğla, Turkey
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20
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Li S, Zhang L, Lin J, Su A, Liu X, Zhang J, Xian X, Hu Y, Li W, Sun S, Zhang M. LncRNA BIRF Promotes Brain Ischemic Tolerance Induced By Cerebral Ischemic Preconditioning Through Upregulating GLT-1 via Sponging miR-330-5p. Mol Neurobiol 2022; 59:3996-4014. [PMID: 35451738 PMCID: PMC9167204 DOI: 10.1007/s12035-022-02841-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/04/2022] [Indexed: 10/24/2022]
Abstract
Long noncoding RNAs (lncRNAs) play an important regulatory role in various diseases. However, the role of lncRNAs in brain ischemic tolerance (BIT) induced by cerebral ischemic preconditioning (CIPC) is still unknown. The lncRNA profile of rat cortical astrocytes pretreated with ischemic preconditioning was analyzed by high-throughput sequencing. The results of Cell-Counting Kit-8 (CCK-8) assay showed that a novel lncRNA, NONRATT009133.2, which we referred to as brain ischemia-related factor (BIRF), was highly correlated with BIT. Through bioinformatics analysis, we predicted that BIRF, miR-330-5p, and GLT-1 (also named Slc1a2) might constitute a ceRNA regulatory network in the induction of BIT. We found that BIRF was upregulated by CIPC, which promoted GLT-1 expression and BIT induction. BIRF could directly bind to miR-330-5p. Furthermore, miR-330-5p directly targeted GLT-1, and miR-330-5p inhibited both GLT-1 expression and BIT induction in vitro and in vivo. Moreover, BIRF acts as a molecular sponge to competitively bind to miR-330-5p with GLT-1 mRNA, while the miR-330-5p inhibitor reversed all the effects of BIRF siRNA on GLT-1 expression and neuronal vitality. Taken together, our results demonstrate the important roles of the BIRF/miR-330-5p/GLT-1 axis in the induction of BIT by CIPC. BIRF may be a potentially effective therapeutic strategy against stroke injury.
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Affiliation(s)
- Shichao Li
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Lingyan Zhang
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Jiajie Lin
- Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Department of Biochemistry and Molecular Biology, Cardiovascular Medical Science Center, Shijiazhuang, China
| | - Achou Su
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Xiyun Liu
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Jingge Zhang
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Xiaohui Xian
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Yuyan Hu
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Wenbin Li
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Shaoguang Sun
- Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Department of Biochemistry and Molecular Biology, Cardiovascular Medical Science Center, Shijiazhuang, China.
| | - Min Zhang
- Key Laboratory of Critical Disease Mechanism and intervention of Hebei Province, Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China.
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21
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Fang XL, Ding SY, Du XZ, Wang JH, Li XL. Ferroptosis—A Novel Mechanism With Multifaceted Actions on Stroke. Front Neurol 2022; 13:881809. [PMID: 35481263 PMCID: PMC9035991 DOI: 10.3389/fneur.2022.881809] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/21/2022] [Indexed: 12/30/2022] Open
Abstract
As a neurological disease with high morbidity, disability, and mortality, the pathological mechanism underlying stroke involves complex processes such as neuroinflammation, oxidative stress, apoptosis, autophagy, and excitotoxicity; but the related research on these molecular mechanisms has not been effectively applied in clinical practice. As a form of iron-dependent regulated cell death, ferroptosis was first discovered in the pathological process of cancer, but recent studies have shown that ferroptosis is closely related to the onset and development of stroke. Therefore, a deeper understanding of the relationship between ferroptosis and stroke may lead to more effective treatment strategies. Herein, we reviewed the mechanism(s) underlying the onset of ferroptosis in stroke, the potential role of ferroptosis in stroke, and the crosstalk between ferroptosis and other pathological mechanisms. This will further deepen our understanding of ferroptosis and provide new approaches to the treatment of stroke.
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Affiliation(s)
- Xiao-Ling Fang
- College of Acupuncture and Massage, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Shao-Yun Ding
- College of Acupuncture and Massage, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Xiao-Zheng Du
- College of Acupuncture and Massage, Gansu University of Traditional Chinese Medicine, Lanzhou, China
- *Correspondence: Xiao-Zheng Du
| | - Jin-Hai Wang
- Department of Traditional Chinese Medicine, The Second Hospital of Lanzhou University, Lanzhou, China
- Jin-Hai Wang
| | - Xing-Lan Li
- College of Acupuncture and Massage, Gansu University of Traditional Chinese Medicine, Lanzhou, China
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22
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Li Y, Zheng W, Lu Y, Zheng Y, Pan L, Wu X, Yuan Y, Shen Z, Ma S, Zhang X, Wu J, Chen Z, Zhang X. BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease. Cell Death Dis 2021; 13:14. [PMID: 34930907 PMCID: PMC8688453 DOI: 10.1038/s41419-021-04469-y] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/26/2021] [Accepted: 12/10/2021] [Indexed: 02/07/2023]
Abstract
Mitophagy is a highly conserved cellular process that maintains the mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. The mitochondrial outer membrane protein BNIP3L/Nix serves as a mitophagy receptor by recognizing autophagosomes. BNIP3L is initially known to clear the mitochondria during the development of reticulocytes. Recent studies indicated it also engages in a variety of physiological and pathological processes. In this review, we provide an overview of how BNIP3L induces mitophagy and discuss the biological functions of BNIP3L and its regulation at the molecular level. We further discuss current evidence indicating the involvement of BNIP3L-mediated mitophagy in human disease, particularly in cancer and neurological disorders.
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Affiliation(s)
- Yue Li
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Wanqing Zheng
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Yangyang Lu
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Yanrong Zheng
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmacology Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ling Pan
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Xiaoli Wu
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Yang Yuan
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Zhe Shen
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Shijia Ma
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Xingxian Zhang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China
| | - Jiaying Wu
- Department of Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhong Chen
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China.
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmacology Science, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Xiangnan Zhang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China.
