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Min F, Dong Z, Zhong S, Li Z, Wu H, Zhang S, Zhang L, Zeng T. Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination. CNS Neurosci Ther 2025; 31:e70191. [PMID: 39764629 PMCID: PMC11705406 DOI: 10.1111/cns.70191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 11/14/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
OBJECTIVE This study aims to investigate how the E3 ubiquitin ligase LITAF influences mitochondrial autophagy by modulating MCL-1 ubiquitination, and its role in the development of epilepsy. METHODS Employing single-cell RNA sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein-protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models. RESULTS Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial autophagy by promoting MCL-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates MCL-1 ubiquitination, aggravating neuronal injury. CONCLUSION Our findings demonstrate that LITAF regulates MCL-1 ubiquitination, significantly impacting mitochondrial autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.
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Affiliation(s)
- Fuli Min
- Department of Neurology, School of Medicine, Guangzhou First People's HospitalSouth China University of TechnologyGuangzhouChina
| | - Zhaofei Dong
- Department of Neurology, the Eighth Affiliated HospitalSun Yat‐Sen UniversityShenzhenChina
| | - Shuisheng Zhong
- Department of NeurologyGuangdong Sanjiu Brain HospitalGuangzhouChina
| | - Ze Li
- Department of Neurology, School of Medicine, Guangzhou First People's HospitalSouth China University of TechnologyGuangzhouChina
| | - Hong Wu
- Department of Neurology, School of Medicine, Guangzhou First People's HospitalSouth China University of TechnologyGuangzhouChina
| | - Sai Zhang
- Department of Neurology, School of Medicine, Guangzhou First People's HospitalSouth China University of TechnologyGuangzhouChina
| | - Linming Zhang
- Department of NeurologyThe First Affliated Hospital of Kunming Medical UniversityKunmingChina
| | - Tao Zeng
- Department of Neurology, School of Medicine, Guangzhou First People's HospitalSouth China University of TechnologyGuangzhouChina
- Department of Neurology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
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Chidambaram SB, Anand N, Varma SR, Ramamurthy S, Vichitra C, Sharma A, Mahalakshmi AM, Essa MM. Superoxide dismutase and neurological disorders. IBRO Neurosci Rep 2024; 16:373-394. [PMID: 39007083 PMCID: PMC11240301 DOI: 10.1016/j.ibneur.2023.11.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 11/21/2023] [Indexed: 07/16/2024] Open
Abstract
Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.
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Affiliation(s)
- Saravana Babu Chidambaram
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Nikhilesh Anand
- Department of Pharmacology, American University of Antigua College of Medicine, University Park, Jabberwock Beach Road, Antigua, Antigua and Barbuda
| | - Sudhir Rama Varma
- Department of Clinical Sciences, College of Dentistry, Ajman University, 346 Ajman, the United Arab Emirates
- Center of Medical and Bio-allied Health Sciences Research, Ajman University, 346 Ajman, the United Arab Emirates
| | - Srinivasan Ramamurthy
- College of Pharmacy & Health Sciences, University of Science and Technology of Fujairah, 2202 Fujairah, the United Arab Emirates
| | - Chandrasekaran Vichitra
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Ambika Sharma
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Arehally M Mahalakshmi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman
- Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
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Huang Y, Wang Q, Liu X, Du W, Hao Z, Wang Y. Transcriptional Signatures of a Dynamic Epilepsy Process Reveal Potential Immune Regulation. Mol Neurobiol 2024; 61:3384-3396. [PMID: 37989981 PMCID: PMC11087345 DOI: 10.1007/s12035-023-03786-x] [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: 11/18/2022] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Epilepsy is a progression of development and advancement over time. However, the molecular features of epilepsy were poorly studied from a dynamic developmental perspective. We intend to investigate the key mechanisms in the process of epilepsy by exploring the roles of stage-specifically expressed genes. By using time-course transcriptomic data of epileptic samples, we first analyzed the molecular features of epilepsy in different stages and divided it into progression and remission stages based on their transcriptomic features. 34 stage-specifically expressed genes were then identified by the Tau index and verified in other epileptic datasets. These genes were then enriched for immune-related biological functions. Furthermore, we found that the level of immune infiltration and mechanisms at different stages were different, which may result from different types of immune cells playing leading roles in distinct stages. Our findings indicated an essential role of immune regulation as the potential mechanism of epilepsy development.
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Affiliation(s)
- Yanruo Huang
- Department of Anesthesiology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, People's Republic of China
| | - Qihang Wang
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Xiaoyin Liu
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Wenjie Du
- Department of Anesthesiology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, People's Republic of China
| | - Zijian Hao
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, People's Republic of China.
- MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, People's Republic of China.
| | - Yingwei Wang
- Department of Anesthesiology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, People's Republic of China.
