|
1
|
Kaurani L, Pradhan R, Schröder S, Burkhardt S, Schuetz AL, Krüger DM, Pena T, Heutink P, Sananbenesi F, Fischer A. A role for astrocytic miR-129-5p in frontotemporal dementia. Transl Psychiatry 2025; 15:142. [PMID: 40216778 PMCID: PMC11992244 DOI: 10.1038/s41398-025-03338-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/26/2025] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Frontotemporal dementia is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe degeneration, resulting in behavioral changes, language difficulties, and cognitive decline. In this study, smallRNA sequencing was conducted on postmortem brain tissues obtained from the frontal and temporal of FTD patients with GRN, MAPT, or C9ORF72 mutations. Our analysis identified miR-129-5p as consistently deregulated across all analyzed mutation conditions and brain regions. Functional investigations in in-vitro models revealed a novel role of miR-129-5p in astrocytes, where its loss led to neuroinflammation and impaired neuronal support functions, including reduced glutamate uptake. Depletion of miR-129-5p in astrocytes also resulted in the loss of neuronal spines and altered neuronal network activity in a cell culture system. These findings highlight miR-129-5p as a potential therapeutic target in neurodegenerative diseases and also sheds light on the role of astrocytes in Frontotemporal dementia pathogenesis.
Collapse
Affiliation(s)
- Lalit Kaurani
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
- Research Group for Genome Dynamics in Brain Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany.
| | - Ranjit Pradhan
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Sophie Schröder
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Susanne Burkhardt
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Anna-Lena Schuetz
- Research Group for Genome Dynamics in Brain Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
| | - Dennis M Krüger
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
- Bioinformatics Unit, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Tonatiuh Pena
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
- Bioinformatics Unit, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Peter Heutink
- German Center for Neurodegenerative Diseases, Tübingen, Germany
| | - Farahnaz Sananbenesi
- Research Group for Genome Dynamics in Brain Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany.
| | - Andre Fischer
- Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
- Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
| |
Collapse
|
|
2
|
Han Z, Zhang L, Ma M, Keshavarzi M. Effects of MicroRNAs and Long Non-coding RNAs on Beneficial Action of Exercise on Cognition in Degenerative Diseases: A Review. Mol Neurobiol 2025; 62:485-500. [PMID: 38869810 DOI: 10.1007/s12035-024-04292-4] [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: 03/01/2024] [Accepted: 06/06/2024] [Indexed: 06/14/2024]
Abstract
Recent research has exposed a growing body of proof underscoring the importance of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in maintaining the physical composition of neurons and influencing cognitive functioning in both standard and atypical circumstances. Extensive research has been conducted on the possible application of miRNAs and lncRNAs as biomarkers for various diseases, with a particular focus on brain disorders, as they possess remarkable durability in cell-free surroundings and can endure repeated freezing and thawing processes. It is intriguing to note that miRNAs and lncRNAs have the ability to function through paracrine mechanisms, thereby playing a role in communication between different organs. Recent research has proposed that the improvement of cognitive abilities through physical exercise in mentally healthy individuals is a valuable method for uncovering potential connections between miRNAs, or microRNAs, and lncRNAs, and human cognitive function. The process of cross-correlating data from disease models and patients with existing data will be crucial in identifying essential miRNAs and lncRNAs, which can potentially act as biomarkers or drug targets in the treatment of cognitive disorders. By combining this method with additional research in animal models, we can determine the function of these molecules and their potential impact on therapy. This article discusses the latest research about the primary miRNAs, lncRNAs, and their exosomes that are affected by physical activity in terms of human cognitive function.
Collapse
Affiliation(s)
- Zhen Han
- Department of Physical Education, Zhejiang International Studies University, Hangzhou, 310023, Zhejiang, China
| | - Lei Zhang
- Institute of Physical Education and Sports, Capital University Of Physical Education And Sports, Beijing, 100191, China.
| | - Minhang Ma
- Department of Physical Education, Zhejiang International Studies University, Hangzhou, 310023, Zhejiang, China
| | - Maryam Keshavarzi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
3
|
Kwon HJ, Mun H, Oh JK, Choi GM, Yoo DY, Hwang IK, Kim DW, Moon SM. Neuroprotective Effects of Chaperonin Containing TCP1 Subunit 2 (CCT2) on Motor Neurons Following Oxidative or Ischemic Stress. Neurochem Res 2024; 50:42. [PMID: 39614031 DOI: 10.1007/s11064-024-04286-7] [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: 06/20/2024] [Revised: 10/11/2024] [Accepted: 11/07/2024] [Indexed: 12/01/2024]
Abstract
Chaperonin containing TCP1 (CCT) is an essential protein that controls proteostasis following spinal cord damage. In particular, CCT2 plays an important role in neuronal death in various neurological disorders; however, few studies have investigated the effects of CCT2 on ischemic damage in the spinal cord. In the present study, we synthesized a cell-permeable Tat-CCT2 fusion protein and observed its effects on H2O2-induced oxidative damage in NSC34 motoneuron-like cells and in the spinal cord after ischemic injury. Tat-CCT2, but not its control protein CCTs, was delivered into NSC34 cells in a concentration- and incubation time-dependent manner, and a clear cytosolic location of the delivered protein was observed. In addition, the delivered protein gradually degraded, and nearly control levels were observed 24 h after Tat-CCT2 treatment. Tat-CCT2 treatment significantly ameliorated 200 µM H2O2-induced neuronal damage in NSC34 cells at 8.0 µM protein treatment. Additionally, Tat-CCT2 significantly ameliorated H2O2-induced reactive oxygen species formation and DNA fragmentation. In the rabbit spinal cord, Tat-CCT2 was efficiently delivered into the spinal cord 4 h after 0.125 mg/kg protein treatment. In addition, treatment with Tat-CCT2 significantly improved the neurological scores based on the Tarlov criteria 24 and 72 h after ischemia/reperfusion. Moreover, the number of surviving neurons in the ventral horn of the spinal cord was significantly increased in the Tat-CCT2-treated group 3 and 7 days after ischemia compared to vehicle-treated group. Treatment with Tat-CCT2 alleviated the ischemia-induced oxidative stress and ferroptosis-related factor (malondialdehyde, 8-iso-prostaglandin F2α, and high mobility group box 1) and pro-inflammatory cytokine (interleukin-1β, interleukin-6, and tumor necrosis factor-α) releases in the ventral horn of the spinal cord 8 and 24 h after ischemia/reperfusion. In addition, Tat-CCT2 treatment significantly ameliorated ischemia-induced microglial activation in the ventral horn of spinal cord 24 h after reperfusion. These results suggest that Tat-CCT2 mitigates ischemia-induced neuronal damage in the spinal cord.
Collapse
Affiliation(s)
- Hyun Jung Kwon
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, 25457, South Korea
- Department of Biomedical Sciences, Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea
| | - Hyunwoong Mun
- Department of Neurosurgery, College of Medicine, Hallym University Sacred Heart Hospital, Hallym University, Anyang, 14068, South Korea
| | - Jae Keun Oh
- Department of Neurosurgery, College of Medicine, Hallym University Sacred Heart Hospital, Hallym University, Anyang, 14068, South Korea
| | - Goang-Min Choi
- Department of Thoracic and Cardiovascular Surgery, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon, 24253, South Korea
| | - Dae Young Yoo
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea
| | - In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea
| | - Dae Won Kim
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, 25457, South Korea.
| | - Seung Myung Moon
- Department of Neurosurgery, Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, 07441, South Korea.
- Research Institute for Complementary & Alternative Medicine, Hallym University, Chuncheon, 24253, South Korea.
| |
Collapse
|
|
4
|
Wang YY, Li K, Wang JJ, Hua W, Liu Q, Sun YL, Qi JP, Song YJ. Bone marrow-derived mesenchymal stem cell-derived exosome-loaded miR-129-5p targets high-mobility group box 1 attenuates neurological-impairment after diabetic cerebral hemorrhage. World J Diabetes 2024; 15:1979-2001. [PMID: 39280179 PMCID: PMC11372641 DOI: 10.4239/wjd.v15.i9.1979] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic intracerebral hemorrhage (ICH) is a serious complication of diabetes. The role and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exo) in neuroinflammation post-ICH in patients with diabetes are unknown. In this study, we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation. AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage. METHODS BMSC-exo were isolated from mouse BMSC media. This was followed by transfection with microRNA-129-5p (miR-129-5p). BMSC-exo or miR-129-5p-overexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1 (HMGB1). Quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors, such as HMGB1, interleukin 6, interleukin 1β, toll-like receptor 4, and tumor necrosis factor α. Brain water content, neural function deficit score, and Evans blue were used to measure the neural function of mice. RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery. MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation. Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases. Furthermore, we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA. CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes, thereby improving the neurological function of the brain.
Collapse
Affiliation(s)
- Yue-Ying Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ke Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Jun Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wei Hua
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Lan Sun
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ji-Ping Qi
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yue-Jia Song
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| |
Collapse
|
|
5
|
Wang YY, Li K, Wang JJ, Hua W, Liu Q, Sun YL, Qi JP, Song YJ. Bone marrow-derived mesenchymal stem cell-derived exosome-loaded miR-129-5p targets high-mobility group box 1 attenuates neurological-impairment after diabetic cerebral hemorrhage. World J Diabetes 2024; 15:1978-2000. [DOI: 10.4239/wjd.v15.i9.1978] [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: 05/29/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic intracerebral hemorrhage (ICH) is a serious complication of diabetes. The role and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exo) in neuroinflammation post-ICH in patients with diabetes are unknown. In this study, we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation.
AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage.
METHODS BMSC-exo were isolated from mouse BMSC media. This was followed by transfection with microRNA-129-5p (miR-129-5p). BMSC-exo or miR-129-5p-overexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1 (HMGB1). Quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors, such as HMGB1, interleukin 6, interleukin 1β, toll-like receptor 4, and tumor necrosis factor α. Brain water content, neural function deficit score, and Evans blue were used to measure the neural function of mice.
RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery. MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation. Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases. Furthermore, we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA.
CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes, thereby improving the neurological function of the brain.