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Yang S, Li X, Bi T. Exosomal microRNA-150-5p from bone marrow mesenchymal stromal cells mitigates cerebral ischemia/reperfusion injury via targeting toll-like receptor 5. Bioengineered 2021; 13:3030-3043. [PMID: 34898357 PMCID: PMC8973841 DOI: 10.1080/21655979.2021.2012402] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
MicroRNA (miR)-150-5p has been investigated in many studies, while the role of exosomal miR-150-5p from bone arrow mesenchymal stromal cells (BMSCs) on cerebral ischemia/reperfusion (I/R) injury is not fully explored. This research aims to probe the effects of exosomal miR-150-5p from BMSCs on cerebral I/R injury via regulating B-cell translocation gene 2 (TLR5). Bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exo) were isolated and identified. The middle cerebral artery occlusion (MCAO) rat model was established and treated by BMSCs-Exo. Then, functional assays were conducted to explore neurological function, pathological changes, neuron apoptosis and inflammatory factors in MCAO rats. miR-150-5p and TLR5 expression in rat brain tissues were detected. Then, gain and loss-function assays were conducted to determine the impact of exosomes, miR-150-5p and TLR5 on neurological function, pathological changes, neuron apoptosis and inflammatory factors of MCAO rats. The binding relation between miR-150-5p and TLR5 was validated. It was found that miR-150-5p expression was decreased while TLR5 level was augmented in MCAO rats. BMSCs-Exo could improve neurological function, pathological changes, decelerate neuron apoptosis and reduce inflammatory factors in MCAO rats. Enriched miR-150-5pcould enhance the protective effects of BMSCs-Exo on cerebral I/R injury. The elevated TLR5 reversed the impacts of elevated exosomal miR-150-5p on cerebral I/R injury. TLR5 was targeted by miR-150-5p. This research manifested that exosomal miR-150-5p from BMSCs exerts protective effects on cerebral I/R injury via repressing TLR5. This study provided novel therapeutic targets for the treatment of cerebral I/R injury.
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Affiliation(s)
- Shuo Yang
- Department of Geriatrics, Daqing Oilfield General Hospital, 163000, Daqing, , Heilongjiang, P.R.China
| | - Xue Li
- Department of Geriatrics, Daqing Oilfield General Hospital, 163000, Daqing, , Heilongjiang, P.R.China
| | - Ting Bi
- Department of Geriatrics, Daqing Oilfield General Hospital, 163000, Daqing, , Heilongjiang, P.R.China
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Zhao L, Li J, Kälviäinen R, Jolkkonen J, Zhao C. Impact of drug treatment and drug interactions in post-stroke epilepsy. Pharmacol Ther 2021; 233:108030. [PMID: 34742778 DOI: 10.1016/j.pharmthera.2021.108030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 12/21/2022]
Abstract
Stroke is a huge burden on our society and this is expected to grow in the future due to the aging population and the associated co-morbidities. The improvement of acute stroke care has increased the survival rate of stroke patients, and many patients are left with permanent disability, which makes stroke the main cause of adult disability. Unfortunately, many patients face other severe complications such as post-stroke seizures and epilepsy. Acute seizures (ASS) occur within 1 week after the stroke while later occurring unprovoked seizures are diagnosed as post-stroke epilepsy (PSE). Both are associated with a poor prognosis of a functional recovery. The underlying neurobiological mechanisms are complex and poorly understood. There are no universal guidelines on the management of PSE. There is increasing evidence for several risk factors for ASS/PSE, however, the impacts of recanalization, drugs used for secondary prevention of stroke, treatment of stroke co-morbidities and antiseizure medication are currently poorly understood. This review focuses on the common medications that stroke patients are prescribed and potential drug interactions possibly complicating the management of ASS/PSE.
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Affiliation(s)
- Lanqing Zhao
- Department of Sleep Medicine Center, The Shengjing Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
| | - Jinwei Li
- Department of Stroke Center, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China
| | - Reetta Kälviäinen
- Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital, Full Member of ERN EpiCARE, Kuopio, Finland; Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jukka Jolkkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
| | - Chuansheng Zhao
- Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
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Research Progress of Ferroptosis: A Bibliometrics and Visual Analysis Study. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:2178281. [PMID: 34413966 PMCID: PMC8370827 DOI: 10.1155/2021/2178281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/13/2021] [Accepted: 07/29/2021] [Indexed: 01/15/2023]
Abstract
Background Ferroptosis is a type of cell death with major topic of debate under current research and plays an important role in disease regulation. Objective In this study, the literature management software Bibexcel and knowledge graph tool VOSviewer were used to summarize and analyze the international research trends and hotspots about ferroptosis in recent years, which highlight the disease mechanism, diagnosis, and treatment related to ferroptosis. Material/Methods. The core collection database of Web of Science was used for retrieving ferroptosis research literature. The information such as the amount of text, the country, the period, the institution, the fund, and the keywords was extracted by the bibliometric tool Bibexcel. The cooccurrence and clustering function of VOSviewer were used to analyze the high-frequency keywords and the cooperative network of the author, institution, and country. Results The research of ferroptosis started late and was formally proposed in 2012. It has developed rapidly and presented an “exponential” growth trend. China, the United States, Germany, Japan, and France are the main national forces of ferroptosis research development. The United States and China have a relatively high degree of support and attention to ferroptosis. Exploring oxidative stress, inducers/inhibitors, synergistic antitumor effect, relationships with other cell death types, GSH/GPX4 and iron metabolism imbalance related mechanisms of ferroptosis, and ferroptosis in the nervous system disease, ischemia-reperfusion injury, tumor, inflammation, and age-related diseases are the hot research directions. Conclusion Ferroptosis has been a research hotspot in the field of biomedicine in recent years and has attracted the attention of scholars all over the world. The occurrence mechanism of ferroptosis and its application in neurological diseases, ischemia and reperfusion injury, tumors, inflammation, and aging are the hot directions of current research. In the future, ferroptosis can be appropriately considered for strengthening new approaches, new diseases, new inductors, new inhibitors, clinical transformation, and traditional medicine research.
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Zhang Y, Lu X, Tai B, Li W, Li T. Ferroptosis and Its Multifaceted Roles in Cerebral Stroke. Front Cell Neurosci 2021; 15:615372. [PMID: 34149358 PMCID: PMC8209298 DOI: 10.3389/fncel.2021.615372] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 04/09/2021] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system xc–, all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.
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Affiliation(s)
- Yongfa Zhang
- Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunhua Hospital, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Xiaoyang Lu
- Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China.,Translational Neurosurgery and Neurobiology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Bai Tai
- Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunhua Hospital, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Weijia Li
- Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunhua Hospital, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Tao Li
- Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunhua Hospital, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
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Song S, Gao Y, Sheng Y, Rui T, Luo C. Targeting NRF2 to suppress ferroptosis in brain injury. Histol Histopathol 2020; 36:383-397. [PMID: 33242213 DOI: 10.14670/hh-18-286] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Brain injury is accompanied by serious iron metabolism disorder and oxidative stress. As a novel form of regulated cell death (RCD) depending on lipid peroxidation caused by iron overload, ferroptosis (FPT) further aggravates brain injury, which is different from apoptosis, autophagy and other traditional cell death in terms of biochemistry, morphology and genetics. Noteworthy, transcriptional regulator NRF2 plays a key role in the cell antioxidant system, and many genes related to FPT are under the control of NRF2, including genes for iron regulation, thiol-dependent antioxidant system, enzymatic detoxification of RCS and carbonyls, NADPH regeneration and ROS sources from mitochondria or extra-mitochondria, which place NRF2 in the key position of regulating the ferroptotic death. Importantly, NRF2 can reduce iron load and resist FPT. In the future, it is expected to open up a new way to treat brain injury by targeting NRF2 to alleviate FPT in brain.