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Hurtado Silva M, van Waardenberg AJ, Mostafa A, Schoch S, Dietrich D, Graham ME. Multiomics of early epileptogenesis in mice reveals phosphorylation and dephosphorylation-directed growth and synaptic weakening. iScience 2024; 27:109534. [PMID: 38600976 PMCID: PMC11005001 DOI: 10.1016/j.isci.2024.109534] [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: 01/26/2022] [Revised: 01/26/2024] [Accepted: 03/16/2024] [Indexed: 04/12/2024] Open
Abstract
To investigate the phosphorylation-based signaling and protein changes occurring early in epileptogenesis, the hippocampi of mice treated with pilocarpine were examined by quantitative mass spectrometry at 4 and 24 h post-status epilepticus at vast depth. Hundreds of posttranscriptional regulatory proteins were the major early targets of increased phosphorylation. At 24 h, many protein level changes were detected and the phosphoproteome continued to be perturbed. The major targets of decreased phosphorylation at 4 and 24 h were a subset of postsynaptic density scaffold proteins, ion channels, and neurotransmitter receptors. Many proteins targeted by dephosphorylation at 4 h also had decreased protein abundance at 24 h, indicating a phosphatase-mediated weakening of synapses. Increased translation was indicated by protein changes at 24 h. These observations, and many additional indicators within this multiomic resource, suggest that early epileptogenesis is characterized by signaling that stimulates both growth and a homeostatic response that weakens excitability.
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Affiliation(s)
- Mariella Hurtado Silva
- Synapse Proteomics, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
| | | | - Aya Mostafa
- Department of Neuropathology, University Hospital Bonn, Synaptic Neuroscience Unit, 53127 Bonn, North Rhine-Westphalia, Germany
| | - Susanne Schoch
- Department of Neuropathology, University Hospital Bonn, Synaptic Neuroscience Unit, 53127 Bonn, North Rhine-Westphalia, Germany
| | - Dirk Dietrich
- Department of Neurosurgery, University Hospital Bonn, Synaptic Neuroscience Unit, 53127 Bonn, North Rhine-Westphalia, Germany
| | - Mark E. Graham
- Synapse Proteomics, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia
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Li X, Quan P, Si Y, Liu F, Fan Y, Ding F, Sun L, Liu H, Huang S, Sun L, Yang F, Yao L. The microRNA-211-5p/P2RX7/ERK/GPX4 axis regulates epilepsy-associated neuronal ferroptosis and oxidative stress. J Neuroinflammation 2024; 21:13. [PMID: 38191407 PMCID: PMC10773122 DOI: 10.1186/s12974-023-03009-z] [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: 10/21/2023] [Accepted: 12/28/2023] [Indexed: 01/10/2024] Open
Abstract
Ferroptosis is an iron-dependent cell death mechanism involving the accumulation of lipid peroxides. As a critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be downregulated in epilepsy. However, the mechanism of ferroptosis in epilepsy remains unclear. In this study, bioinformatics analysis, analysis of epilepsy patient blood samples and cell and mouse experiments revealed strong associations among epilepsy, ferroptosis, microRNA-211-5p and purinergic receptor P2X 7 (P2RX7). P2RX7 is a nonselective ligand-gated homotrimeric cation channel, and its activation mainly increases neuronal activity during epileptic seizures. In our study, the upregulation of P2RX7 in epilepsy was attributed to the downregulation of microRNA (miR)-211-5p. Furthermore, P2RX7 has been found to regulate GPX4/HO-1 by alleviating lipid peroxidation induced by suppression of the MAPK/ERK signaling pathway in murine models. The dynamic decrease in miR-211-5p expression induces hypersynchronization and both nonconvulsive and convulsive seizures, and forebrain miR-211-5p suppression exacerbates long-lasting pentylenetetrazole-induced seizures. Additionally, in this study, induction of miR-211-5p expression or genetic-silencing of P2RX7 significantly reduced the seizure score and duration in murine models through the abovementioned pathways. These results suggest that the miR-211-5p/P2RX7 axis is a novel target for suppressing both ferroptosis and epilepsy.