Collapse
Affiliation(s)
- Yue-Ying Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ke Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Jun Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wei Hua
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Lan Sun
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ji-Ping Qi
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yue-Jia Song
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| |
Collapse
|
|
6
|
Xia GQ, Xu M, Sun C, Zhang ZL, Li XQ. Elevated microRNA-214-3p level ameliorates neuroinflammation after spinal cord ischemia-reperfusion injury by inhibiting Nmb/Cav3.2 pathway. Int Immunopharmacol 2024; 133:112031. [PMID: 38631219 DOI: 10.1016/j.intimp.2024.112031] [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: 01/09/2024] [Revised: 03/28/2024] [Accepted: 04/05/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Neuromedin B (Nmb) plays a pivotal role in the transmission of neuroinflammation, particularly during spinal cord ischemia-reperfusion injury (SCII). However, the detailed molecular mechanisms underlying this process remain elusive. METHODS The SCII model was established by clamping the abdominal aorta of male Sprague-Dawley (SD) rats for 60 min. The protein expression levels of Nmb, Cav3.2, and IL-1β were detected by Western blotting, while miR-214-3p expression was quantified by qRT-PCR. The targeted regulation between miR-214-3p and Nmb was investigated using a dual-luciferase reporter gene assay. The cellular localization of Nmb and Cav3.2 with cell-specific markers was visualized by immunofluorescence staining. The specific roles of miR-214-3p on the Nmb/Cav3.2 interactions in SCII-injured rats were explored by intrathecal injection of Cav3.2-siRNA, PD168368 (a specific NmbR inhibitor) and synthetic miR-214-3p agomir and antagomir in separate experiments. Additionally, hind-limb motor function was evaluated using the modified Tarlov scores. RESULTS Compared to the Sham group, the protein expression levels of Nmb, Cav3.2, and the proinflammatory factor Interleukin(IL)-1β were significantly elevated at 24 h post-SCII. Intrathecal injection of PD168368 and Cav3.2-siRNA significantly suppressed the expression of Cav3.2 and IL-1β compared to the SCII group. The miRDB database and dual-luciferase reporter gene assay identified Nmb as a direct target of miR-214-3p. As expected, in vivo overexpression of miR-214-3p by agomir-214-3p pretreatment significantly inhibited the increases in Nmb, Cav3.2 and IL-1β expression and improved lower limb motor function in SCII-injured rats, while antagomiR-214-3p pretreatment reversed these effects. CONCLUSIONS Nmb protein levels positively correlated with Cav3.2 expression in SCII rats. Upregulating miR-214-3p ameliorated hind-limb motor function and protected against neuroinflammation via inhibiting the aberrant Nmb/Cav3.2 interactions and downstream IL-1β release. These findings provide novel therapeutic targets for clinical prevention and treatment of SCII.
Collapse
Affiliation(s)
- Guo-Qiang Xia
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
| | - Miao Xu
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
| | - Cong Sun
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
| | - Zai-Li Zhang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China.
| | - Xiao-Qian Li
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China.
| |
Collapse
|
|
7
|
Lv S, Zhao K, Li R, Meng C, Li G, Yin F. EGFR-Activated JAK2/STAT3 Pathway Confers Neuroprotection in Spinal Cord Ischemia-Reperfusion Injury: Evidence from High-Throughput Sequencing and Experimental Models. Mol Neurobiol 2024; 61:646-661. [PMID: 37656314 DOI: 10.1007/s12035-023-03548-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/24/2023] [Indexed: 09/02/2023]
Abstract
This study aimed to investigate the molecular mechanisms underlying spinal cord ischemia-reperfusion (SCI/R) injury. Through RNA-Seq high-throughput sequencing and bioinformatics analysis, we found that EGFR was downregulated in the spinal cord of SCI/R mice and may function via mediating the JAK2/STAT3 signaling pathway. In vitro cell experiments indicated that overexpression of EGFR activated the JAK2/STAT3 signaling pathway and reduced neuronal apoptosis levels. In vivo animal experiments further confirmed this conclusion, suggesting that EGFR inhibits SCI/R-induced neuronal apoptosis by activating the JAK2/STAT3 signaling pathway, thereby improving SCI/R-induced spinal cord injury in mice. This study revealed the molecular mechanisms of SCI/R injury and provided new therapeutic strategies for treating neuronal apoptosis.
Collapse
Affiliation(s)
- Shijie Lv
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Kunchi Zhao
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Ran Li
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Chunyang Meng
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Guangchun Li
- Department of Orthopedics, Jilin Province People's Hospital, Changchun, 130021, People's Republic of China
| | - Fei Yin
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China.
| |
Collapse
|
|
8
|
Guo L, Zhang D, Ren X, Liu D. SYVN1 attenuates ferroptosis and alleviates spinal cord ischemia-reperfusion injury in rats by regulating the HMGB1/NRF2/HO-1 axis. Int Immunopharmacol 2023; 123:110802. [PMID: 37591122 DOI: 10.1016/j.intimp.2023.110802] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND The ferroptosis of neurons is an important pathological mechanism of spinal cord ischemia reperfusion injury (SCIRI). Previous studies showed that synoviolin 1 (SYVN1) is a good prognostic marker of neurodegenerative diseases, but its mechanism is still unclear. This study aims to explore the role of SYVN1 in the ferroptosis of neurons and to clarify its internal mechanism. METHODS Rat primary spinal cord neurons were treated with oxygen-glucose deprivation (OGD) for 1, 4 or 8 h, and then cell viability, ROS and MDA levels, glutathione peroxidase (GSH-Px) activity, and the expression of ferroptosis-related proteins GPX4, FTH1 and PTGS2 were detected. OGD/R-induced neurons were transfected with pcDNA-SYVN1 or si-HMGB1, and then cell functions were detected. Transmission electron microscope (TEM) was used to detect cell ferroptosis. The interplay between SYVN1 and high mobility group box 1 (HMGB1) was confirmed with Co-immunoprecipitation (Co-IP) assay. The stability of HMGB1 was measured by ubiquitination assay. Also, cells were treated with pcDNA-SYVN1 or together with ubiquitination inhibitor MG132, as well as treated with pcDNA-SYVN1 and pcDNA-HMGB1 or together with NRF2 activator dimethyl fumarate (DMF), and then Western blotting was used to detect the expression of HMGB1, nuclear NRF2 and HO-1 proteins. In addition, SD rats were occluded left common carotid artery and aortic arch to establish a SCIRI rat model. And rats were injected intrathecal with adenovirus-mediated SYVN1 overexpression vector (Ad-SYVN1, 2 μL, virus titer 5 × 1013 transduction unit [TU]/mL) to overexpress SYVN1. The motion function of rats was quantified using the Basso Rat Scale (BMS) for Locomotion. The ferroptosis and the number of neurons in the spinal cord tissue of rats were detected. RESULTS SYVN1 overexpression inhibited ferroptosis of SCIRI rats and OGD/R-treated primary spinal cord neurons, and down-regulated the expression of HMGB1. In terms of mechanism, the binding of SYVN1 and HMGB1 promoted the ubiquitination and degradation of HMGB1, and negatively regulated the expression of HMGB1. Moreover, under OGD/R conditions, MG132 treatment or HMGB1 overexpression eliminated the inhibitory effect of SYVN1 overexpression on the ferroptosis of neurons and the activation of the NRF2/HO-1 pathway, and DMF treatment abolished the inhibition of HMGB1 overexpression on the NRF2/HO-1 pathway. Finally, in vivo experiments showed that SYVN1 overexpression could alleviate the spinal cord ischemia-reperfusion injury in rats by down-regulating HMGB1 and promoting the activation of the NRF2/HO-1 pathway. CONCLUSION SYVN1 regulates ferroptosis through the HMGB1/NRF2/HO-1 axis to prevent spinal cord ischemia-reperfusion injury.
Collapse
Affiliation(s)
- Lili Guo
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Dong Zhang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiaoyan Ren
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Dingsheng Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China.
| |
Collapse
|
|
9
|
Guo X. A state-of-the-art review on miRNA in prevention and treatment of Alzheimer 's disease. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 52:485-498. [PMID: 37643982 PMCID: PMC10495246 DOI: 10.3724/zdxbyxb-2023-0324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 08/15/2023] [Indexed: 08/24/2023]
Abstract
Alzheimer's disease (AD) is a multifactorial and heterogenic disorder. MiRNA is a class of non-coding RNAs with 19-22 nucleotides in length that can regulate the expression of target genes in the post-transcriptional level. It has been found that the miRNAome in AD patients is significantly altered in brain tissues, cerebrospinal fluid and blood circulation, as compared to healthy subjects. Experimental studies have suggested that expression changes in miRNA could drive AD onset and development via different mechanisms. Therefore, targeting miRNA expression to regulate the key genes involved in AD progression is anticipated to be a promising approach for AD prevention and treatment. Rodent AD models have demonstrated that targeting miRNAs could block biogenesis and toxicity of amyloid β, inhibit the production and hyper-phosphorylation of τ protein, prevent neuronal apoptosis and promote neurogenesis, maintain neural synaptic and calcium homeostasis, as well as mitigate neuroinflammation mediated by microglia. In addition, animal and human studies support the view that miRNAs are critical players contributing to the beneficial effects of cell therapy and lifestyle intervention to AD. This article reviews the most recent advances in the roles, mechanisms and applications of targeting miRNA in AD prevention and treatment based on rodent AD models and human intervention studies. The potential opportunities and challenges in clinical application of targeting miRNA for AD patients are also discussed.
Collapse
Affiliation(s)
- Xihan Guo
- School of Life Science, Yunnan Normal University, Engineering Research Center, Sustainable Development and Utilization of Biomass Energy of the Ministry of Education, Kunming 650500, China.
| |
Collapse
|
|
10
|
Xin W, Baokun Z, Zhiheng C, Qiang S, Erzhu Y, Jianguang X, Xiaofeng L. Biodegradable bilayer hydrogel membranes loaded with bazedoxifene attenuate blood-spinal cord barrier disruption via the NF-κB pathway after acute spinal cord injury. Acta Biomater 2023; 159:140-155. [PMID: 36736849 DOI: 10.1016/j.actbio.2023.01.056] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023]
Abstract
After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption and hemorrhage lead to blood cell infiltration and progressive secondary injuries. Therefore, early restoration of the BSCB represents a key step in the treatment of SCI. Bazedoxifene (BZA), a third-generation estrogen receptor modulator, has recently been reported to inhibit inflammation and alleviate blood-brain barrier disruption caused by traumatic brain injury, attracting great interest in the field of central nervous system injury and repair. However, whether BZA can attenuate BSCB disruption and contribute to SCI repair remains unknown. Here, we developed a new type of biomaterial carrier and constructed a BZA-loaded HSPT (hyaluronic acid (HA), sodium alginate (SA), polyvinyl alcohol (PVA), tetramethylpropane (TPA) material construction) (HSPT@Be) system to effectively deliver BZA to the site of SCI. We found that HSPT@Be could significantly reduce inflammation in the spinal cord in SCI rats and attenuate BSCB disruption by providing covering scaffold, inhibiting oxidative stress, and upregulating tight junction proteins, which was mediated by regulation of the NF-κB/MMP signaling pathway. Importantly, functional assessment showed the evident improvement of behavioral functions in the HSPT@Be-treated SCI rats. These results indicated that HSPT@Be can attenuate BSCB disruption via the NF-κB pathway after SCI, shedding light on its potential therapeutic benefit for SCI. STATEMENT OF SIGNIFICANCE: After spinal cord injury, blood-spinal cord barrier disruption and hemorrhage lead to blood cell infiltration and progressive secondary injuries. Bazedoxifene has recently been reported to inhibit inflammation and alleviate blood-brain barrier disruption caused by traumatic brain injury. However, whether BZA can attenuate BSCB disruption and contribute to SCI repair remains unknown. In this study, we developed a new type of biomaterial carrier and constructed a bazedoxifene-loaded HSPT (HSPT@Be) system to efficiently treat SCI. HSPT@Be could provide protective coverage, inhibit oxidative stress, and upregulate tight junction proteins through NF-κB/MMP pathway both in vivo and in vitro, therefore attenuating BSCB disruption. Our study fills the application gap of biomaterials in BSCB restoration.