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Affiliation(s)
- Shunchen Song
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yaxuan Gao
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yi Sheng
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Tongyu Rui
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chengliang Luo
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China.
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She X, Lan B, Tian H, Tang B. Cross Talk Between Ferroptosis and Cerebral Ischemia. Front Neurosci 2020; 14:776. [PMID: 32848555 PMCID: PMC7423876 DOI: 10.3389/fnins.2020.00776] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022] Open
Abstract
Recently, ferroptosis has been revealed as a new form of regulated cell death. Distinct from apoptosis and necrosis, ferroptosis is evoked by iron-dependent lipid peroxidation. Furthermore, the metabolism of iron, lipids, and amino acids plays a significant regulatory role in ferroptosis, which can be reversed by glutathione peroxidase 4 and ferroptosis suppressor protein 1. Ferroptosis is implicated in the onset and development of numerous neurological diseases. Emerging studies have reported that ferroptosis induces and aggravates brain tissue damage following cerebral ischemia, whereas inhibition of ferroptosis dramatically attenuates induced damage. In this review, we have summarized the mechanistic relationship between ferroptosis and cerebral ischemia, including through iron overload, downregulation of glutathione peroxidase 4, and upregulation of lipid peroxidation. Although considerable attention has been paid to the effect of ferroptosis on cerebral ischemic injury, specific mechanisms need to be experimentally confirmed, including how cerebral ischemia induces ferroptosis and how ferroptosis deteriorates cerebral ischemia.
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Affiliation(s)
- Xu She
- Department of Physiology, Hunan University of Chinese Medicine, Changsha, China
| | - Bin Lan
- Department of Physiology, Hunan University of Chinese Medicine, Changsha, China
| | - Haomei Tian
- Department of Physiology, Hunan University of Chinese Medicine, Changsha, China
| | - Biao Tang
- Department of Physiology, Hunan University of Chinese Medicine, Changsha, China
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Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury. Sci Rep 2020; 10:7012. [PMID: 32332879 PMCID: PMC7181679 DOI: 10.1038/s41598-020-63686-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 04/03/2020] [Indexed: 12/17/2022] Open
Abstract
Stroke and subsequent cerebral ischemia/reperfusion (I/R) injury is a frequently occurring disease that can have serious consequences in the absence of timely intervention. Circular RNAs (circRNAs) in association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression. However, whether circRNAs have a role in cerebral I/R injury pathogenesis, especially soon after onset, is unclear. In this study, we used the SD rat middle cerebral artery occlusion (MCAO) model of stroke to examine the role of circRNAs in cerebral I/R injury. We used high-throughput sequencing (HTS) to compare the expression levels of circRNAs in cerebral cortex tissue from MCAO rats during the occlusion-reperfusion latency period 3 hours after I/R injury with those in control cerebral cortices. Our sequencing results revealed that expression levels of 44 circRNAs were significantly altered after I/R, with 16 and 28 circRNAs showing significant up- and down-regulation, respectively, relative to levels in control cortex. We extended these results in vitro in primary cultured neuron cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) using qRT-PCR to show that levels of circ-camk4 were increased in OGD/R neurons relative to control neurons. Bioinformatics analyses predicted that several miRNAs could be associated with circ-camk4 and this prediction was confirmed in a RNA pull-down assay. KEGG analysis to predict pathways that involve circ-camk4 included the glutamatergic synapse pathway, MAPK signaling pathway, and apoptosis signaling pathways, all of which are known to be involved in brain injury after I/R. Our results also demonstrate that levels of the human homolog to circ-camk4 (hsa-circ-camk4) are elevated in SH-SY5Y cells exposed to OGD/R treatment. Overexpression of hsa-circ-camk4 in SH-SY5Y cells significantly increased the rate of cell death after OGD/R, suggesting that circ-camk4 may play a key role in progression of cerebral I/R injury.
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30
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Yan N, Zhang JJ. The Emerging Roles of Ferroptosis in Vascular Cognitive Impairment. Front Neurosci 2019; 13:811. [PMID: 31447633 PMCID: PMC6691122 DOI: 10.3389/fnins.2019.00811] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/22/2019] [Indexed: 12/16/2022] Open
Abstract
Vascular cognitive impairment (VCI) is a clinical syndrome that encompasses all forms of cognitive deficits caused by cerebrovascular disease, from mild cognitive impairment to dementia. Vascular dementia, the second most common type of dementia after Alzheimer’s disease (AD), accounts for approximately 20% of dementia patients. Ferroptosis is a recently defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death. Emerging evidence suggests that ferroptosis has significant implications in neurological diseases such as stroke, traumatic brain injury, and AD. Additionally, ferroptosis inhibition has an obvious neuroprotective effect and ameliorates cognitive impairment in various animal models. Here, we summarize the underlying mechanisms of ferroptosis and review the close relationship between ferroptosis and VCI.
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Affiliation(s)
- Nao Yan
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jun-Jian Zhang
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China
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Forouzanfar F, Shojapour M, Asgharzade S, Amini E. Causes and Consequences of MicroRNA Dysregulation Following Cerebral Ischemia-Reperfusion Injury. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2019; 18:212-221. [DOI: 10.2174/1871527318666190204104629] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/31/2018] [Accepted: 01/25/2019] [Indexed: 12/31/2022]
Abstract
Stroke continues to be a major cause of death and disability worldwide. In this respect, the
most important mechanisms underlying stroke pathophysiology are inflammatory pathways, oxidative
stress, as well as apoptosis. Accordingly, miRNAs are considered as non-coding endogenous RNA
molecules interacting with their target mRNAs to inhibit mRNA translation or reduce its transcription.
Studies in this domain have similarly shown that miRNAs are strongly associated with coronary artery
disease and correspondingly contributed to the brain ischemia molecular processes. To retrieve articles
related to the study subject, i.e. the role of miRNAs involved in inflammatory pathways, oxidative
stress, and apoptosis in stroke from the databases of Web of Science, PubMed (NLM), Open Access
Journals, LISTA (EBSCO), and Google Scholar; keywords including cerebral ischemia, microRNA
(miRNA), inflammatory pathway, oxidative stress, along with apoptosis were used. It was consequently
inferred that, miRNAs could be employed as potential biomarkers for diagnosis and prognosis, as
well as therapeutic goals of cerebral ischemia.