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Affiliation(s)
- Xueying Li
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Pusheng Quan
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
- Department of Neurology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yao Si
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Fei Liu
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Yuwei Fan
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Feifan Ding
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Lina Sun
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Han Liu
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Shuo Huang
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Linlin Sun
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
| | - Fan Yang
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
| | - Lifen Yao
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
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Chen S, Jin X, He T, Zhang M, Xu H. Identification of ferroptosis-related genes in acute phase of temporal lobe epilepsy based on bioinformatic analysis. BMC Genomics 2023; 24:675. [PMID: 37946105 PMCID: PMC10636915 DOI: 10.1186/s12864-023-09782-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 11/02/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Epilepsy is a prevalent neurological disorder, and while its precise mechanism remains elusive, a connection to ferroptosis has been established. This study investigates the potential clinical diagnostic significance of ferroptosis-related genes (FRGs) during the acute phase of temporal lobe epilepsy. METHODS To identify differentially expressed genes (DEGs), we accessed data from the GEO database and performed an intersection analysis with the FerrDB database to pinpoint FRGs. A protein-protein interaction (PPI) network was constructed. To assess the diagnostic utility of the discovered feature genes for the disease, ROC curve analysis was conducted. Subsequently, qRT-PCR was employed to validate the expression levels of these feature genes. RESULTS This study identified a total of 25 FRGs. PPI network analysis revealed six feature genes: IL6, PTGS2, HMOX1, NFE2L2, TLR4, and JUN. ROC curve analysis demonstrated that the combination of these six feature genes exhibited the highest diagnostic potential. qRT-PCR validation confirmed the expression of these feature genes. CONCLUSION We have identified six feature genes (IL6, PTGS2, HMOX1, NFE2L2, TLR4, and JUN) strongly associated with ferroptosis in epilepsy, suggesting their potential as biomarkers for the diagnosis of temporal lobe epilepsy.
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Affiliation(s)
- Shihao Chen
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xing Jin
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Tao He
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Mulan Zhang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huiqin Xu
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou, China.
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Liao Y, Huang S, Zhang Y, Zhang H, Zhao H. Decrease of Cellular Communication Network Factor 1 (CCN1) Attenuates PTZ-Kindled Epilepsy in Mice. Cell Mol Neurobiol 2023; 43:4279-4293. [PMID: 37864627 PMCID: PMC11407709 DOI: 10.1007/s10571-023-01420-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 09/27/2023] [Indexed: 10/23/2023]
Abstract
To investigate the molecular mechanism of communication network factor 1 (CCN1) regulating pentylenetetrazol (PTZ)-induced epileptogenesis, deepen the understanding of epilepsy seizure pathogenesis, and provide new drug action targets for its clinical prevention and treatment. Differentially expressed genes (DEGs) on microarrays GSE47516 and GSE88992 were analyzed online using GEO2R. Pathway enrichment and protein-protein interaction network (PPI) analysis of DEGs were carried out using Metascape. Brain tissue samples of severe traumatic brain injury patients (named Healthy group) and refractory epilepsy patients (named Epilepsy group) were obtained and analyzed by qRT-PCR and immunohistochemistry (IHC) staining. A PTZ-induced epilepsy mouse model was established and verified. Morphological changes of neurons in mouse brain tissue were detected using hematoxylin and eosin (HE) staining. qRT-PCR was conducted to detect the mRNA expressions of apoptosis-associated proteins Bax, Caspase-3 and bcl2. TUNEL staining was performed to detect brain neuron apoptosis. The levels of myocardial enzymology, GSH, MDA and ROS in blood of mouse were detected by biochemical assay. CCN1 expression was increased in epilepsy brain tissue samples. CCN1 decreasing effectively prolongs seizure incubation period and decreases seizure duration. Silencing of CCN1 also reduces neuronal damage and apoptosis, decreases mRNA and protein expression of proapoptotic proteins Bax and Caspase-3, increases mRNA expression of antiapoptotic protein Bcl2. Moreover, decrease of CCN1 decreases myocardial enzymatic indexes CK and CK-MB levels, reduces myocardial tissue hemorrhage, and relieves oxidative stress response in hippocampal and myocardial tissue. CCN1 expression is increased in epileptic samples. CCN1 decreasing protects brain tissue by attenuating oxidative stress and inhibiting neuronal apoptosis triggered by PTZ injection, which probably by regulating Nrf2/HO-1 pathway.
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Affiliation(s)
- Yiwei Liao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Sha Huang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
- Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, 410008, China
| | - Yuhu Zhang
- Department of Emergency, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China
| | - Honghai Zhang
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Haiting Zhao
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.
- Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, 410008, China.
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Brindley E, Heiland M, Mooney C, Diviney M, Mamad O, Hill TDM, Yan Y, Venø MT, Reschke CR, Batool A, Langa E, Sanz-Rodriguez A, Heller JP, Morris G, Conboy K, Kjems J, Brennan GP, Henshall DC. Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy. Front Mol Neurosci 2023; 16:1230942. [PMID: 37808470 PMCID: PMC10556253 DOI: 10.3389/fnmol.2023.1230942] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.