Collapse
Affiliation(s)
- Wang Xin
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zhang Baokun
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Chen Zhiheng
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Shi Qiang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yang Erzhu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Xu Jianguang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Lian Xiaofeng
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| |
Collapse
|
|
11
|
Expression Profiles of Long Noncoding RNAs and Messenger RNAs in a Rat Model of Spinal Cord Injury. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2023; 2023:6033020. [PMID: 36714328 PMCID: PMC9879695 DOI: 10.1155/2023/6033020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 01/20/2023]
Abstract
Spinal cord injury (SCI) is a serious disorder of the central nervous system with a high disability rate. Long noncoding RNAs (lncRNAs) are reported to mediate many biological processes. The aim of this study was to explore lncRNA and mRNA expression profiles and functional networks after SCI. Differentially expressed genes between SCI model rats and sham controls were identified by microarray assays and analyzed by functional enrichment. Key lncRNAs were identified using a support vector machine- (SVM-) recursive feature elimination (RFE) algorithm. A trans and cis regulation model was used to analyze the regulatory relationships between lncRNAs and their targets. An lncRNA-related ceRNA network was established. We identified 5465 differentially expressed lncRNAs (DE lncRNAs) and 8366 differentially expressed mRNAs (DE mRNAs) in the SCI group compared with the sham group (fold change > 2.0, p < 0.05). Four genes were confirmed by qRT-PCR which were consistent with the microarray data. GSEA analysis showed that most marked changes occurred in pathways related to immune inflammation and nerve cell function, including cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and GABAergic synapse. Enrichment analysis identified 30 signaling pathways, including those associated with immune inflammation response. A total of 40 key lncRNAs were identified using the SVM-RFE algorithm. A key lncRNA-mRNAs coexpression network was generated for 230 951 lncRNA-mRNA pairs with half showing positive correlations. Several key DE lncRNAs were predicted to have "cis"- or "trans"-regulated target genes. The transcription factors, Sp1, JUN, and SOX10, may regulate the interaction between XR_001837123.1 and ETS 1. In addition, five pairs of ceRNA regulatory sequences were constructed. Many mRNAs and lncRNAs were found to be dysregulated after SCI. Bioinformatic analysis showed that DE lncRNAs may play crucial roles in SCI. It is anticipated that these findings will provide new insights into the underlying mechanisms and potential therapeutic targets for SCI.
Collapse
|
|
12
|
Song Z, Gao Y, Zhao Y, Feng X, Zhao Z, Wang W. miR-129-5p Induces Cell Apoptosis and Inhibits Inflammation by Inflammatory Signaling to Alleviate Spinal Cord Injury (SCI). J BIOMATER TISS ENG 2023. [DOI: 10.1166/jbt.2023.3197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Spinal cord injury (SCI) is a spinal cord nerve dysfunction secondary to trauma. Until now, still no appropriate drug with unclear etiology. Therefore, it is to develop effective SCI treatment methods. Herein, we intended to detect the impact of miR-129-5p in SCI After establishment
of a mouse SCI model, the animals received intrathecal injection of agomir-miR-129-5p or normal saline. Then, the miR-129-5p’s effect was evaluated by assessing motor function, spinal cord tissue edema, apoptosis and inflammation of mice upon treatments and potential targeted pathways
of the miRNA were detected. Overexpressed miR-129-5p facilitated the wound healing with less spare tissue and water content. Additionally, overexpressed miR-129-5p suppressed the in vivo inflammation with decreased apoptotic rate of neurons. As SCI induced increased expression of HMGB1,
TLR4, and NF-κB in tissues, but the presence of miR-129-5p reversed the expressions. Collectively, this study elucidate miR-129-5p significantly improves inflammatory response and apoptosis, thereby improving the condition of SCI. These findings might provide a new theory for
the disorder, and promote the research progress on the disease.
Collapse
Affiliation(s)
- Zhengdong Song
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Yuwei Gao
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Yuhao Zhao
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Xiaofei Feng
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Zhenrui Zhao
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Wenji Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, 730030, China
| |
Collapse
|
|
13
|
Guo L, Wang D, Alexander HY, Ren X, Ma H. Long non-coding RNA H19 contributes to spinal cord ischemia/reperfusion injury through increasing neuronal pyroptosis by miR-181a-5p/HMGB1 axis. Aging (Albany NY) 2022; 14:5449-5463. [PMID: 35793244 PMCID: PMC9320554 DOI: 10.18632/aging.204160] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 06/18/2022] [Indexed: 12/23/2022]
Abstract
Pyroptosis, a programmed inflammatory necrotizing cell death, is likely involved in spinal cord ischemia-reperfusion (SCI/R) injury, but the mechanisms initiating driving neuronal pyroptosis must be further revealed. The aim of this study is to unravel the mechanism of long non-coding RNA (lncRNA) H19 during SCI/R. SCI/R model was induced in C57BL/6 mice by blocking the aortic arch in vivo, and oxygen-glucose deprivation/reperfusion (OGD/R) injury model of PC12 cells was established in vitro. Our results showed that H19 and HMGB1 expression was upregulated, while miR-181a-5p was downregulated in the SCI/R mice and OGD/R-treated PC12 cells. SCI/R induced pathological damage, pyroptosis and inflammation compared with the sham group. H19 acted as a molecular sponge to suppress miR-181a-5p, and HMGB1 was identified as a direct target of miR-181a-5p. MiR-181a-5p overexpression inhibited the increase of IL-1β, IL-18 and TNF-α production and NLRP3, ASC, and Cleaved-caspase-1 expression in OGD/R-treated PC12 cells; while miR-181a-5p silencing exerted opposite effects. HMGB1 overexpression reversed H19 knockdown-mediated the inhibition of pyroptosis and inflammation in OGD/R-treated PC12 cells. In vivo, H19 knockdown promoted the hind limb motor function recovery and alleviated the pathological damage, pyroptosis and inflammation induced by SCI/R. LncRNA H19/miR-181a-5p/HMGB1 pathway contributes to pyroptosis via activating caspase1 signaling during SCI/R, suggesting that this axis may be a potent therapeutic target in SCI/R.
Collapse
Affiliation(s)
- Lili Guo
- Department of Anesthesiology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Dan Wang
- Department of Anesthesiology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hildrich Yasmal Alexander
- Department of Anesthesiology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiaoyan Ren
- Department of Anesthesiology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hong Ma
- Department of Anesthesiology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| |
Collapse
|
|
14
|
The Role of Non-Coding RNAs in the Pathogenesis of Parkinson’s Disease: Recent Advancement. Pharmaceuticals (Basel) 2022; 15:ph15070811. [PMID: 35890110 PMCID: PMC9315906 DOI: 10.3390/ph15070811] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/19/2022] [Accepted: 06/21/2022] [Indexed: 01/27/2023] Open
Abstract
Parkinson’s disease (PD) is a prevalent neurodegenerative aging disorder that manifests as motor and non-motor symptoms, and its etiopathogenesis is influenced by non-coding RNAs (ncRNAs). Signal pathway and gene sequence studies have proposed that alteration of ncRNAs is relevant to the occurrence and development of PD. Furthermore, many studies on brain tissues and body fluids from patients with PD indicate that variations in ncRNAs and their target genes could trigger or exacerbate neurodegenerative pathogenesis and serve as potential non-invasive biomarkers of PD. Numerous ncRNAs have been considered regulators of apoptosis, α-syn misfolding and aggregation, mitochondrial dysfunction, autophagy, and neuroinflammation in PD etiology, and evidence is mounting for the determination of the role of competing endogenous RNA (ceRNA) mechanisms in disease development. In this review, we discuss the current knowledge regarding the regulation and function of ncRNAs as well as ceRNA networks in PD pathogenesis, focusing on microRNAs, long ncRNAs, and circular RNAs to increase the understanding of the disease and propose potential target identification and treatment in the early stages of PD.
Collapse
|
|
15
|
Cai L, Gao L, Zhang G, Zeng H, Wu X, Tan X, Qian C, Chen G. DJ-1 Alleviates Neuroinflammation and the Related Blood-Spinal Cord Barrier Destruction by Suppressing NLRP3 Inflammasome Activation via SOCS1/Rac1/ROS Pathway in a Rat Model of Traumatic Spinal Cord Injury. J Clin Med 2022; 11:jcm11133716. [PMID: 35807002 PMCID: PMC9267719 DOI: 10.3390/jcm11133716] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/19/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
DJ-1 has been shown to play essential roles in neuronal protection and anti-inflammation in nervous system diseases. This study aimed to explore how DJ-1 regulates neuroinflammation after traumatic spinal cord injury (t-SCI). The rat model of spinal cord injury was established by the clamping method. The Basso, Beattie, Bresnahan (BBB) score and the inclined plane test (IPT) were used to evaluate neurological function. Western blot was then applied to test the levels of DJ-1, NLRP3, SOCS1, and related proinflammatory factors (cleaved caspase 1, IL-1β and IL-18); ROS level was also examined. The distribution of DJ-1 was assessed by immunofluorescence staining (IF). BSCB integrity was assessed by the level of MMP-9 and tight junction proteins (Claudin-5, Occludin and ZO-1). We found that DJ-1 became significantly elevated after t-SCI and was mainly located in neurons. Knockdown of DJ-1 with specific siRNA aggravated NLRP3 inflammasome-related neuroinflammation and strengthened the disruption of BSCB integrity. However, the upregulation of DJ-1 by Sodium benzoate (SB) reversed these effects and improved neurological function. Furthermore, SOCS1-siRNA attenuated the neuroprotective effects of DJ-1 and increased the ROS, Rac1 and NLRP3. In conclusion, DJ-1 may alleviate neuroinflammation and the related BSCB destruction after t-SCI by suppressing NLRP3 inflammasome activation by SOCS1/Rac1/ROS pathways. DJ-1 shows potential as a feasible target for mediating neuroinflammation after t-SCI.
Collapse
Affiliation(s)
- Lingxin Cai
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
| | - Liansheng Gao
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
| | - Guoqiang Zhang
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
| | - Hanhai Zeng
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
| | - Xinyan Wu
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
| | - Xiaoxiao Tan
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
| | - Cong Qian
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
- Correspondence: (C.Q.); (G.C.)
| | - Gao Chen
- Department of Neurological Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; (L.C.); (L.G.); (G.Z.); (H.Z.); (X.W.); (X.T.)
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou 310009, China
- Correspondence: (C.Q.); (G.C.)
| |
Collapse
|
|
16
|
Luo J, Li J, Xiong L, Fan L, Peng L, Yang Y, Lu D, Shao J. MicroRNA-27a-3p relieves inflammation and neurologic impairment after cerebral ischemia reperfusion via inhibiting LITAF and the TLR4/NF-κB pathway. Eur J Neurosci 2022; 56:4013-4030. [PMID: 35584745 DOI: 10.1111/ejn.15720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 04/12/2022] [Accepted: 05/12/2022] [Indexed: 11/30/2022]
Abstract
Cerebral ischemia reperfusion (CIR) affects microRNA (miR) expression and causes substantial inflammation. Here, we investigated the influence and underlying mechanism of miR-27a-3p in rats with CIR. Firstly, Biliverdin treatment relieved cerebral infarction and decreased the levels of serum interleukin (IL)-1β, IL-6 and TNF-α. Through our previous study, we found key miR-27a-3p and its targeted gene LITAF might involve in the molecular mechanism of CIR. Then, the regulation between miR-27a-3p and LITAF was verified by the temporal miR-27a-3p and LITAF expression profiles and luciferase assay. Moreover, intracerebroventricular injection of the miR-27a-3p mimic significantly decreased the LITAF, TLR4, NF-κB and IL-6 levels at 24h post-surgery, whereas miR-27a-3p inhibitor reversed these effects. Furthermore, miR-27a-3p mimic could relieve cerebral infarct and neurologic deficit after CIR. In addition, injection of miR-27a-3p mimic decreased neuronal damage induced by CIR. Taken together, our results suggest that miR-27a-3p protect against CIR by relieving inflammation, neuronal damage and neurologic deficit via regulating LITAF and the TLR4/NF-κB pathway.