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Affiliation(s)
- Fatemeh Forouzanfar
- Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mana Shojapour
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
| | - Samira Asgharzade
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Amini
- UKM Medical Centre [HUKM], Department of Medicine, Faculty of Medicine, Malaysia
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32
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Ma Q, Zhang L, Pearce WJ. MicroRNAs in brain development and cerebrovascular pathophysiology. Am J Physiol Cell Physiol 2019; 317:C3-C19. [PMID: 30840494 DOI: 10.1152/ajpcell.00022.2019] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
MicroRNAs (miRNAs) are a class of highly conserved non-coding RNAs with 21-25 nucleotides in length and play an important role in regulating gene expression at the posttranscriptional level via base-paring with complementary sequences of the 3'-untranslated region of the target gene mRNA, leading to either transcript degradation or translation inhibition. Brain-enriched miRNAs act as versatile regulators of brain development and function, including neural lineage and subtype determination, neurogenesis, synapse formation and plasticity, neural stem cell proliferation and differentiation, and responses to insults. Herein, we summarize the current knowledge regarding the role of miRNAs in brain development and cerebrovascular pathophysiology. We review recent progress of the miRNA-based mechanisms in neuronal and cerebrovascular development as well as their role in hypoxic-ischemic brain injury. These findings hold great promise, not just for deeper understanding of basic brain biology but also for building new therapeutic strategies for prevention and treatment of pathologies such as cerebral ischemia.
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Affiliation(s)
- Qingyi Ma
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine , Loma Linda, California
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine , Loma Linda, California
| | - William J Pearce
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine , Loma Linda, California
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Zhang R, Zhou W, Yu Z, Yang L, Liu G, Yu H, Zhou Q, Min Z, Zhang C, Wu Q, Hu XM, Yuan Q. miR-1247-3p mediates apoptosis of cerebral neurons by targeting caspase-2 in stroke. Brain Res 2019; 1714:18-26. [PMID: 30779911 DOI: 10.1016/j.brainres.2019.02.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/14/2019] [Accepted: 02/15/2019] [Indexed: 11/28/2022]
Abstract
Brain stroke is one of the leading causes of death worldwide. We explored a potential stroke-related role for a newly found microRNA, miR-1247-3p, and one of its target genes, caspase-2, predicted by TargetScanVert. In the present study, we found that miR-1247-3p was downregulated during ischemia/reperfusion (I/R) and that LV-miR-1247-3p overexpression attenuated brain impairment induced by I/R. Similar results were observed in neuro2a (N2a) cells treated with oxygen-glucose deprivation/reoxygenation (OGD/R). Caspase-2 was upregulated in the I/R and OGD/R model, while Z-VDVAD-FMK - the inhibitor of caspase-2-inhibited apoptosis of N2a cells induced by OGD/R. An miR-1247-3p mimic inhibited caspase-2 expression and attenuated apoptosis of N2a cells induced by OGD/R. Myocardin-related transcription factor-A (MRTF-A) overexpression upregulated miR-1247 and mature miR-1247-3p levels and attenuated apoptosis induced by OGD/R, whereas its anti-apoptotic function could be blocked by a miR-1247-3p inhibitor. Hence, we conclude that miR-1247-3p may protect cells during brain stroke. This study offers insights for the development of effective therapeutics for promoting the survival of cerebral neurons during brain I/R injury.
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Affiliation(s)
- Rong Zhang
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China; Department of Biomedical Engineering, School of Medicine and School of Engineering, The University of Alabama at Birmingham, USA
| | - Weipin Zhou
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Zhijun Yu
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Ling Yang
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Guangqi Liu
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Haotian Yu
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Qianyi Zhou
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Zhenli Min
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Chunxiang Zhang
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China; Department of Biomedical Engineering, School of Medicine and School of Engineering, The University of Alabama at Birmingham, USA; Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Qingming Wu
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
| | - Xia-Min Hu
- College of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Qiong Yuan
- New Drug Innovation and Development Institute, Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, China; Department of Biomedical Engineering, School of Medicine and School of Engineering, The University of Alabama at Birmingham, USA; Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
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Oh SE, Park HJ, He L, Skibiel C, Junn E, Mouradian MM. The Parkinson's disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress. Redox Biol 2018; 19:62-73. [PMID: 30107296 PMCID: PMC6092527 DOI: 10.1016/j.redox.2018.07.021] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/28/2018] [Accepted: 07/31/2018] [Indexed: 12/18/2022] Open
Abstract
DJ-1 is a highly conserved protein that protects neurons against oxidative stress and whose loss of function mutations are linked to recessively inherited Parkinson's disease (PD). While a number of signaling pathways have been shown to be regulated by DJ-1, its role in controlling cell survival through non-coding RNAs remains poorly understood. Here, using a microarray screen, we found that knocking down DJ-1 in human neuroblastoma cells results in down-regulation of microRNA-221 (miR-221). This is one of the most abundant miRNAs in the human brain and promotes neurite outgrowth and neuronal differentiation. Yet the molecular mechanism linking miR-221 to genetic forms of PD has not been studied. Consistent with the microarray data, miR-221 expression is also decreased in DJ-1-/- mouse brains. Re-introduction of wild-type DJ-1, but not its PD-linked pathogenic M26I mutant, restores miR-221 expression. Notably, over-expression of miR-221 is protective against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death, while inhibition of endogenous miR-221 sensitizes cells to this toxin. Additionally, miR-221 down-regulates the expression of several pro-apoptotic proteins at basal conditions and prevents oxidative stress-induced up-regulation of bcl-2-like protein 11 (BIM). Accordingly, miR-221 protects differentiated DJ-1 knock-down ReNcell VM human dopaminergic neuronal cells from MPP+-induced neurite retraction and cell death. DJ-1 is a known activator of the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) pathway and may modulate miR-221 levels in part through this pathway. We found that inhibiting ERK1/2 decreases miR-221 levels, whereas over-expressing ERK1 in DJ-1 knock-down cells increases miR-221 levels. These findings point to a new cytoprotective mechanism by which DJ-1 may increase miR-221 expression through the MAPK/ERK pathway, subsequently leading to repression of apoptotic molecules. The inability of a pathogenic DJ-1 mutant to modulate miR-221 further supports the relevance of this mechanism in neuronal health and its failure in DJ-1-linked PD.
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Affiliation(s)
- Stephanie E Oh
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA
| | - Hye-Jin Park
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA
| | - Liqiang He
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA
| | - Catherine Skibiel
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA
| | - Eunsung Junn
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA
| | - M Maral Mouradian
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA.
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Yang H, Rajah G, Guo A, Wang Y, Wang Q. Pathogenesis of epileptic seizures and epilepsy after stroke. Neurol Res 2018; 40:426-432. [PMID: 29681214 DOI: 10.1080/01616412.2018.1455014] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Huajun Yang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Beijing Institute for Brain Disorders, Beijing, China
| | - Gary Rajah
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Anchen Guo
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Beijing Institute for Brain Disorders, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Beijing Institute for Brain Disorders, Beijing, China
| | - Qun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Beijing Institute for Brain Disorders, Beijing, China
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Aitbaev KA, Murkamilov IT, Fomin VV, Murkamilova JA, Yusupov FA. MicroRNA in ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118:48-56. [DOI: 10.17116/jnevro20181183248-56] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Salta E, De Strooper B. microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer's disease. FASEB J 2017; 31:424-433. [PMID: 28148775 DOI: 10.1096/fj.201601308] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 12/12/2016] [Indexed: 12/20/2022]
Abstract
With the consideration of the broad involvement of microRNAs (miRNAs) in the regulation of molecular networks in the brain, it is not surprising that miRNA dysregulation causes neurodegeneration in animal models. miRNA profiling in the human brain has revealed miR-132 as one of the most severely down-regulated miRNAs at the intermediate and late Braak stages of Alzheimer's disease (AD), as well as in other neurodegenerative disorders. Suppression of miR-132 aggravates multiple layers of pathology at the molecular and functional level. We describe the potential therapeutic implications of these findings and suggest miRNA targeting or replacement as a realistic multi-hit, therapeutic strategy for AD. Salta, E., De Strooper, B. microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer's disease.