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Affiliation(s)
- Elizabeth Brindley
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Mona Heiland
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Catherine Mooney
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Computer Science, University College Dublin, Dublin, Ireland
| | - Mairead Diviney
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Omar Mamad
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Thomas D. M. Hill
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Yan Yan
- Interdisciplinary Nanoscience Centre (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Omiics ApS, Aarhus, Denmark
| | - Morten T. Venø
- Interdisciplinary Nanoscience Centre (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Omiics ApS, Aarhus, Denmark
| | - Cristina R. Reschke
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Aasia Batool
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Elena Langa
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Amaya Sanz-Rodriguez
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Janosch P. Heller
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Biotechnology, Dublin City University, Dublin, Ireland
| | - Gareth Morris
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
- Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Karen Conboy
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Centre (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Gary P. Brennan
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Dublin, Ireland
| | - David C. Henshall
- Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland
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Lu M, Feng R, Zhang C, Xiao Y, Yin C. Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis. Mol Neurobiol 2023; 60:5055-5066. [PMID: 37246165 PMCID: PMC10415436 DOI: 10.1007/s12035-023-03382-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 05/04/2023] [Indexed: 05/30/2023]
Abstract
Epilepsy is a severe neurological condition affecting 50-65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE Consortium cohort were used to conduct transcriptome-wide association studies (TWAS) and protein-wide association studies (PWAS). Furthermore, a protein-protein interaction (PPI) network was generated using the STRING database, and significant epilepsy-susceptible genes were verified using chip data. Chemical-related gene set enrichment analysis (CGSEA) was performed to determine novel drug targets for epilepsy. TWAS analysis identified 21,170 genes, of which 58 were significant (TWASfdr < 0.05) in ten brain regions, and 16 differentially expressed genes were verified based on mRNA expression profiles. The PWAS identified 2249 genes, of which 2 were significant (PWASfdr < 0.05). Through chemical-gene set enrichment analysis, 287 environmental chemicals associated with epilepsy were identified. We identified five significant genes (WIPF1, IQSEC1, JAM2, ICAM3, and ZNF143) that had causal relationships with epilepsy. CGSEA identified 159 chemicals that were significantly correlated with epilepsy (Pcgsea < 0.05), such as pentobarbital, ketone bodies, and polychlorinated biphenyl. In summary, we performed TWAS, PWAS (for genetic factors), and CGSEA (for environmental factors) analyses and identified several epilepsy-associated genes and chemicals. The results of this study will contribute to our understanding of genetic and environmental factors for epilepsy and may predict novel drug targets.
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Affiliation(s)
- Mengnan Lu
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710054, Shanxi, China
| | - Ruoyang Feng
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shanxi, China
| | - Chenglin Zhang
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710054, Shanxi, China
| | - Yanfeng Xiao
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710054, Shanxi, China.
| | - Chunyan Yin
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710054, Shanxi, China.
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10
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Liu C, Zhao XM, Wang Q, Du TT, Zhang MX, Wang HZ, Li RP, Liang K, Gao Y, Zhou SY, Xue T, Zhang JG, Han CL, Shi L, Zhang LW, Meng FG. Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy. J Neuroinflammation 2023; 20:161. [PMID: 37422673 DOI: 10.1186/s12974-023-02840-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 06/22/2023] [Indexed: 07/10/2023] Open
Abstract
Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.
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Affiliation(s)
- Chong Liu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Xue-Min Zhao
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
| | - Qiao Wang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Ting-Ting Du
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
| | - Mo-Xuan Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Hui-Zhi Wang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Ren-Peng Li
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Kun Liang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Yuan Gao
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Si-Yu Zhou
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
| | - Tao Xue
- Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Jian-Guo Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China
- Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Chun-Lei Han
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China.
- Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
| | - Lin Shi
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China.
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China.
- Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
| | - Liang-Wen Zhang
- Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Fan-Gang Meng
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China.
- Beijing Key Laboratory of Neurostimulation, Beijing, 100070, China.
- Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
- Chinese Institute for Brain Research, Beijing, 102206, China.