Collapse
Affiliation(s)
- Jing Luo
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| | - Junjie Li
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| | - Li Xiong
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| | - Linna Fan
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| | - Lijia Peng
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| | - Yuan Yang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| | - Di Lu
- Incubation center for Scientific and technological achievements, Kunming Medical University
| | - Jianlin Shao
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University
| |
Collapse
|
|
17
|
Lv B, Shen N, Cheng Z, Chen Y, Ding H, Yuan J, Zhao K, Zhang Y. Strategies for Biomaterial-Based Spinal Cord Injury Repair via the TLR4-NF-κB Signaling Pathway. Front Bioeng Biotechnol 2022; 9:813169. [PMID: 35600111 PMCID: PMC9116428 DOI: 10.3389/fbioe.2021.813169] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/13/2021] [Indexed: 12/23/2022] Open
Abstract
The repair and motor functional recovery after spinal cord injury (SCI) has remained a clinical challenge. Injury-induced gliosis and inflammation lead to a physical barrier and an extremely inhibitory microenvironment, which in turn hinders the recovery of SCI. TLR4-NF-κB is a classic implant-related innate immunomodulation signaling pathway and part of numerous biomaterial-based treatment strategies for SCI. Numerous experimental studies have demonstrated that the regulation of TLR4-NF-κB signaling pathway plays an important role in the alleviation of inflammatory responses, the modulation of autophagy, apoptosis and ferroptosis, and the enhancement of anti-oxidative effect post-SCI. An increasing number of novel biomaterials have been fabricated as scaffolds and carriers, loaded with phytochemicals and drugs, to inhibit the progression of SCI through regulation of TLR4-NF-κB. This review summarizes the empirical strategies for the recovery after SCI through individual or composite biomaterials that mediate the TLR4-NF-κB signaling pathway.
Collapse
Affiliation(s)
- Bin Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Naiting Shen
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangrong Cheng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhang Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Ding
- Department of Orthopedics, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Jishan Yuan
- Department of Orthopedics, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Kangchen Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yukun Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
18
|
Zhou S, Chen R, She Y, Liu X, Zhao H, Li C, Jia Y. A new perspective on depression and neuroinflammation: Non-coding RNA. J Psychiatr Res 2022; 148:293-306. [PMID: 35193033 DOI: 10.1016/j.jpsychires.2022.02.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 12/19/2022]
Abstract
The high incidence and relapse rate of depression, as well comorbidity with other diseases, has made depression one of the primary causes of years of life lived with disability. Moreover, the unknown biological mechanism of depression has made treatment difficult. Neuroinflammation is important in the pathogenesis of depression. Neuroinflammation may affect depression by regulating the production of immune factors, immune cell activation, neuron generation, synaptic plasticity, and neurotransmission. Non-coding RNAs (ncRNAs) may be a breakthrough link between depression and neuroinflammation, as ncRNAs participate in these biological changes. We summarize the functions and mechanisms of ncRNAs in neuroinflammation and depression, and predict ncRNAs that may regulate the occurrence and progression of depression through neuritis. These findings not only broaden our understanding of the genetic regulation of depression and neuroinflammation but also provide a new perspective of the underlying mechanism and aid in the design of novel prevention, diagnosis, and treatment strategies.
Collapse
Affiliation(s)
- Shanyao Zhou
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, 466 Xin Gang Zhong Road, Guangzhou, 510317, China
| | - Rui Chen
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, 466 Xin Gang Zhong Road, Guangzhou, 510317, China.
| | - Yanling She
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, 466 Xin Gang Zhong Road, Guangzhou, 510317, China
| | - Xuanjun Liu
- Department of Psychiatry, First Affiliated Hospital of Jinan University, 613 W. Huangpu Avenue, Guangzhou, 510630, China
| | - Hui Zhao
- Department of Psychiatry, First Affiliated Hospital of Jinan University, 613 W. Huangpu Avenue, Guangzhou, 510630, China
| | - Cheng Li
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, 466 Xin Gang Zhong Road, Guangzhou, 510317, China.
| | - Yanbin Jia
- Department of Psychiatry, First Affiliated Hospital of Jinan University, 613 W. Huangpu Avenue, Guangzhou, 510630, China.
| |
Collapse
|
|
19
|
Sun P, Hamblin MH, Yin KJ. Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders. Fluids Barriers CNS 2022; 19:27. [PMID: 35346266 PMCID: PMC8959280 DOI: 10.1186/s12987-022-00317-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/17/2022] [Indexed: 12/26/2022] Open
Abstract
The blood–brain barrier (BBB) is an essential component of the neurovascular unit that controls the exchanges of various biological substances between the blood and the brain. BBB damage is a common feature of different central nervous systems (CNS) disorders and plays a vital role in the pathogenesis of the diseases. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs), are important regulatory RNA molecules that are involved in almost all cellular processes in normal development and various diseases, including CNS diseases. Cumulative evidences have demonstrated ncRNA regulation of BBB functions in different CNS diseases. In this review, we have summarized the miRNAs, lncRNAs, and circRNAs that can be served as diagnostic and prognostic biomarkers for BBB injuries, and demonstrated the involvement and underlying mechanisms of ncRNAs in modulating BBB structure and function in various CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), Alzheimer's disease (AD), vascular cognitive impairment and dementia (VCID), brain tumors, brain infections, diabetes, sepsis-associated encephalopathy (SAE), and others. We have also discussed the pharmaceutical drugs that can regulate BBB functions via ncRNAs-related signaling cascades in CNS disorders, along with the challenges, perspective, and therapeutic potential of ncRNA regulation of BBB functions in CNS diseases.
Collapse
|
|
20
|
Chopra N, Menounos S, Choi JP, Hansbro PM, Diwan AD, Das A. Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies. NEUROSCI 2022; 3:1-27. [PMID: 39484675 PMCID: PMC11523733 DOI: 10.3390/neurosci3010001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/14/2021] [Indexed: 11/03/2024] Open
Abstract
The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause-effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.
Collapse
Affiliation(s)
- Neha Chopra
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
- Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia
| | - Spiro Menounos
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
| | - Jaesung P Choi
- Centre for Inflammation, Faculty of Science, Centenary Institute, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2050, Australia; (J.P.C.); (P.M.H.)
| | - Philip M Hansbro
- Centre for Inflammation, Faculty of Science, Centenary Institute, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2050, Australia; (J.P.C.); (P.M.H.)
| | - Ashish D Diwan
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
- Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia
| | - Abhirup Das
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
- Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia
| |
Collapse
|
|
21
|
Liu FJ, Gu TJ, Wei DY. Emodin alleviates sepsis-mediated lung injury via inhibition and reduction of NF-kB and HMGB1 pathways mediated by SIRT1. Kaohsiung J Med Sci 2022; 38:253-260. [PMID: 34806822 DOI: 10.1002/kjm2.12476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 09/27/2021] [Accepted: 10/15/2021] [Indexed: 11/11/2022] Open
Abstract
Inflammation plays an important role during sepsis, and excessive inflammation can result in organ damage, chronic inflammation, fibrosis, and scarring. The study aimed to investigate the specific mechanism of emodin by constructing in vivo and in vitro septic lung injury models via inhibition and reduction of NF-kB and high mobility group box 1 (HMGB1) pathways. A cecal ligation and puncture (CLP) model was built for adult male Sprague-Dawley rats. Concentrations of TNF-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid were determined using commercially available ELISA kits. Hematoxylin and eosin staining was used for the right lung inferior lobes. Myeloperoxidase (MPO) activity of the lung tissue was detected by using the MPO kit. Murine alveolar epithelial cell line (MLE-12) cells were used for flow cytometry and Western blot to analyze the apoptosis rate and protein expression. Emodin significantly decreased CLP-induced cell apoptosis, upregulated expression of sirtuin 1 (SIRT1), and inhibited p-p65/p65 and HMGB1. In lipopolysaccharide (LPS) treated cell model, emodin treatment markedly decreased LPS-induced release of IL-1, IL-6, and tumor necrosis factor (TNF)-α, inhibited LPS-induced cell apoptosis and suppressed protein levels of P-P65/P65 and HMGB1. However, science of SIRT1 reversed the above effects by treatment of emodin. In summarize, this study found that emodin can alleviate sepsis-induced lung injury in vivo and in vitro through regulation of SIRT1.
Collapse
Affiliation(s)
- Fu-Jing Liu
- Department of Emergency, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ti-Jun Gu
- Department of Emergency, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China
| | - Dong-Yue Wei
- Department of Pediatric, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China
| |
Collapse
|
|
22
|
Zhang ZL, Wang D, Chen FS. MicroRNA-101a-3p mimic ameliorates spinal cord ischemia/reperfusion injury. Neural Regen Res 2022; 17:2022-2028. [PMID: 35142692 PMCID: PMC8848611 DOI: 10.4103/1673-5374.335164] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
miR-101a-3p is expressed in a variety of organs and tissues and plays a regulatory role in many diseases, but its role in spinal cord ischemia/reperfusion injury remains unclear. In this study, we established a rat model of spinal cord ischemia/reperfusion injury by clamping the aortic arch for 14 minutes followed by reperfusion for 24 hours. Results showed that miR-101a-3p expression in L4–L6 spinal cord was greatly decreased, whereas MYCN expression was greatly increased. Dual-luciferase reporter assay results showed that miR-101a-3p targeted MYCN. MYCN immunoreactivity, which was primarily colocalized with neurons in L4–L6 spinal tissue, greatly increased after spinal cord ischemia/reperfusion injury. However, intrathecal injection of an miR-101a-3p mimic within 24 hours before injury decreased MYCN, p53, caspase-9 and interleukin-1β expression, reduced p53 immunoreactivity, reduced the number of MYCN/NeuN-positive cells and the number of necrotic cells in L4–L6 spinal tissue, and increased Tarlov scores. These findings suggest that the miR-101a-3p mimic improved spinal ischemia/reperfusion injury-induced nerve cell apoptosis and inflammation by inhibiting MYCN and the p53 signaling pathway. Therefore, miR-101a-3p mimic therapy may be a potential treatment option for spinal ischemia/reperfusion injury.