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Affiliation(s)
- Evgenia Salta
- Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease, VIB-Leuven, Leuven, Belgium; .,Center for Human Genetics, Universitaire Ziekenhuizen and Leuven Research Institute for Neuroscience and Disease, KU-Leuven, Leuven, Belgium; and
| | - Bart De Strooper
- Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease, VIB-Leuven, Leuven, Belgium; .,Center for Human Genetics, Universitaire Ziekenhuizen and Leuven Research Institute for Neuroscience and Disease, KU-Leuven, Leuven, Belgium; and.,Institute of Neurology, University College London, London, United Kingdom
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Maitrias P, Metzinger-Le Meuth V, Nader J, Reix T, Caus T, Metzinger L. The Involvement of miRNA in Carotid-Related Stroke. Arterioscler Thromb Vasc Biol 2017; 37:1608-1617. [PMID: 28775076 DOI: 10.1161/atvbaha.117.309233] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 07/19/2017] [Indexed: 12/18/2022]
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in developed countries. Stroke is associated with a marked disability burden and has a major economic impact; this is especially true for carotid artery stroke. Major advances in primary and secondary prevention during the last few decades have helped to tackle this public health problem. However, better knowledge of the physiopathology of stroke and its underlying genetic mechanisms is needed to improve diagnosis and therapy. miRNAs are an important, recently identified class of post-transcriptional regulators of gene expression and are known to be involved in cerebrovascular disease. These endogenous, small, noncoding RNAs may have applications as noninvasive biomarkers and therapeutic tools in practice. Here, we review the involvement of several miRNAs in cell-based and whole-animal models of stroke, with a focus on human miRNA profiling studies of carotid artery stroke. Lastly, we describe the miRNAs' potential role as a biomarker of stroke.
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Affiliation(s)
- Pierre Maitrias
- From the Department of Cardiovascular Surgery, Amiens University Hospital, France (P.M., J.N., T.R., T.C.); University Paris 13, Sorbonne Paris Cite, UFR SMBH, Bobigny, France (V.M.-L.M.); INSERM Unit-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, Centre Universitaire de Recherche en Santé, University Picardie Jules Verne, Amiens, France (P.M., V.M.-L.M., J.N., T.C., L.M.); Medicine College, Jules Verne University of Picardie, Amiens, France (P.M., T.R.); and Department of Biochemistry, Center of Human Biology, Amiens University Hospital, France (L.M.).
| | - Valérie Metzinger-Le Meuth
- From the Department of Cardiovascular Surgery, Amiens University Hospital, France (P.M., J.N., T.R., T.C.); University Paris 13, Sorbonne Paris Cite, UFR SMBH, Bobigny, France (V.M.-L.M.); INSERM Unit-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, Centre Universitaire de Recherche en Santé, University Picardie Jules Verne, Amiens, France (P.M., V.M.-L.M., J.N., T.C., L.M.); Medicine College, Jules Verne University of Picardie, Amiens, France (P.M., T.R.); and Department of Biochemistry, Center of Human Biology, Amiens University Hospital, France (L.M.)
| | - Joseph Nader
- From the Department of Cardiovascular Surgery, Amiens University Hospital, France (P.M., J.N., T.R., T.C.); University Paris 13, Sorbonne Paris Cite, UFR SMBH, Bobigny, France (V.M.-L.M.); INSERM Unit-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, Centre Universitaire de Recherche en Santé, University Picardie Jules Verne, Amiens, France (P.M., V.M.-L.M., J.N., T.C., L.M.); Medicine College, Jules Verne University of Picardie, Amiens, France (P.M., T.R.); and Department of Biochemistry, Center of Human Biology, Amiens University Hospital, France (L.M.)
| | - Thierry Reix
- From the Department of Cardiovascular Surgery, Amiens University Hospital, France (P.M., J.N., T.R., T.C.); University Paris 13, Sorbonne Paris Cite, UFR SMBH, Bobigny, France (V.M.-L.M.); INSERM Unit-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, Centre Universitaire de Recherche en Santé, University Picardie Jules Verne, Amiens, France (P.M., V.M.-L.M., J.N., T.C., L.M.); Medicine College, Jules Verne University of Picardie, Amiens, France (P.M., T.R.); and Department of Biochemistry, Center of Human Biology, Amiens University Hospital, France (L.M.)
| | - Thierry Caus
- From the Department of Cardiovascular Surgery, Amiens University Hospital, France (P.M., J.N., T.R., T.C.); University Paris 13, Sorbonne Paris Cite, UFR SMBH, Bobigny, France (V.M.-L.M.); INSERM Unit-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, Centre Universitaire de Recherche en Santé, University Picardie Jules Verne, Amiens, France (P.M., V.M.-L.M., J.N., T.C., L.M.); Medicine College, Jules Verne University of Picardie, Amiens, France (P.M., T.R.); and Department of Biochemistry, Center of Human Biology, Amiens University Hospital, France (L.M.)
| | - Laurent Metzinger
- From the Department of Cardiovascular Surgery, Amiens University Hospital, France (P.M., J.N., T.R., T.C.); University Paris 13, Sorbonne Paris Cite, UFR SMBH, Bobigny, France (V.M.-L.M.); INSERM Unit-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, Centre Universitaire de Recherche en Santé, University Picardie Jules Verne, Amiens, France (P.M., V.M.-L.M., J.N., T.C., L.M.); Medicine College, Jules Verne University of Picardie, Amiens, France (P.M., T.R.); and Department of Biochemistry, Center of Human Biology, Amiens University Hospital, France (L.M.)