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11
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Erisken S, Nune G, Chung H, Kang JW, Koh S. Time and age dependent regulation of neuroinflammation in a rat model of mesial temporal lobe epilepsy: Correlation with human data. Front Cell Dev Biol 2022; 10:969364. [PMID: 36172274 PMCID: PMC9512631 DOI: 10.3389/fcell.2022.969364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/03/2022] [Indexed: 11/25/2022] Open
Abstract
Acute brain insults trigger diverse cellular and signaling responses and often precipitate epilepsy. The cellular, molecular and signaling events relevant to the emergence of the epileptic brain, however, remain poorly understood. These multiplex structural and functional alterations tend also to be opposing - some homeostatic and reparative while others disruptive; some associated with growth and proliferation while others, with cell death. To differentiate pathological from protective consequences, we compared seizure-induced changes in gene expression hours and days following kainic acid (KA)-induced status epilepticus (SE) in postnatal day (P) 30 and P15 rats by capitalizing on age-dependent differential physiologic responses to KA-SE; only mature rats, not immature rats, have been shown to develop spontaneous recurrent seizures after KA-SE. To correlate gene expression profiles in epileptic rats with epilepsy patients and demonstrate the clinical relevance of our findings, we performed gene analysis on four patient samples obtained from temporal lobectomy and compared to four control brains from NICHD Brain Bank. Pro-inflammatory gene expressions were at higher magnitudes and more sustained in P30. The inflammatory response was driven by the cytokines IL-1β, IL-6, and IL-18 in the acute period up to 72 h and by IL-18 in the subacute period through the 10-day time point. In addition, a panoply of other immune system genes was upregulated, including chemokines, glia markers and adhesion molecules. Genes associated with the mitogen activated protein kinase (MAPK) pathways comprised the largest functional group identified. Through the integration of multiple ontological databases, we analyzed genes belonging to 13 separate pathways linked to Classical MAPK ERK, as well as stress activated protein kinases (SAPKs) p38 and JNK. Interestingly, genes belonging to the Classical MAPK pathways were mostly transiently activated within the first 24 h, while genes in the SAPK pathways had divergent time courses of expression, showing sustained activation only in P30. Genes in P30 also had different regulatory functions than in P15: P30 animals showed marked increases in positive regulators of transcription, of signaling pathways as well as of MAPKKK cascades. Many of the same inflammation-related genes as in epileptic rats were significantly upregulated in human hippocampus, higher than in lateral temporal neocortex. They included glia-associated genes, cytokines, chemokines and adhesion molecules and MAPK pathway genes. Uniquely expressed in human hippocampus were adaptive immune system genes including immune receptors CDs and MHC II HLAs. In the brain, many immune molecules have additional roles in synaptic plasticity and the promotion of neurite outgrowth. We propose that persistent changes in inflammatory gene expression after SE leads not only to structural damage but also to aberrant synaptogenesis that may lead to epileptogenesis. Furthermore, the sustained pattern of inflammatory genes upregulated in the epileptic mature brain was distinct from that of the immature brain that show transient changes and are resistant to cell death and neuropathologic changes. Our data suggest that the epileptogenic process may be a result of failed cellular signaling mechanisms, where insults overwhelm the system beyond a homeostatic threshold.
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Affiliation(s)
- Sinem Erisken
- Department of Pediatrics, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago, IL, United States
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, United States
| | - George Nune
- Department of Pediatrics, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago, IL, United States
- Department of Neurology, University of Southern California, Los Angeles, CA, United States
| | - Hyokwon Chung
- Department of Pediatrics, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago, IL, United States
- Department of Pediatrics, Children’s Hospital & Medical Center, University of Nebraska, Omaha, NE, United States
| | - Joon Won Kang
- Department of Pediatrics, Children’s Hospital & Medical Center, University of Nebraska, Omaha, NE, United States
- Department of Pediatrics & Medical Science, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon, South Korea
| | - Sookyong Koh
- Department of Pediatrics, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University School of Medicine, Chicago, IL, United States
- Department of Pediatrics, Children’s Hospital & Medical Center, University of Nebraska, Omaha, NE, United States
- *Correspondence: Sookyong Koh,
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12
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Berger TC, Taubøll E, Heuser K. The potential role of DNA methylation as preventive treatment target of epileptogenesis. Front Cell Neurosci 2022; 16:931356. [PMID: 35936496 PMCID: PMC9353008 DOI: 10.3389/fncel.2022.931356] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/27/2022] [Indexed: 11/23/2022] Open
Abstract
Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures—the process of epileptogenesis—could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis.
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Affiliation(s)
- Toni Christoph Berger
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- *Correspondence: Toni Christoph Berger
| | - Erik Taubøll
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kjell Heuser
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Kjell Heuser
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13
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Cao J, Gan H, Xiao H, Chen H, Jian D, Jian D, Zhai X. Key protein-coding genes related to microglia in immune regulation and inflammatory response induced by epilepsy. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2021; 18:9563-9578. [PMID: 34814358 DOI: 10.3934/mbe.2021469] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Several studies have shown a link between immunity, inflammatory processes, and epilepsy. Active neuroinflammation and marked immune cell infiltration occur in epilepsy of diverse etiologies. Microglia, as the first line of defense in the central nervous system, are the main effectors of neuroinflammatory processes. Discovery of new biomarkers associated with microglia activation after epileptogenesis indicates that targeting specific molecules may help control seizures. In this research, we used a combination of several bioinformatics approaches, including RNA sequencing, to explore differentially expressed genes (DEGs) in epileptic lesions and control samples, and to construct a protein-protein interaction (PPI) network for DEGs, which was examined utilizing plug-ins in Cytoscape software. Finally, we aimed to identify 10 hub genes in immune and inflammation-related sub-networks, which were subsequently validated in real-time quantitative polymerase chain reaction analysis in a mouse model of kainic acid-induced epilepsy. The expression patterns of nine genes were consistent with sequencing outcomes. Meanwhile, several genes, including CX3CR1, CX3CL1, GPR183, FPR1, P2RY13, P2RY12 and LPAR5, were associated with microglial activation and migration, providing novel candidate targets for immunotherapy in epilepsy and laying the foundation for further research.