Collapse
Affiliation(s)
- Zai-Li Zhang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Dan Wang
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Feng-Shou Chen
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| |
Collapse
|
|
23
|
Li XQ, Chen FS, Tan WF, Fang B, Zhang ZL, Ma H. Correction to: Elevated microRNA-129-5p level ameliorates neuroinflammation and blood-spinal cord barrier damage after ischemia-reperfusion by inhibiting HMGB1 and the TLR3-cytokine pathway. J Neuroinflammation 2021; 18:308. [PMID: 34963474 PMCID: PMC8715607 DOI: 10.1186/s12974-021-02345-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Affiliation(s)
- Xiao-Qian Li
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning, China
| | - Feng-Shou Chen
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning, China
| | - Wen-Fei Tan
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning, China
| | - Bo Fang
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning, China
| | - Zai-Li Zhang
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning, China
| | - Hong Ma
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning, China.
| |
Collapse
|
|
24
|
The Influence of Mitochondrial-DNA-Driven Inflammation Pathways on Macrophage Polarization: A New Perspective for Targeted Immunometabolic Therapy in Cerebral Ischemia-Reperfusion Injury. Int J Mol Sci 2021; 23:ijms23010135. [PMID: 35008558 PMCID: PMC8745401 DOI: 10.3390/ijms23010135] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/14/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022] Open
Abstract
Cerebral ischemia-reperfusion injury is related to inflammation driven by free mitochondrial DNA. At the same time, the pro-inflammatory activation of macrophages, that is, polarization in the M1 direction, aggravates the cycle of inflammatory damage. They promote each other and eventually transform macrophages/microglia into neurotoxic macrophages by improving macrophage glycolysis, transforming arginine metabolism, and controlling fatty acid synthesis. Therefore, we propose targeting the mtDNA-driven inflammatory response while controlling the metabolic state of macrophages in brain tissue to reduce the possibility of cerebral ischemia-reperfusion injury.
Collapse
|
|
25
|
Singh V, Kushwaha S, Ansari JA, Gangopadhyay S, Mishra SK, Dey RK, Giri AK, Patnaik S, Ghosh D. MicroRNA-129-5p-regulated microglial expression of the surface receptor CD200R1 controls neuroinflammation. J Biol Chem 2021; 298:101521. [PMID: 34952004 PMCID: PMC8762073 DOI: 10.1016/j.jbc.2021.101521] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 11/28/2022] Open
Abstract
CD200R1 is an inhibitory surface receptor expressed in microglia and blood macrophages. Microglial CD200R1 is known to control neuroinflammation by keeping the microglia in resting state, and therefore, tight regulation of its expression is important. CCAAT/enhancer-binding protein β (CEBPβ) is the known regulator of CD200R1 transcription. In the present study, our specific intention was to find a possible posttranscriptional regulatory mechanism of CD200R1 expression. Here we investigated a novel regulatory mechanism of CD200R1 expression following exposure to an environmental stressor, arsenic, combining in silico analysis, in vitro, and in vivo experiments, as well as validation in human samples. The in silico analysis and in vitro studies with primary neonatal microglia and BV2 microglia revealed that arsenic demethylates the promoter of a microRNA, miR-129-5p, thereby increasing its expression, which subsequently represses CD200R1 by binding to its 3′-untranslated region and shuttling the CD200R1 mRNA to the cytoplasmic-processing body in mouse microglia. The role of miR-129-5p was further validated in BALB/c mouse by stereotaxically injecting anti-miR-129. We found that anti-miR-129 reversed the expression of CD200R1, as well as levels of inflammatory molecules IL-6 and TNF-α. Experiments with a CD200R1 siRNA-induced loss-of-function mouse model confirmed an miR-129-5p→CD200R1→IL-6/TNF-α signaling axis. These main findings were replicated in a human cell line and validated in human samples. Taken together, our study revealed miR-129-5p as a novel posttranscriptional regulator of CD200R1 expression with potential implications in neuroinflammation and related complications.
Collapse
Affiliation(s)
- Vikas Singh
- Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shaivya Kushwaha
- Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jamal Ahmad Ansari
- Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Siddhartha Gangopadhyay
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Shubhendra K Mishra
- Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Rajib K Dey
- Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ashok K Giri
- CSIR-Indian Institute of Chemical Biology, 4, Raja Subodh Chandra Mallick Rd, Poddar Nagar, Jadavpur, Kolkata, West Bengal 700032, India
| | - Satyakam Patnaik
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Water Analysis Laboratory, Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh 226001, India
| | - Debabrata Ghosh
- Immunotoxicology Laboratory, Food, Drug & Chemical Toxicology Group and Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
|
26
|
MicroRNA-21-5p Reduces Hypoxia/Reoxygenation-Induced Neuronal Cell Damage through Negative Regulation of CPEB3. Anal Cell Pathol (Amst) 2021; 2021:5543212. [PMID: 34900520 PMCID: PMC8660214 DOI: 10.1155/2021/5543212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 09/04/2021] [Accepted: 11/07/2021] [Indexed: 11/26/2022] Open
Abstract
Objectives To explore the role of microRNA-21-5p (miR-21-5p) in hypoxia/reoxygenation- (H/R-) induced HT22 cell damage. Methods The hypoxia/reoxygenation (H/R) model was established in mouse neuronal cells HT22. Cell Counting Kit-8 (CCK-8) and qRT-PCR were used to determine the effects of H/R treatment on cell viability and miR-21-5p expression. HT22 cells were transfected with miR-21-5p mimic or negative control (NC) followed by the induction of H/R; cell viability, apoptosis, and SOD, MDA, and LDH activities were detected. Besides, the apoptosis-related proteins including BAX, BCL2, cleaved caspase-3, and caspase-3 as well as proteins of EGFR/PI3K/AKT signaling pathways were measured by Western blot. To verify the target relation between cytoplasmic polyadenylation element binding protein 3 (CPEB3) and miR-21-5p, luciferase reporter gene experiment was performed. After cotransfection with miR-21-5p mimic and CPEB3 plasmids, the reversal effects of CPEB3 on miR-21-5p in H/R damage were studied. Results H/R treatment could significantly reduce the cell viability (P < 0.05) and miR-21-5p levels (P < 0.05) in HT22 cells. After overexpressing miR-21-5p, cell viability was increased (P < 0.05) under H/R treatment, and the apoptosis rate and the levels of apoptosis-related proteins were suppressed (all P < 0.05). Furthermore, SOD activity was increased (P < 0.05), while MDA and LDH activity was decreased (both P < 0.05). Besides, miR-21-5p could restore the activation of the EGFR/PI3K/AKT signaling pathway inhibited by H/R treatment (all P < 0.05). The luciferase reporter gene experiment verified that CPEB3 is the target of miR-21-5p (P < 0.05). When coexpressing miR-21-5p mimic and CPEB3 in the cells, the protective effects of miR-21-5p under H/R were reversed (all P < 0.05), and the activation of the EGFR/PI3K/AKT pathway was also inhibited (all P < 0.05). Conclusion This study showed that miR-21-5p may regulate the EGFR/PI3K/AKT signaling pathway by targeting CPEB3 to reduce H/R-induced cell damage and apoptosis.
Collapse
|
|
27
|
Liu Y, Liu L, Xing W, Sun Y. Anesthetics mediated the immunomodulatory effects via regulation of TLR signaling. Int Immunopharmacol 2021; 101:108357. [PMID: 34785143 DOI: 10.1016/j.intimp.2021.108357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/29/2021] [Accepted: 11/07/2021] [Indexed: 11/29/2022]
Abstract
Anesthetics have been widely used in surgery and found to suppress inflammatory injury and affect the outcomes of the surgery and diseases. In contrast, anesthetics are also found to induce neuronal injury and inflammation. However, the immune-modulation mechanism of anesthetics is still not clear. Recent studies have shown that the immune-modulation of anesthetics is associated with the regulation of toll-like receptor (TLR)-mediated signaling. Moreover, the regulation of anesthetics in TLR signaling is related to modulations of non-coding RNAs (nc RNAs). Consistently, nc RNAs are mainly divided into micro RNAs (miRs) and long non-coding RNAs (lnc RNAs), which have been found to exert regulatory effects on the immune system. In this review, we summarize the immunomodulatory functions of the widely used anesthetic agents, which are associated with regulation of TLR signaling. In addition, we also focus on the roles of nc RNAs induced by anesthetics in regulations of TLR signaling.
Collapse
Affiliation(s)
- Yan Liu
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Li Liu
- Department of Obstetrics and Gynecology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Wanying Xing
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Yan Sun
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
| |
Collapse
|
|
28
|
Zhou X, Li S, Chao D, Chen Z, Zhang J, Lin J, Ji Y, Ji Q. Serum small extracellular vesicles promote M1 activation of microglia after cerebral ischemia/reperfusion injury. Neurosci Lett 2021; 766:136307. [PMID: 34737022 DOI: 10.1016/j.neulet.2021.136307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 10/19/2022]
Abstract
Microglial M1 activation is detrimental to stroke outcomes. Recent studies have shown that circulating small extracellular vesicles (sEVs) can deliver miRNAs to target cells and regulate recipient cell functions. Herein, we tested the hypothesis that miRNA delivery by serum sEVs after cerebral ischemia/reperfusion (I/R) injury promote microglial M1 activation, demonstrating that serum sEVs from middle cerebral artery occlusion (MCAO) mice promoted proliferation and M1 activation of BV2 microglia. To explore the underlying mechanism of serum sEVs-mediated microglial activation in the early phase of cerebral I/R injury, we examined the effects of ischemic brain injury on the serum sEVs miRNAs profile in a mouse MCAO model using small RNAseq. Of the 1257 detected miRNA replications, the levels of 72 were significantly modulated. Bioinformatics analysis revealed that a panel of miRNAs was closely associated with inflammation, and in vitro experiments demonstrated that serum sEVs from MCAO mice could effectively transfer inflammatory miRNAs to BV2 microglia. Collectively, our data suggested that miRNAs delivered by serum sEVs after cerebral I/R injury promoted microglial M1 activation. The identification of microglial activation regulators in future studies will give rise to more effective treatments for stroke.
Collapse
Affiliation(s)
- Xin Zhou
- Institute of Immunology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang 524023, China
| | - Shuyuan Li
- Institute of Immunology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Dachong Chao
- Institute of Immunology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Zixin Chen
- Institute of Immunology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Junyu Zhang
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
| | - Jianhang Lin
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
| | - Yuhua Ji
- Institute of Immunology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
| | - Qiuhong Ji
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226019, China.
| |
Collapse
|
|
29
|
Ling X, Lu J, Yang J, Qin H, Zhao X, Zhou P, Zheng S, Zhu P. Non-Coding RNAs: Emerging Therapeutic Targets in Spinal Cord Ischemia-Reperfusion Injury. Front Neurol 2021; 12:680210. [PMID: 34566835 PMCID: PMC8456115 DOI: 10.3389/fneur.2021.680210] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 08/09/2021] [Indexed: 01/01/2023] Open
Abstract
Paralysis or paraplegia caused by transient or permanent spinal cord ischemia–reperfusion injury (SCIRI) remains one of the most devastating post-operative complications after thoracoabdominal aortic surgery, even though perioperative strategies and surgical techniques continue to improve. Uncovering the molecular and cellular pathophysiological processes in SCIRI has become a top priority. Recently, the expression, function, and mechanism of non-coding RNAs (ncRNAs) in various diseases have drawn wide attention. Non-coding RNAs contain a variety of biological functions but do not code for proteins. Previous studies have shown that ncRNAs play a critical role in SCIRI. However, the character of ncRNAs in attenuating SCIRI has not been systematically summarized. This review article will be the first time to assemble the knowledge of ncRNAs regulating apoptosis, inflammation, autophagy, and oxidative stress to attenuate SCIRI. A better understanding of the functional significance of ncRNAs following SCIRI could help us to identify novel therapeutic targets and develop potential therapeutic strategies. All the current research about the function of nRNAs in SCIRI will be summarized one by one in this review.