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Sørensen SS, Nygaard AB, Carlsen AL, Heegaard NHH, Bak M, Christensen T. Elevation of brain-enriched miRNAs in cerebrospinal fluid of patients with acute ischemic stroke. Biomark Res 2017; 5:24. [PMID: 28702194 PMCID: PMC5504978 DOI: 10.1186/s40364-017-0104-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 07/03/2017] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the potential of cerebrospinal fluid miRNAs as diagnostic biomarkers of acute ischemic stroke using three different profiling techniques in order to identify and bypass any influence from technical variation. METHODS Cerebrospinal fluid (CSF) from patients with acute ischemic stroke (n = 21) and controls (n = 21) was collected by lumbar puncture. miRNA analysis was performed with three different methods: 1) Trizol RNA extraction followed by Illumina Next Generation Sequencing (NGS) on all small RNAs, 2) Exiqon RNA extraction protocol and miRNA qPCR assays, and 3) validation of 24 selected miRNAs with Norgen Biotek RNA extraction protocol and Applied Biosystems qPCR assays. RESULTS NGS detected 71 frequently expressed miRNAs in CSF of which brain-enriched miR-9-5p and miR-128-3p were significantly higher in CSF of stroke patients compared to controls. When dividing stroke patients into groups according to infarct size several brain-enriched miRNAs (miR-9-5p, miR-9-3p, miR-124-3p, and miR-128-3p) were elevated in patients with infarcts >2 cm3. This trend appeared in data from both NGS, qPCR (Exiqon), and qPCR (Applied Biosystems) but was only statistically significant in some of the measurement platforms. CONCLUSIONS Several brain-enriched miRNAs are elevated in the CSF three days after stroke onset, suggesting that these miRNAs reflect the brain damage caused by ischemia. The expression differences seem, however, limited to patients with larger ischemic brain injury, which argues against the use of CSF miRNAs as diagnostic biomarkers of stroke based on current methods.
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Affiliation(s)
- Sofie Sølvsten Sørensen
- Department of Neurology, Nordsjællands Hospital, University of Copenhagen, Dyrehavevej 29, 3400 Hillerød, Denmark
| | - Ann-Britt Nygaard
- Department of Clinical Biochemistry, Nordsjællands Hospital, Hillerød, Denmark
| | - Anting Liu Carlsen
- Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark
| | - Niels H H Heegaard
- Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark
| | - Mads Bak
- Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Christensen
- Department of Neurology, Nordsjællands Hospital, University of Copenhagen, Dyrehavevej 29, 3400 Hillerød, Denmark
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An rs13293512 polymorphism in the promoter of let-7 is associated with a reduced risk of ischemic stroke. J Thromb Thrombolysis 2017; 42:610-5. [PMID: 27530126 DOI: 10.1007/s11239-016-1400-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The expression of let-7 family members was differentiated in ischemic stroke (IS), functioning as an important regulating molecular in the pathophysiology of stroke. We hypothesized that genetic polymorphism in the promoters of let-7 family may be associated with the risk of IS. To test this hypothesis, we investigated the association of the rs10877887 and rs13293512 in the promoters of let-7 family with the susceptibility to IS. A hospital-based case-control study was performed. The rs10877887 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay, and the rs13293512 genotype was determined by using a TaqMan assay. We found that the rs13293512CC genotype was associated with a reduced risk of IS (CC vs. TT: adjusted OR = 0.43, 95 % CI 0.26-0.71; dominant model: adjusted OR = 0.70, 95 % CI 0.49-0.98; recessive model: adjusted OR = 0.45, 95 % CI, 0.28-0.73). Stratification analysis showed that the rs10877887TT carriers had a higher level of total cholesterol compared to rs10877887TC/CC carriers (P = 0.03). Combined analysis showed that the rs10877887TC/CC and rs13293512TC/CC genotypes had a reduced risk of IS risk (adjusted OR = 0.58, 95 % CI 0.36-0.95). Our findings suggest that the rs13293512 polymorphism may be a protective factor for the development of IS.
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Chandran R, Mehta SL, Vemuganti R. Non-coding RNAs and neuroprotection after acute CNS injuries. Neurochem Int 2017; 111:12-22. [PMID: 28131900 DOI: 10.1016/j.neuint.2017.01.015] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 01/17/2017] [Accepted: 01/24/2017] [Indexed: 02/07/2023]
Abstract
Accumulating evidence indicates that various classes of non-coding RNAs (ncRNAs) including microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and long non-coding RNAs (lncRNAs) play important roles in normal state as well as the diseases of the CNS. Interestingly, ncRNAs have been shown to interact with messenger RNA, DNA and proteins, and these interactions could induce epigenetic modifications and control transcription and translation, thereby adding a new layer of genomic regulation. The ncRNA expression profiles are known to be altered after acute CNS injuries including stroke, traumatic brain injury and spinal cord injury that are major contributors of morbidity and mortality worldwide. Hence, a better understanding of the functional significance of ncRNAs following CNS injuries could help in developing potential therapeutic strategies to minimize the neuronal damage in those conditions. The potential of ncRNAs in blood and CSF as biomarkers for diagnosis and/or prognosis of acute CNS injuries has also gained importance in the recent years. This review highlighted the current progress in the understanding of the role of ncRNAs in initiation and progression of secondary neuronal damage and their application as biomarkers after acute CNS injuries.
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Affiliation(s)
- Raghavendar Chandran
- Department of Neurological Surgery, University of Wisconsin-Madison and William S. Middleton Veterans Hospital, Madison, WI, USA
| | - Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin-Madison and William S. Middleton Veterans Hospital, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin-Madison and William S. Middleton Veterans Hospital, Madison, WI, USA.
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Zheng HZ, Jiang W, Zhao XF, Du J, Liu PG, Chang LD, Li WB, Hu HT, Shi XM. Electroacupuncture induces acute changes in cerebral cortical miRNA profile, improves cerebral blood flow and alleviates neurological deficits in a rat model of stroke. Neural Regen Res 2016; 11:1940-1950. [PMID: 28197190 PMCID: PMC5270432 DOI: 10.4103/1673-5374.197135] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2016] [Indexed: 01/19/2023] Open
Abstract
Electroacupuncture has been shown to improve cerebral blood flow in animal models of stroke. However, it is unclear whether electroacupuncture alters miRNA expression in the cortex. In this study, we examined changes in the cerebral cortical miRNA profile, cerebral blood flow and neurological function induced by electroacupuncture in a rat model of stroke. Electroacupuncture was performed at Renzhong (GV26) and Neiguan (PC6), with a frequency of 2 Hz, continuous wave, current intensity of 3.0 mA, and stimulation time of 1 minute. Electroacupuncture increased cerebral blood flow and alleviated neurological impairment in the rats. miRNA microarray profiling revealed that the vascular endothelial growth factor signaling pathway, which links cell proliferation with stroke, was most significantly affected by electroacupuncture. Electroacupuncture induced changes in expression of rno-miR-206-3p, rno-miR-3473, rno-miR-6216 and rno-miR-494-3p, and these changes were confirmed by quantitative real-time polymerase chain reaction. Our findings suggest that changes in cell proliferation-associated miRNA expression induced by electroacupuncture might be associated with the improved cerebral blood supply and functional recovery following stroke.