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Affiliation(s)
- Jing Cao
- Department of Pathophysiology, Chongqing Medical University, Chongqing 400010, China
- Institute of Neuroscience, Chongqing Medical University, Chongqing 400010, China
| | - Hui Gan
- Department of Pathophysiology, Chongqing Medical University, Chongqing 400010, China
- Institute of Neuroscience, Chongqing Medical University, Chongqing 400010, China
| | - Han Xiao
- Ministry of Education Key Laboratory of Child Development and Disorders, Childrenӳ Hospital of Chongqing Medical University, Chongqing, P.R China, Chongqing 400010, China
| | - Hui Chen
- Ministry of Education Key Laboratory of Child Development and Disorders, Childrenӳ Hospital of Chongqing Medical University, Chongqing, P.R China, Chongqing 400010, China
| | - Dan Jian
- Ministry of Education Key Laboratory of Child Development and Disorders, Childrenӳ Hospital of Chongqing Medical University, Chongqing, P.R China, Chongqing 400010, China
| | - Dan Jian
- Institute of Neuroscience, Chongqing Medical University, Chongqing 400010, China
- Department of Pathology, Chongqing Medical University, Chongqing 400010, China
| | - Xuan Zhai
- Ministry of Education Key Laboratory of Child Development and Disorders, Childrenӳ Hospital of Chongqing Medical University, Chongqing, P.R China, Chongqing 400010, China
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14
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Wang J, Ma S, Yu J, Zuo D, He X, Peng H, Shi X, Huang W, Li Q. MiR-9-5p promotes M1 cell polarization in osteoarthritis progression by regulating NF-κB and AMPK signaling pathways by targeting SIRT1. Int Immunopharmacol 2021; 101:108207. [PMID: 34628269 DOI: 10.1016/j.intimp.2021.108207] [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: 08/06/2021] [Revised: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To investigate the roles and regulatory mechanisms of miR-9-5p in the development of osteoarthritis (OA). METHODS Synovial tissues from mouse OA model and control groups were collected and miR-9-5p expression levels and macrophage markers were measured with qPCR. The function of miR-9-5p in macrophage polarization was analyzed by flow cytometry and qPCR. Various databases were employed to screen the target genes one of which was validated with dual-luciferase analysis. Following the validation, rescue research was applied, and the signaling pathways were analyzed with Western blotting. Finally, the role of miR-9-5p in the progression of OA was validated in the mouse model. RESULTS MiR-9-5p was highly expressed in the synovial tissues of the OA model and was positively associated with M1 markers. Function analysis demonstrated that miR-9-5p could promote the progression of OA by promoting M1 polarization and inhibiting M2 polarization in vivo and in vitro. The mechanism analysis demonstrated that miR-9-5p could regulate macrophage polarization via NF-κB and AMPK signaling pathways by inhibiting SIRT1 expression. CONCLUSIONS MiR-9-5p could promote M1 polarization and OA progression by regulating NF-κB and AMPK signaling pathways by inhibiting SIRT1 expression.
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Affiliation(s)
- Jing Wang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Sha Ma
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Juan Yu
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Dachen Zuo
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Xia He
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Haiting Peng
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Xiaoqing Shi
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Weijuan Huang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Qin Li
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China.
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15
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Forero DA. Functional Genomics of Epileptogenesis in Animal Models and Humans. Cell Mol Neurobiol 2021; 41:1579-1587. [PMID: 32725455 PMCID: PMC11448571 DOI: 10.1007/s10571-020-00927-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 07/20/2020] [Indexed: 12/14/2022]
Abstract
It has been estimated that epilepsies are among the top five neurological diseases with the highest burden of disease. In recent years, genome-wide expression studies (GWES) have been carried out in experimental models of epilepsy and in samples from human patients. In this study, I carried out meta-analyses and analyses of convergence for available GWES for epileptogenesis in humans and in mouse, rat, zebrafish and fruit fly models. Multiple lines of evidence (such as genome-wide association data and known druggable genes) were integrated to prioritize top candidate genes for epileptogenesis and a functional enrichment analysis was carried out. Several top candidate genes, which are supported by multiple lines of genomic evidence, such as GRIN1, KCNAB1 and STX1B, were identified. Druggable genes of potential interest (such as GABRA2, GRIK1, KCNAB1 and STX4) were also identified. An enrichment of genes regulated by the MEF2 and SOX5 transcription factors and the miR-106b-5p and miR-101-3p miRNAs was found. The current work is the first meta-analysis and convergent analysis of GWES for epileptogenesis in humans and in multiple animal models, integrating results from several genomic studies. Novel candidate genes and pathways for epileptogenesis were identified in this analysis.