Collapse
Affiliation(s)
- Xiao Ling
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Lu
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Yang
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hanjun Qin
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xingqi Zhao
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pengyu Zhou
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shaoyi Zheng
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Zhu
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
30
|
Inhibiting miR-129-5p alleviates inflammation and modulates autophagy by targeting ATG14 in fungal keratitis. Exp Eye Res 2021; 211:108731. [PMID: 34411602 DOI: 10.1016/j.exer.2021.108731] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 07/16/2021] [Accepted: 08/13/2021] [Indexed: 01/04/2023]
Abstract
To investigate the role of miR-129-5p in inflammation and autophagy in fungal keratitis, we established a keratitis mouse model infected with Fusarium solani (F. solani) and conducted experiments on corneal stromal cells infected with F. solani. The expression of miR-129-5p was detected via quantitative real-time polymerase chain reaction (PCR). The miR-129-5p antagomir was used to transfect cells and mice to study the regulatory role of miR-129-5p in autophagy and inflammation after fungal infection. The expression of Beclin1 and LC3B and colocalization of LC3B with lysosomes were detected via Western blotting and immunofluorescence. CCK-8 was used to determine the viability of corneal stromal cells. The expression of IL-1β were detected by ELISA. Bioinformatics software was used to predict the potential targets of miR-129-5p, which were verified by a luciferase reporter gene assay. RT-PCR showed that miR-129-5p expression in mouse corneas was significantly increased after infection with F. solani. Subconjunctival injection of the miR-129-5p antagomir significantly enhanced the proteins Beclin-1 and LC3B. At the same time, inhibiting miR-129-5p expression could reduce the inflammatory response in FK and significantly increase the viability of corneal stromal cells infected with F. solan. Moreover, the dual luciferase reporter assay indicated that Atg14 was a direct target of miR-129-5p. Our study shows that miR-129-5p is a novel small molecule that regulates autophagy by targeting Atg14, indicating that it may be a proinflammatory and therapeutic target for fungal keratitis.
Collapse
|
|
31
|
miR-129-5p Ameliorates Ischemic Brain Injury by Binding to SIAH1 and Activating the mTOR Signaling Pathway. J Mol Neurosci 2021; 71:1761-1771. [PMID: 34355355 DOI: 10.1007/s12031-021-01872-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/09/2021] [Indexed: 10/20/2022]
Abstract
Aberrant expression of microRNAs (miRNAs) has been linked with ischemic brain injury (IBI), but the mechanistic actions behind the associated miRNAs remain to be determined. Of note, miR-129-5p was revealed to be downregulated in the serum of patients with IBI. In silico prediction identified a putative target gene, siah E3 ubiquitin protein ligase 1 (SIAH1), of miR-129-5p. Accordingly, this study plans to clarify the functional relevance of the interplay of miR-129-5p and SIAH1 in IBI. IBI was modeled by exposing human hippocampal neuronal cells to oxygen-glucose deprivation (OGD) in vitro and by occluding the middle cerebral artery (MCAO) in a mouse model in vivo. Apoptosis of hippocampal neuronal cells was assessed by annexin V-FITC/PI staining and TUNEL staining. The area of cerebral infarction was measured using TTC staining, along with neurological scoring on modeled mice. Loss of hippocampal neuronal cells in the peri-infarct area was monitored using Nissl staining. Downregulated miR-129-5p expression was found in OGD-induced hippocampal neuronal cells and MCAO-treated mice. Mechanistically, miR-129-5p was validated to target and inhibit SIAH1 through the application of dual-luciferase reporter assay. Additionally, enforced miR-129-5p inhibited the apoptosis of OGD-induced cells and decreased the cerebral infarct area, neurological scores and apoptosis of hippocampal neuronal cells by downregulating SIAH1 and activating the mTOR signaling pathway. Taken together, the results of this study reveal the important role and underlying mechanism of miR-129-5p in IBI, providing a promising biomarker for preventive and therapeutic strategies.
Collapse
|
|
32
|
Kashif H, Shah D, Sukumari-Ramesh S. Dysregulation of microRNA and Intracerebral Hemorrhage: Roles in Neuroinflammation. Int J Mol Sci 2021; 22:8115. [PMID: 34360881 PMCID: PMC8347974 DOI: 10.3390/ijms22158115] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 12/23/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a major public health problem and devastating subtype of stroke with high morbidity and mortality. Notably, there is no effective treatment for ICH. Neuroinflammation, a pathological hallmark of ICH, contributes to both brain injury and repair and hence, it is regarded as a potential target for therapeutic intervention. Recent studies document that microRNAs, small non-coding RNA molecules, can regulate inflammatory brain response after ICH and are viable molecular targets to alter brain function. Therefore, there is an escalating interest in studying the role of microRNAs in the pathophysiology of ICH. Herein, we provide, for the first time, an overview of the microRNAs that play roles in ICH-induced neuroinflammation and identify the critical knowledge gap in the field, as it would help design future studies.
Collapse
Affiliation(s)
| | | | - Sangeetha Sukumari-Ramesh
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (H.K.); (D.S.)
| |
Collapse
|
|
33
|
Li Z, Chen Q, Liu J, Du Y. Physical Exercise Ameliorates the Cognitive Function and Attenuates the Neuroinflammation of Alzheimer's Disease via miR-129-5p. Dement Geriatr Cogn Disord 2021; 49:163-169. [PMID: 32434194 DOI: 10.1159/000507285] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/13/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Physical exercise has a significant neuroprotective role in Alzheimer's disease (AD), but the underlying mechanisms remain elusive. OBJECTIVE This study aimed to explore the molecular mechanisms of physical exercise by analyzing the role of microRNA-129-5p (miR-129-5p) in AD mice and patients. METHODS AD mice and patients were treated with 4-week and 3-month physical exercise, respectively. The expression of miR-129-5p was measured using quantitative real-time PCR. The Morris water-maze test was used for cognition evaluation, and enzyme-linked immunosorbent assay was used for inflammation analysis. RESULTS In both AD mice and patients, the expression of miR-129-5p was elevated by physical exercise. By in vivoregulation of miR-129-5p, we found that the improved cognitive function and reduced inflammatory responses were reversed by the knockdown of miR-129-5p. In patients with AD, the serum expression of miR-129-5p was further found to be correlated with the serum levels of cognitive function markers and proinflammatory cytokines. CONCLUSION All data indicated that the expression of miR-129-5p in AD mice and patients is significantly upregulated by physical exercise. The knockdown of miR-129-5p can abrogate the neuroprotective effect of exercise on cognition and neuroinflammation in AD mice. This study provides a novel insight into the molecular mechanisms underlying the neuroprotective effect of physical exercise in AD, and miR-129-5p may provide a novel therapeutic target for AD treatment.
Collapse
Affiliation(s)
- Zhen Li
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Department of Neurology, Yidu Central Hospital of Weifang, Weifang, China
| | - Qi Chen
- Department of Neurosurgery, Qingzhou Hospital Affiliated to Shandong First Medical University, Weifang, China.,Department of Neurosurgery, Qingzhou People's Hospital, Weifang, China
| | - Jinxia Liu
- Department of Neurology, Yidu Central Hospital of Weifang, Weifang, China
| | - Yifeng Du
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China,
| |
Collapse
|
|
34
|
Yao W, Xu L, Jia X, Li S, Wei L. MicroRNA‑129 plays a protective role in sepsis‑induced acute lung injury through the suppression of pulmonary inflammation via the modulation of the TAK1/NF‑κB pathway. Int J Mol Med 2021; 48:139. [PMID: 34080641 PMCID: PMC8175065 DOI: 10.3892/ijmm.2021.4972] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 05/07/2021] [Indexed: 12/18/2022] Open
Abstract
Excessive inflammatory response and apoptosis play key roles in the pathogenic mechanisms of sepsis-induced acute lung injury (ALI); however, the molecular pathways linked to ALI pathogenesis remain unclear. Recently, microRNAs (miRNAs/miRs) have emerged as important regulators of inflammation and apoptosis in sepsis-induced ALI; however, the exact regulatory mechanisms of miRNAs remain poorly understood. In the present study, the gene microarray dataset GSE133733 obtained from the Gene Expression Omnibus database was analyzed and a total of 38 differentially regulated miRNAs were identified, including 17 upregulated miRNAs and 21 downregulated miRNAs, in mice with lipopolysaccharide (LPS)-induced ALI, in comparison to the normal control mice. miR-129 was found to be the most significant miRNA, among the identified miRNAs. The upregulation of miR-129 markedly alleviated LPS-induced lung injury, as indicated by the decrease in lung permeability in and the wet-to-dry lung weight ratio, as well as the improved survival rate of mice with ALI administered miR-129 mimic. Moreover, the upregulation of miR-129 reduced pulmonary inflammation and apoptosis in mice with ALI. Of note, transforming growth factor activated kinase-1 (TAK1), a well-known regulator of the nuclear factor-κB (NF-κB) pathway, was directly targeted by miR-129 in RAW 264.7 cells. More importantly, miR-129 upregulation impeded the LPS-induced activation of the TAK1/NF-κB signaling pathway, as illustrated by the suppression of the nuclear phosphorylated-p65, p-IκB-α and p-IKKβ expression levels. Collectively, the findings of the present study indicate that miR-129 protects mice against sepsis-induced ALI by suppressing pulmonary inflammation and apoptosis through the regulation of the TAK1/NF-κB signaling pathway. This introduces the basis for future research concerning the application of miR-129 and its targets for the treatment of ALI.
Collapse
Affiliation(s)
- Wenjian Yao
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Lei Xu
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Xiangbo Jia
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Saisai Li
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
| |
Collapse
|
|
35
|
Chen F, Han J, Li X, Zhang Z, Wang D. Identification of the biological function of miR-9 in spinal cord ischemia-reperfusion injury in rats. PeerJ 2021; 9:e11440. [PMID: 34035993 PMCID: PMC8126262 DOI: 10.7717/peerj.11440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/21/2021] [Indexed: 12/14/2022] Open
Abstract
Spinal cord ischemia–reperfusion injury (SCII) is still a serious problem, and the mechanism is not fully elaborated. In the rat SCII model, qRT-PCR was applied to explore the altered expression of miR-9 (miR-9a-5p) after SCII. The biological function of miR-9 and its potential target genes based on bioinformatics analysis and experiment validation in SCII were explored next. Before the surgical procedure of SCII, miR-9 mimic and inhibitor were intrathecally infused. miR-9 mimic improved neurological function. In addition, miR-9 mimic reduced blood-spinal cord barrier (BSCB) disruption, inhibited apoptosis and decreased the expression of IL-6 and IL-1β after SCII. Gene Ontology (GO) analysis demonstrated that the potential target genes of miR-9 were notably enriched in several biological processes, such as “central nervous system development”, “regulation of growth” and “response to cytokine”. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the potential target genes of miR-9 were significantly enriched in several signaling pathways, including “Notch signaling pathway”, “MAPK signaling pathway”, “Focal adhesion” and “Prolactin signaling pathway”. We further found that the protein expression of MAP2K3 and Notch2 were upregulated after SCII while miR-9 mimic reduced the increase of MAP2K3 and Notch2 protein. miR-9 mimic or MAP2K3 inhibitor reduced the release of IL-6 and IL-1β. miR-9 mimic or si-Notch2 reduced the increase of cleaved-caspase3. Moreover, MAP2K3 inhibitor and si-Notch2 reversed the effects of miR-9 inhibitor. In conclusion, overexpression of miR-9 improves neurological outcomes after SCII and might inhibit BSCB disruption, neuroinflammation, and apoptosis through MAP2K3-, or Notch2-mediated signaling pathway in SCII.