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Affiliation(s)
- Hai-zhen Zheng
- VIP of Acupuncture Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wei Jiang
- Department of Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiao-feng Zhao
- VIP of Acupuncture Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jing Du
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Pan-gong Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Li-dan Chang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wen-bo Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Han-tong Hu
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xue-min Shi
- VIP of Acupuncture Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Hu Z, Zhong B, Tan J, Chen C, Lei Q, Zeng L. The Emerging Role of Epigenetics in Cerebral Ischemia. Mol Neurobiol 2016; 54:1887-1905. [PMID: 26894397 DOI: 10.1007/s12035-016-9788-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 02/11/2016] [Indexed: 12/14/2022]
Abstract
Despite great progresses in the treatment and prevention of ischemic stroke, it is still among the leading causes of death and serious long-term disability all over the world, indicating that innovative neural regenerative and neuroprotective agents are urgently needed for the development of therapeutic approaches with greater efficacy for ischemic stroke. More and more evidence suggests that a spectrum of epigenetic processes play an important role in the pathophysiology of cerebral ischemia. In the present review, we first discuss recent developments in epigenetic mechanisms, especially their roles in the pathophysiology of cerebral ischemia. Specifically, we focus on DNA methylation, histone deacetylase, histone methylation, and microRNAs (miRNAs) in the regulation of vascular and neuronal regeneration after cerebral ischemia. Additionally, we highlight epigenetic strategies for ischemic stroke treatments, including the inhibition of histone deacetylase enzyme and DNA methyltransferase activities, and miRNAs. These therapeutic strategies are far from clinic use, but preliminary data indicate that neuroprotective agents targeting these pathways can modulate neural cell regeneration and promote brain repair and functional recovery after cerebral ischemia. A better understanding of how epigenetics influences the process and progress of cerebral ischemia will pave the way for discovering more sensitive and specific biomarkers and new targets and therapeutics for ischemic stroke.
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Affiliation(s)
- Zhiping Hu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Bingwu Zhong
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Department of Traditional Chinese Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Jieqiong Tan
- National Key Laboratory of Medical Genetics, Central South University, Changsha, 410078, Hunan, China
| | - Chunli Chen
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Qiang Lei
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Liuwang Zeng
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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Crosstalk between miRNAs and their regulated genes network in stroke. Sci Rep 2016; 6:20429. [PMID: 26830013 PMCID: PMC4735861 DOI: 10.1038/srep20429] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 01/04/2016] [Indexed: 12/22/2022] Open
Abstract
In recent years, more and more studies focus on the roles of genes or miRNAs in stroke. However, the molecular mechanism connecting miRNAs and their targetgenes remains unclear. The aim of this study was to determine the differential regulation and correlations between miRNAs and their targetgenes in human stroke. Stroke-related miRNAs were obtained from the Human MicroRNA Disease Database (HMDD) and their targetgenes were generated from three independent sources. Kappa score was used to create the network and the functional modules. A total of 11 stroke-related miRNAs were identified from the HMDD and 441 overlapping targetgenes were extracted from the three databases. By network construction and GO analysis, 13 functional modules, 186 biological processes, and 21 pathways were found in the network, of which functional module 8 was the largest module, cellular-related process and phosphate-related process were the most important biological processes, and MAPK signaling pathway was the most significant pathway. In our study, all miRNAs regulate the stroke modular network by their targetgenes. After the validation of miRNAs, we found that miR-605 and miR-181d were highly expressed in the blood of stroke patients which never reported before may supply novel target for treatment.
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Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke. Lancet Neurol 2015; 15:185-197. [PMID: 26597090 DOI: 10.1016/s1474-4422(15)00248-3] [Citation(s) in RCA: 152] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/16/2015] [Accepted: 09/16/2015] [Indexed: 12/20/2022]
Abstract
For about 30% of patients with epilepsy the cause is unknown. Even in patients with a known risk factor for epilepsy, such as ischaemic stroke, only a subpopulation of patients develops epilepsy. Factors that contribute to the risk for epileptogenesis in a given individual generally remain unknown. Studies in the past decade on epilepsy in patients with ischaemic stroke suggest that, in addition to the primary ischaemic injury, existing difficult-to-detect microscale changes in blood vessels and white matter present as epileptogenic pathologies. Injury severity, location and type of pathological changes, genetic factors, and pre-injury and post-injury exposure to non-genetic factors (ie, the exposome) can divide patients with ischaemic stroke into different endophenotypes with a variable risk for epileptogenesis. These data provide guidance for animal modelling of post-stroke epilepsy, and for laboratory experiments to explore with increased specificity the molecular 'mechanisms, biomarkers, and treatment targets of post-stroke epilepsy in different circumstances, with the aim of modifying epileptogenesis after ischaemic stroke in individual patients without compromising recovery.
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Affiliation(s)
- Asla Pitkänen
- Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
| | - Reina Roivainen
- Department of Neurology, Hyvinkää Hospital, Hyvinkää, Finland
| | - Katarzyna Lukasiuk
- The Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
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Tao J, Liu W, Shang G, Zheng Y, Huang J, Lin R, Chen L. MiR-207/352 regulate lysosomal-associated membrane proteins and enzymes following ischemic stroke. Neuroscience 2015; 305:1-14. [PMID: 26232047 DOI: 10.1016/j.neuroscience.2015.07.064] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Revised: 07/21/2015] [Accepted: 07/24/2015] [Indexed: 11/16/2022]
Abstract
The role of microRNAs (miRNAs) in lysosome-mediated neuronal death and survival following ischemic stroke remains unknown. Herein, using miRNA and mRNA gene expression profiling microarrays, we identified the differentially expressed 24 miRNAs and 494 genes in the cortical peri-infarct area, respectively. Integrating the miRNA targets and mRNA expression profiles, we found 47 genes of miRNA targets, including lysosomal-associated membrane protein 2 (LAMP2), Hexb, Bcl2, etc. MiR-207 and miR-352 were mainly downregulated after ischemic stroke, followed by a slight return to baseline during post-middle cerebral artery occlusion (MCAO) 1d to 7d. Furthermore, the luciferase reporter assay demonstrated that LAMP2 and Hexb were the direct targets of miR-207 and miR-352, respectively. After lateral ventricle injection with miR-207 agonist mimics, the neurological deficit scores and infarct volumes were attenuated, and the structure of mitochondria ridges was improved. In addition, miR-207 mimics could reduce the number of cellular lysosome and autophagosome, whereas increase the number of autophagic vacuoles, indicating miR-207 might affect the latter part of lysosomal-autophagy pathway and mitochondria-induced apoptosis. These results suggested that miR-207 and miR-352 were involved in lysosomal pathway for mediating ischemic injury and spontaneous recovery. MiR-207 mimics as potential target drugs could protect against autophagic cell death after ischemic stroke.