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Affiliation(s)
- Diego A Forero
- Health and Sport Sciences Research Group, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá, Colombia.
- MSc Program in Epidemiology, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá, Colombia.
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16
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Borowicz-Reutt KK, Czuczwar SJ. Role of oxidative stress in epileptogenesis and potential implications for therapy. Pharmacol Rep 2020; 72:1218-1226. [PMID: 32865811 PMCID: PMC7550371 DOI: 10.1007/s43440-020-00143-w] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023]
Abstract
In a state of balance between oxidants and antioxidants, free radicals play an advantageous role of “redox messengers”. In a state of oxidative stress, they trigger a cascade of events leading to epileptogenesis. During this latent, free of seizures period, a cascade of neurological changes takes place and finally leads to spontaneous recurrent seizures. The main processes involved in seizure generation are: neuroinflammation, neurodegeneration with anomalous neuroregeneration and lowering seizure threshold. Time of epileptogenesis offers a unique therapeutic window to prevent or at least attenuate seizure development. Animal data indicate that some antioxidants (for instance, resveratrol) may bear an anti-epileptogenic potential.
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Affiliation(s)
- Kinga K Borowicz-Reutt
- Independent Unit of Experimental Pathophysiology, Medical University of Lublin, Lublin, Poland.
| | - Stanisław J Czuczwar
- Department of Pathophysiology, Medical University of Lublin, 20-090, Lublin, Poland
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17
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Cacabelos R. Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia. Int J Mol Sci 2020; 21:E3059. [PMID: 32357528 PMCID: PMC7246738 DOI: 10.3390/ijms21093059] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/21/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6-10 drugs/day with the consequent risk for drug-drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
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Affiliation(s)
- Ramon Cacabelos
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165-Bergondo, Corunna, Spain
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18
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Bouquier N, Girard B, Aparicio Arias J, Fagni L, Bertaso F, Perroy J. Gelatinase Biosensor Reports Cellular Remodeling During Epileptogenesis. Front Synaptic Neurosci 2020; 12:15. [PMID: 32372941 PMCID: PMC7186352 DOI: 10.3389/fnsyn.2020.00015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/19/2020] [Indexed: 12/26/2022] Open
Abstract
Epileptogenesis is the gradual process responsible for converting a healthy brain into an epileptic brain. This process can be triggered by a wide range of factors, including brain injury or tumors, infections, and status epilepticus. Epileptogenesis results in aberrant synaptic plasticity, neuroinflammation and seizure-induced cell death. As Matrix Metalloproteinases (MMPs) play a crucial role in cellular plasticity by remodeling the extracellular matrix (ECM), gelatinases (MMP-2 and MMP-9) were recently highlighted as key players in epileptogenesis. In this work, we engineered a biosensor to report in situ gelatinase activity in a model of epileptogenesis. This biosensor encompasses a gelatinase-sensitive activatable cell penetrating peptide (ACPP) coupled to a TAMRA fluorophore, allowing fluorescence uptake in cells displaying endogenous gelatinase activities. In a preclinical mouse model of temporal lobe epilepsy (TLE), the intrahippocampal kainate injection, ACPPs revealed a localized distribution of gelatinase activities, refining temporal cellular changes during epileptogenesis. The activity was found particularly but not only in the ipsilateral hippocampus, starting from the CA1 area and spreading to dentate gyrus from the early stages throughout chronic epilepsy, notably in neurons and microglial cells. Thus, our work shows that ACPPs are suitable molecular imaging probes for detecting the spatiotemporal pattern of gelatinase activity during epileptogenesis, suggesting their possible use as vectors to target cellular reactive changes with treatment for epileptogenesis.