Collapse
Affiliation(s)
- Fengshou Chen
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jie Han
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaoqian Li
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zaili Zhang
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Dan Wang
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
36
|
Liu S, Liao Q, Xu W, Zhang Z, Yin M, Cao X. MiR-129-5p Protects H9c2 Cardiac Myoblasts From Hypoxia/Reoxygenation Injury by Targeting TRPM7 and Inhibiting NLRP3 Inflammasome Activation. J Cardiovasc Pharmacol 2021; 77:586-593. [PMID: 33951695 DOI: 10.1097/fjc.0000000000000991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 01/16/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT As a biomarker for heart failure, miR-129-5p is abnormally expressed during myocardial I/R, but its specific functions and mechanisms remain largely unclear. Thus, this study explored the roles and possible mechanisms of miR-129-5p in hypoxia/reoxygenation (H/R)-insulted H9c2 cardiac myoblasts. After H/R insult, miR-129-5p expression levels were decreased, along with reduced cell viability and enhanced lactate dehydrogenase release in H9c2 cells. Overexpression of miR-129-5p through transfection of miR-129-5p mimics effectively improved cell viability and reduced lactate dehydrogenase release in H9c2 cells exposed to H/R, along with decreased apoptosis and caspase-3 activities. Moreover, miR-129-5p mimics inhibited reactive oxygen species production and upsurged superoxide dismutase activity in H9c2 cells exposed to H/R, and suppressed H/R-caused massive release of proinflammatory cytokines TNF-α and IL-1β. TRPM7 was identified as the target of miR-129-5p and was negatively regulated by miR-129-5p. TRPM7 overexpression counteracted the antagonistic effect of miR-129-5p on H/R-induced increase in intracellular calcium levels. TRPM7 overexpression also abolished miR-129-5p-induced elevation on cell viability and reduction on apoptosis as well as attenuated miR-129-5p-induced inhibition on reactive oxygen species and IL-1β production. Besides, H/R-induced NLRP3 inflammasome activation was inhibited by miR-129-5p mimic but reactivated by TRPM7. In conclusion, miR-129-5p alleviates H/R injury of H9c2 cardiomyocytes by targeting TRPM7 and inhibiting NLRP3 inflammasome activation, suggesting that miR-129-5p and TRPM7 may be potential therapeutic targets for myocardial I/R injury.
Collapse
Affiliation(s)
- Shuke Liu
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China
- Graduate School of Dalian Medical University, Dalian, Liaoning, China
| | - Qingchi Liao
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China
- Graduate School of Central South University, Changsha, Hubei, China ; and
| | - Wei Xu
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China
- Graduate School of Yangzhou University, Yangzhou, Jiangsu, China
| | - Zhen Zhang
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China
- Graduate School of Dalian Medical University, Dalian, Liaoning, China
| | - Minming Yin
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China
- Graduate School of Dalian Medical University, Dalian, Liaoning, China
| | - Xiaohu Cao
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China
- Graduate School of Yangzhou University, Yangzhou, Jiangsu, China
| |
Collapse
|
|
37
|
Polydatin Attenuates OGD/R-Induced Neuronal Injury and Spinal Cord Ischemia/Reperfusion Injury by Protecting Mitochondrial Function via Nrf2/ARE Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6687212. [PMID: 33995825 PMCID: PMC8081604 DOI: 10.1155/2021/6687212] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/10/2021] [Accepted: 03/24/2021] [Indexed: 02/08/2023]
Abstract
Spinal cord ischemia/reperfusion injury (SCII) is a devastating complication of spinal or thoracic surgical procedures and can lead to paraplegia or quadriplegia. Neuronal cell damage involving mitochondrial dysfunction plays an important role in the pathogenesis of SCII. Despite the availability of various treatment options, there are currently no mitochondria-targeting drugs that have proven effective against SCII. Polydatin (PD), a glucoside of resveratrol, is known to preserve mitochondrial function in central nervous system (CNS) diseases. The aim of the present study was to explore the neuro- and mito-protective functions of PD and its underlying mechanisms. An in vitro model of SCII was established by exposing spinal cord motor neurons (SMNs) to oxygen–glucose-deprivation/reperfusion (OGD/R), and the cells were treated with different dosages of PD for varying durations. PD improved neuronal viability and protected against OGD/R-induced apoptosis and mitochondrial injury in a dose-dependent manner. In addition, PD restored the activity of neuronal mitochondria in terms of mitochondrial membrane potential (MMP), intracellular calcium levels, mitochondrial permeability transition pore (mPTP) opening, generation of reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels. Mechanistically, PD downregulated Keap1 and upregulated Nrf2, NQO-1, and HO-1 in the OGD/R-treated SMNs. Likewise, PD treatment also reversed the neuronal and mitochondrial damage induced by SCII in a mouse model. Furthermore, the protective effects of PD were partially blocked by the Nrf2 inhibitor. Taken together, PD relieves mitochondrial dysfunction-induced neuronal cell damage by activating the Nrf2/ARE pathway and is a suitable therapeutic option for SCII.
Collapse
|
|
38
|
MicroRNA-129-5p alleviates spinal cord injury in mice via suppressing the apoptosis and inflammatory response through HMGB1/TLR4/NF-κB pathway. Biosci Rep 2021; 40:222205. [PMID: 32096822 PMCID: PMC7069919 DOI: 10.1042/bsr20193315] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/15/2020] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
Secondary injury after spinal cord injury (SCI) is one reversible pathological change mainly involving excessive inflammatory response and neuro-apoptosis. Since in recent years, microRNAs (miRNAs) have been proposed as novel regulators of inflammation in different disease conditions. However, the role of miRNAs in the inflammatory response and apoptosis of secondary injury after SCI remains to be fully elucidated. Here, we tried to explore the influence and mechanism of miRNAs on the neuron inflammatory response and apoptosis after SCI. The expression profiles of miRNA were examined using miRNA microarray, and among the candidate miRNAs, miR-129-5p was found to be the most down-regulated miRNA in spinal tissues. Overexpression of miR-129-5p using agomir-miR-129-5p promoted injury mice functional recovery, suppressed the apoptosis and alleviated inflammatory response in spinal tissues. Using LPS-induced BV-2 cell model, we found miR-129-5p was also proved in protecting inflammatory response and cell apoptosis in vitro. High-mobility group protein B1 (HMGB1), a well-known inflammatory mediator, was found to be directly targeted by miR-129-5p and it was associated with the inhibitory effect of miR-129-5p on the activation of toll-like receptor (TLR)-4 (TLR4)/ nuclear factor-κB (NF-κB) pathway in vitro and in vivo. Further experiments revealed that the anti-apoptosis and anti-inflammatory effects of miR-129-5p were reversed by HMGB1 overexpression in BV-2 cells. Collectively, these data revealed that miR-129-5p alleviated SCI in mice via suppressing the apoptosis and inflammatory response through HMGB1//TLR4/NF-κB pathway. Our data suggest that up-regulation of miR-129-5p may be a novel therapeutic target for SCI.
Collapse
|
|
39
|
Yangi R, Huang H, Zhou Q. Long noncoding RNA MALAT1 sponges miR-129-5p to regulate the development of bronchopulmonary dysplasia by increasing the expression of HMGB1. J Int Med Res 2021; 48:300060520918476. [PMID: 32397779 PMCID: PMC7223211 DOI: 10.1177/0300060520918476] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE To explore the function and mechanism of long noncoding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in bronchopulmonary dysplasia. METHODS Alveolar epithelial cell line BEAS-2B was used as the cell model. The role of MALAT1 and microRNA miR-129-5p in regulating cellular viability and migration were examined by using the CCK-8 and Transwell assays, respectively, in vitro. The luciferase reporter assay and real-time (RT)-PCR were performed to confirm that miR-129-5p was a target of MALAT1. ELISA was conducted to validate MALAT1 and show that miR-129-5p regulated the gene encoding high-mobility group protein 1 (HMGB1). RESULTS Overexpression of MALAT1 significantly promoted cellular viability, whereas miR-129-5p had the opposite effect. miR-129-5p was shown to be a target of MALAT1, and HMGB1 could be upregulated by MALAT1 overexpression or miR-129-5p inhibition. CONCLUSION MALAT1 reduced the expression of miR-129-5p, promoting the viability of cells and blocking the development of bronchopulmonary dysplasia. In addition, MALAT1 increased the expression of HMGB1, which contributed to inflammation as the disease progressed.
Collapse
Affiliation(s)
- Rongwe Yangi
- Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang, China
| | - Huafei Huang
- Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang, China
| | - Qingnv Zhou
- Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang, China
| |
Collapse
|
|
40
|
Fang H, Li HF, Pan Q, Jin HL, Yang M, Wang RR, Wang QY, Zhang JP. MiR-132-3p Modulates MEKK3-Dependent NF-κB and p38/JNK Signaling Pathways to Alleviate Spinal Cord Ischemia-Reperfusion Injury by Hindering M1 Polarization of Macrophages. Front Cell Dev Biol 2021; 9:570451. [PMID: 33644040 PMCID: PMC7905026 DOI: 10.3389/fcell.2021.570451] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 01/08/2021] [Indexed: 02/05/2023] Open
Abstract
Spinal cord ischemia-reperfusion (SCIR) injury is a serious complication of open surgical and endovascular aortic procedures. MicroRNA-132-3p (miR-132-3p) has been reported to be involved in the progression of various diseases, but its role in SCIR injury is unclear. Thus, we aimed in this study to investigate the mechanism of miR-132-3p in SCIR injury and explore its pathway as a therapeutic target for SCIR injury. We first constructed a SCIR injury rat model and documented motor function in the model. Reverse transcription quantitative polymerase chain reaction (RT-qPC)R and Western blot analysis were used to detect the expression of miR-132-3p and mitogen-activated protein kinase kinase kinase 3 (MEKK3) in SCIR injury rats. The interaction between miR-132-3p and MEKK3 was identified by dual-luciferase reporter gene assay. Then, the effects of miR-132-3p and MEKK3 on macrophage M1 polarization were evaluated in vitro and in vivo by altering their expression in macrophages of SCIR injury rats, with treatments altering the nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)/p38 signaling pathways using SP600125, SB203580, or PDTC. The SCIR injury rats had a high Tarlov score and low miR-132-3p expression along with high MEKK3 expression. miR-132-3p could directly bind to MEKK3, and that macrophage M1 polarization and inflammation could be inhibited by overexpression of miR-132-3p through downregulating MEKK3 and inactivating the NF-κB and p38/JNK signaling pathways. Besides, increased miR-132-3p expression could decrease the injured rat Tarlov score. Overall, our study demonstrated that miR-132-3p can suppress M1 polarization of macrophages and alleviate SCIR injury by blocking the MEKK3-dependent activation of the NF-κB and p38/JNK signaling pathway. Thus, miR-132-3p and its downstream pathways may be useful targets to alleviate the symptoms of SCIR injury.