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Affiliation(s)
- J Tao
- College of Rehabilitation Medicine & TCM Rehabilitation Research Center Of SATCM, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China
| | - W Liu
- College of Rehabilitation Medicine & TCM Rehabilitation Research Center Of SATCM, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China
| | - G Shang
- Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China
| | - Y Zheng
- Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China
| | - J Huang
- Fujian Rehabilitation Engineering Research Center & Fujian Key Lab of Motor Function Rehabilitation, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China
| | - R Lin
- Fujian Rehabilitation Tech Co-innovation Center (2011 Project), Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China
| | - L Chen
- College of Rehabilitation Medicine & TCM Rehabilitation Research Center Of SATCM, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, PR China.
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Saugstad JA. Non-Coding RNAs in Stroke and Neuroprotection. Front Neurol 2015; 6:50. [PMID: 25821444 PMCID: PMC4358219 DOI: 10.3389/fneur.2015.00050] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 02/23/2015] [Indexed: 01/08/2023] Open
Abstract
This review will focus on the current state of knowledge regarding non-coding RNAs (ncRNA) in stroke and neuroprotection. There will be a brief introduction to microRNAs (miRNA), long ncRNAs (lncRNA), and piwi-interacting RNAs (piRNA), followed by evidence for the regulation of ncRNAs in ischemia. This review will also discuss the effect of neuroprotection induced by a sublethal duration of ischemia or other stimuli given before a stroke (preconditioning) on miRNA expression and the role of miRNAs in preconditioning-induced neuroprotection. Experimental manipulation of miRNAs and/or their targets to induce pre- or post-stroke protection will also be presented, as well as discussion on miRNA responses to current post-stroke therapies. This review will conclude with a brief discussion of future directions for ncRNAs studies in stroke, such as new approaches to model complex ncRNA datasets, challenges in ncRNA studies, and the impact of extracellular RNAs on human diseases such as stroke.
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Affiliation(s)
- Julie A Saugstad
- Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University , Portland, OR , USA
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Kan CFK, Singh AB, Dong B, Shende VR, Liu J. PPARδ activation induces hepatic long-chain acyl-CoA synthetase 4 expression in vivo and in vitro. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:577-87. [PMID: 25645621 DOI: 10.1016/j.bbalip.2015.01.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 01/07/2015] [Accepted: 01/14/2015] [Indexed: 12/29/2022]
Abstract
The arachidonic acid preferred long-chain acyl-CoA synthetase 4 (ACSL4) is a key enzyme for fatty acid metabolism in various metabolic tissues. In this study, we utilized hamsters fed a normal chow diet, a high-fat diet or a high cholesterol and high fat diet (HCHFD) as animal models to explore novel transcriptional regulatory mechanisms for ACSL4 expression under hyperlipidemic conditions. Through cloning hamster ACSL4 homolog and tissue profiling ACSL4 mRNA and protein expressions we observed a selective upregulation of ACSL4 in testis and liver of HCHFD fed animals. Examination of transcriptional activators of the ACSL family revealed an increased hepatic expression of PPARδ but not PPARα in HCHFD fed hamsters. To explore a role of PPARδ in dietary cholesterol-mediated upregulation of ACSL4, we administered a PPARδ specific agonist L165041 to normolipidemic and dyslipidemic hamsters. We observed significant increases of hepatic ACSL4 mRNA and protein levels in all L165041-treated hamsters as compared to control animals. The induction of ACSL4 expression by L165041 in liver tissue in vivo was recapitulated in human primary hepatocytes and hepatocytes isolated from hamster and mouse. Moreover, employing the approach of adenovirus-mediated gene knockdown, we showed that depletion of PPARδ in hamster hepatocytes specifically reduced ACSL4 expression. Finally, utilizing HepG2 as a model system, we demonstrate that PPARδ activation leads to increased ACSL4 promoter activity, mRNA and protein expression, and consequently higher arachidonoyl-CoA synthetase activity. Taken together, we have discovered a novel PPARδ-mediated regulatory mechanism for ACSL4 expression in liver tissue and cultured hepatic cells.
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Affiliation(s)
- Chin Fung Kelvin Kan
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States
| | - Amar Bahadur Singh
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States
| | - Bin Dong
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States
| | - Vikram Ravindra Shende
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States; Department of Medicine, Stanford University, Stanford, CA 94305, United States
| | - Jingwen Liu
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States.
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Volný O, Kašičková L, Coufalová D, Cimflová P, Novák J. microRNAs in Cerebrovascular Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 888:155-95. [PMID: 26663183 DOI: 10.1007/978-3-319-22671-2_9] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cardiovascular diseases are major causes of morbidity and mortality in developed countries. Cerebrovascular diseases, especially stroke, represent major burden of disability and economy impact. Major advances in primary and secondary prevention and therapy are needed in order to tackle this public health problem. Our better understanding of pathophysiology is essential in order to develop novel diagnostic and therapeutic tools and strategies. microRNAs are a family of important post-transcriptional regulators of gene expression and their involvement in the pathophysiology of cerebrovascular diseases has already been reported. Moreover, microRNAs may represent above-mentioned potential diagnostic and therapeutic tools in clinical practice. Within this chapter, we briefly describe basic epidemiology, aetiology and clinical manifestation of following cerebrovascular diseases: extracranial carotid atherosclerosis, acute stroke, intracranial aneurysms and cerebral arterio-venous malformations. Further, in each chapter, the current knowledge about the involvement of specific microRNAs and their potential use in clinical practice will be summarized. More specifically, within the subchapter "miRNAs in carotid atherosclerosis", general information about miRNA involvement in atherosclerosis will be described (miR-126, miR-17-92, miR-155 and others) with special emphasis put on miRNAs affecting carotid plaque progression and stability (e.g. miR-145, miR-146 or miR-217). In the subchapter "miRNAs in acute stroke", we will provide insight into recent knowledge from animal and human studies concerning miRNA profiling in acute stroke and their expression dynamics in brain tissue and extracellular fluids (roles of, e.g. let-7 family, miR-21, miR-29 family, miR-124, miR-145, miR-181 family, miR-210 and miR-223). Subchapters dealing with "miRNAs and AV malformations" and "miRNAs and intracranial aneurysms" will focus on miR-21, miR-26, miR-29 family and miR-143/145.
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Affiliation(s)
- Ondřej Volný
- Department of Neurology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Pekarska 53, Brno, 656 91, Czech Republic. .,Department of Anatomy, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic. .,International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, Brno, 656 91, Czech Republic.
| | - Linda Kašičková
- Department of Neurology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Pekarska 53, Brno, 656 91, Czech Republic. .,Department of Anatomy, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
| | - Dominika Coufalová
- Department of Anatomy, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic. .,International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, Brno, 656 91, Czech Republic.
| | - Petra Cimflová
- Department of Radiology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Pekarska 53, Brno, 656 91, Czech Republic.
| | - Jan Novák
- 2nd Department of Internal Medicine, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Pekarska 53, Brno, 656 91, Czech Republic. .,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic. .,Department of Physiology, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic.
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