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Affiliation(s)
| | - Benoit Girard
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Laurent Fagni
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Federica Bertaso
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Julie Perroy
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
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19
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Cacabelos R. Pharmacogenomics of drugs used to treat brain disorders. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1738217] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Ramon Cacabelos
- International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, Corunna, Spain
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20
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Fu Y, Wu Z, Guo Z, Chen L, Ma Y, Wang Z, Xiao W, Wang Y. Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy. Genomics 2020; 112:1768-1780. [DOI: 10.1016/j.ygeno.2019.09.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/31/2019] [Accepted: 09/25/2019] [Indexed: 01/05/2023]
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21
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Xu J, Sun M, Wang Y, Xie A, Gao J. Identification of Hub Genes of Mesio Temporal Lobe Epilepsy and Prognostic Biomarkers of Brain Low-grade Gliomas Based on Bioinformatics Analysis. Cell Transplant 2020; 29:963689720978722. [PMID: 33327771 PMCID: PMC7873767 DOI: 10.1177/0963689720978722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/20/2020] [Accepted: 11/16/2020] [Indexed: 12/16/2022] Open
Abstract
Mesio temporal lobe epilepsy (MTLE) syndrome is the most common form of intractable epilepsies. Meanwhile, seizures are common in patients with cancer as a consequence of brain tumors, including brain low-grade gliomas (LGG). However, the underlying molecular mechanisms of MTLE remain poorly understood. Also, the relationship between MTLE and LGG needs our attention. In this study, we aimed to investigate the hub genes and potential mechanism in MTLE, and the relationship between MTLE and LGG, the gene expression profiles (GSE88992) were downloaded from the Gene Expression Omnibus (GEO) database. Difference analysis for MTLE versus control groups under the three time points was conducted to select the differentially expressed genes (DEGs). Time series clustering analysis was used to select the trend genes. Then a series of bioinformatics analyses including functional enrichment analysis, protein-protein interaction (PPI) network and module analyses, and transcription factor (TF) and miRNA prediction were performed. Also, the overall survival analysis and expression of hub genes in LGG were performed using UALCAN from TCGA database. At 6 h, there were 351 upregulated and 80 downregulated DEGs. At 12 h, there were 499 upregulated and 231 downregulated DEGs. Additionally, 532 upregulated and 402 downregulated DEGs were obtained at 24 h. After time series clustering analysis of the DEGs, we obtained 323 uptrend and 248 downtrend genes. We identified 10 key genes with higher degrees, including C3, TIMP1, PENK, CKAP4, etc. Five PPI modules were identified by MCODE. TF analysis predicted four TFs: JUN, STAT3, NR4A2, and Myc. A total of 26,834 miRNA-mRNA pairs were predicted. Moreover, survival analysis of UALCAN suggested that C3, TIMP1, PENK, GNG2, CKAP4, TNC, JUN, STAT3, NR4A2, and Myc can be potential biomarkers for the prognosis of LGG. In summary, DEGs and hub genes were identified in the present study, which provides novel insight into the development of MTLE.
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Affiliation(s)
- Jian Xu
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mingqiang Sun
- Department of Clinical Lab, Maternal and Child Health Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yuanyuan Wang
- Department of Pediatric, Maternal and Child Health Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Anmu Xie
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jian Gao
- Department of Pediatric, Maternal and Child Health Hospital of Weifang Medical University, Weifang, Shandong, China
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Sepulveda-Rodriguez A, Li P, Khan T, Ma JD, Carlone CA, Bozzelli PL, Conant KE, Forcelli PA, Vicini S. Electroconvulsive Shock Enhances Responsive Motility and Purinergic Currents in Microglia in the Mouse Hippocampus. eNeuro 2019; 6:ENEURO.0056-19.2019. [PMID: 31058213 PMCID: PMC6498419 DOI: 10.1523/eneuro.0056-19.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/09/2019] [Indexed: 12/24/2022] Open
Abstract
Microglia are in a privileged position to both affect and be affected by neuroinflammation, neuronal activity and injury, which are all hallmarks of seizures and the epilepsies. Hippocampal microglia become activated after prolonged, damaging seizures known as status epilepticus (SE). However, since SE causes both hyperactivity and injury of neurons, the mechanisms triggering this activation remain unclear, as does the relevance of the microglial activation to the ensuing epileptogenic processes. In this study, we use electroconvulsive shock (ECS) to study the effect of neuronal hyperactivity without neuronal degeneration on mouse hippocampal microglia. Unlike SE, ECS did not alter hippocampal CA1 microglial density, morphology, or baseline motility. In contrast, both ECS and SE produced a similar increase in ATP-directed microglial process motility in acute slices, and similarly upregulated expression of the chemokine C-C motif chemokine ligand 2 (CCL2). Whole-cell patch-clamp recordings of hippocampal CA1sr microglia showed that ECS enhanced purinergic currents mediated by P2X7 receptors in the absence of changes in passive properties or voltage-gated currents, or changes in receptor expression. This differs from previously described alterations in intrinsic characteristics which coincided with enhanced purinergic currents following SE. These ECS-induced effects point to a "seizure signature" in hippocampal microglia characterized by altered purinergic signaling. These data demonstrate that ictal activity per se can drive alterations in microglial physiology without neuronal injury. These physiological changes, which up until now have been associated with prolonged and damaging seizures, are of added interest as they may be relevant to electroconvulsive therapy (ECT), which remains a gold-standard treatment for depression.
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Affiliation(s)
- Alberto Sepulveda-Rodriguez
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20007
| | - Pinggan Li
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tahiyana Khan
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20007
| | - James D Ma
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
| | - Colby A Carlone
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
| | - P Lorenzo Bozzelli
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20007
- Department of Neuroscience, Georgetown University, Washington, DC 20007
| | - Katherine E Conant
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20007
- Department of Neuroscience, Georgetown University, Washington, DC 20007
| | - Patrick A Forcelli
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20007
| | - Stefano Vicini
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC 20007
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