Collapse
Affiliation(s)
- Hua Fang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China.,Laboratory of Anesthesiology and Perioperative Medicine, Guizhou University School of Medicine, Guiyang, China
| | - Hua-Feng Li
- Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Qin Pan
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China.,Laboratory of Anesthesiology and Perioperative Medicine, Guizhou University School of Medicine, Guiyang, China
| | - Hon-Ling Jin
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China.,Laboratory of Anesthesiology and Perioperative Medicine, Guizhou University School of Medicine, Guiyang, China
| | - Miao Yang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China.,Laboratory of Anesthesiology and Perioperative Medicine, Guizhou University School of Medicine, Guiyang, China
| | - Ru-Rong Wang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Quan-Yun Wang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Ping Zhang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.,Department of Anesthesiology, Guizhou University People's Hospital, Guiyang, China.,Laboratory of Anesthesiology and Perioperative Medicine, Guizhou University School of Medicine, Guiyang, China
| |
Collapse
|
|
41
|
Gao Q, Chang N, Liu D. In vitro and in vivo assessment of the protective effect of sufentanil in acute lung injury. J Int Med Res 2021; 49:300060520986351. [PMID: 33535837 PMCID: PMC7869068 DOI: 10.1177/0300060520986351] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objectives To investigate the mechanisms underlying the protective effect of sufentanil
against acute lung injury (ALI). Material and Methods Rats were administered lipopolysaccharide (LPS) by endotracheal instillation
to establish a model of ALI. LPS was used to stimulate BEAS-2B cells. The
targets and promoter activities of IκB were assessed using a luciferase
reporter assay. Apoptosis of BEAS-2B cells was evaluated by terminal
deoxynucleotidyl transferase dUTP nick end labeling. Results Sufentanil treatment markedly reduced pathological changes in lung tissue,
pulmonary edema and secretion of inflammatory factors associated with ALI
in vivo and in vitro. In addition,
sufentanil suppressed apoptosis induced by LPS and activated NF-κB both
in vivo and in vitro. Furthermore,
upregulation of high mobility group box protein 1 (HMGB1) protein levels and
downregulation of miR-129-5p levels were observed in vivo
and in vitro following sufentanil treatment. miR-129-5p
targeted the 3ʹ untranslated region and its inhibition decreased promoter
activities of IκB-α. miR-129-5p inhibition significantly weakened the
protective effect of sufentanil on LPS-treated BEAS-2B cells. Conclusion Sufentanil regulated the miR-129-5p/HMGB1 axis to enhance IκB-α expression,
suggesting that sufentanil represents a candidate drug for ALI protection
and providing avenues for clinical treatment.
Collapse
Affiliation(s)
- Qi Gao
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China
| | - Ningqing Chang
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China
| | - Donglian Liu
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China
| |
Collapse
|
|
42
|
Zhang YY, Bao HL, Dong LX, Liu Y, Zhang GW, An FM. Silenced lncRNA H19 and up-regulated microRNA-129 accelerates viability and restrains apoptosis of PC12 cells induced by Aβ 25-35 in a cellular model of Alzheimer's disease. Cell Cycle 2021; 20:112-125. [PMID: 33410377 DOI: 10.1080/15384101.2020.1863681] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Accumulating data manifest that long non-coding RNA (lncRNAs) are involved in all kinds of neurodegenerative disorders, consisting of the onset and progression of Alzheimer's disease (AD). The study was for the research of the mechanism of lncRNA H19 (H19) in viability and apoptosis of PC12 cells induced by Aβ25-35 in a cellular model of AD with the regulation of microRNA (miR)-129 and high mobility group box-1 protein (HMGB1). An AD cellular model of PC12 cells was established using Aβ25-35. The Aβ25-35-induced PC12 cells were transfected with si-H19 or miR-129 mimic to figure their roles in cell viability,apoptosis, mitochondrial membrane potential dysfunction and oxidative stress in AD. Luciferase reporter assay and RNA-pull down assay were employed for verification of the binding relationship between H19 and miR-129 and the targeting relationship between miR-129 and HMGB1. An AD mouse model was induced and brain tissues were collected. H19, miR-129 and HMGB1 were detected in Aβ25-35-treated cells and brain tissues of AD mice. Elevated H19, HMGB1 and decreased miR-129 were found in Aβ25-35-treated PC12 cells as well as in brain tissues of AD mice. Silenced H19 or elevated miR-129 promoted viability, inhibited apoptosis, prevented mitochondrial membrane potential dysfunction and decreased oxidative stress in Aβ25-35-treated PC12 cells. H19 could specifically bind to miR-129. MiR-129 specifically suppressed HMGB1 expression. This study suggests that silenced H19 and up-regulated miR-129 accelerates viability and represses apoptosis of PC12 cells stimulated by Aβ25-35 in AD, which is beneficial for AD treatment.
Collapse
Affiliation(s)
- Yan-Yun Zhang
- College of Nursing, Inner Mongolia University for Nationalities , Tongliao, P.R. China.,Institute of Dementia, Inner Mongolia University for Nationalities , Tongliao, P.R. China
| | - Hai-Lan Bao
- College of Nursing, Inner Mongolia University for Nationalities , Tongliao, P.R. China.,Institute of Dementia, Inner Mongolia University for Nationalities , Tongliao, P.R. China
| | - Li-Xia Dong
- College of Nursing, Inner Mongolia University for Nationalities , Tongliao, P.R. China.,Institute of Dementia, Inner Mongolia University for Nationalities , Tongliao, P.R. China
| | - Yu Liu
- College of Nursing, Inner Mongolia University for Nationalities , Tongliao, P.R. China.,Institute of Dementia, Inner Mongolia University for Nationalities , Tongliao, P.R. China
| | - Guo-Wei Zhang
- College of Nursing, Inner Mongolia University for Nationalities , Tongliao, P.R. China.,Institute of Dementia, Inner Mongolia University for Nationalities , Tongliao, P.R. China
| | - Feng-Mao An
- Institute of Dementia, Inner Mongolia University for Nationalities , Tongliao, P.R. China.,Inner Mongolia Key Laboratory, Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China
| |
Collapse
|
|
43
|
Ta Na HS, An M, Zhang T, Deni W, Hou L, Jin K. Dexmedetomidine inhibits microglial activation through SNHG14/HMGB1 pathway in spinal cord ischemia-reperfusion injury mice. Int J Neurosci 2020; 132:77-88. [PMID: 33045891 DOI: 10.1080/00207454.2020.1835901] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Microglial activation is an essential pathological mechanism of spinal cord ischemia-reperfusion injury (SCIRI). Previous studies showed dexmedetomidine (DEX) could alleviate SCIRI while the mechanism was not clear. This study aims to investigate the role of DEX in microglial activation and clarify the underlying mechanism. METHODS The motion function of mice was quantified using the Basso Mouse Scale for Locomotion. The expression of long non-coding RNA (lncRNA) small nucleolar RNA host gene 14 (SNHG14) was determined by qRT-PCR. The expression of high-mobility group box 1 (HMGB1) was measured by western blot. The activation of microglia was evaluated by the expression of ED-1 and the levels of TNF-α and IL-6. The interplay between SNHG14 and HMGB1 was confirmed with RNA pull-down and RIP assay. The stability of HMGB1 was measured by ubiquitination assay and cycloheximide-chase assay. RESULTS DEX inhibited microglial activation and down-regulated SNHG14 expression in SCIRI mice and oxygen and glucose deprivation/reoxygenation (OGD/R)-treated primary microglia. Functionally, SNHG14 overexpression reversed the inhibitory effect of DEX on OGD/R-induced microglial activation. Further investigation confirmed that SNHG14 bound to HMGB1, positively regulated HMGB1 expression by enhancing its stability. In addition, the silence of HMGB1 eliminated the pro-activation impact of SNHG14 overexpression on DEX-treated microglia under the OGD/R condition. Finally, in vivo experiments showed SNHG14 overexpression abrogated the therapeutic effect of DEX on SCIRI mice by up-regulating HMGB1. CONCLUSION DEX accelerated HMGB1 degradation via down-regulating SNHG14, thus inhibiting microglial activation in SCIRI mice.
Collapse
Affiliation(s)
- Ha Sen Ta Na
- Department of Anesthesiology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, PR China
| | - Min An
- Department of Anesthesiology, Second Affiliated Hospital of Inner Mongolia Medical College, Hohhot, Inner Mongolia, PR China
| | - Tianwen Zhang
- Department of Anesthesiology, Inner Mongolia Autonomous Region International Mongolian Hospital, Hohhot, Inner Mongolia, PR China
| | - Wuyuner Deni
- Department of Anesthesiology, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, PR China
| | - Lichao Hou
- Department of Anesthesiology, Xiang'an Hospital of Xiamen University, Fujian, PR China
| | - Kai Jin
- Department of Anesthesiology, Xiang'an Hospital of Xiamen University, Fujian, PR China.,Department of Thyroid Neoplasms Surgery, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, PR China
| |
Collapse
|
|
44
|
Wang D, Chen F, Fang B, Zhang Z, Dong Y, Tong X, Ma H. MiR-128-3p Alleviates Spinal Cord Ischemia/Reperfusion Injury Associated Neuroinflammation and Cellular Apoptosis via SP1 Suppression in Rat. Front Neurosci 2020; 14:609613. [PMID: 33424542 PMCID: PMC7785963 DOI: 10.3389/fnins.2020.609613] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/04/2020] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Neuroinflammation and cellular apoptosis caused by spinal cord ischemia/reperfusion (I/R) injury result in neurological dysfunction. MicroRNAs (miRs) have crucial functions in spinal cord I/R injury pathogenesis according to previous evidences. Herein, whether miR-128-3p contributes to spinal cord I/R injury by regulating specificity protein 1 (SP1) was assessed. METHODS A rat model of spinal cord I/R injury was established by occluding the aortic arch for 14 min. Then, miR-128-3p's interaction with SP1 was detected by dual-luciferase reporter assays. Next, miR-128-3p mimic and inhibitor, as well as adenovirus-delivered shRNA specific for SP1 were injected intrathecally for assessing the effects of miR-128-3p and SP1 on rats with spinal cord I/R injury. SP1, Bax and Bcl-2 expression levels in I/R injured spinal cord tissues were evaluated by Western blotting, while IL-1β, TNF-α, and IL-6 were quantitated by ELISA. Tarlov scores were obtained to detect hind-limb motor function. Evans blue (EB) dye extravasation was utilized to examine blood-spinal cord barrier (BSCB) permeability. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining was performed for neuronal apoptosis assessment. RESULTS MiR-128-3p expression was decreased, while SP1 amounts were increased in rat spinal cord tissue specimens following I/R. SP1 was identified as a miR-128-3p target and downregulated by miR-128-3p. MiR-128-3p overexpression or SP1 silencing alleviated I/R-induced neuroinflammation and cell apoptosis, and improved Tarlov scores, whereas pretreatment with miR-128-3p inhibitor aggravated the above injuries. CONCLUSION Overexpression of miR-128-3p protects neurons from neuroinflammation and apoptosis during spinal cord I/R injury partially by downregulating SP1.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Hong Ma
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
45
|
Zhang Z, Li X, Chen F, Li Z, Wang D, Ren X, Ma H. Downregulation of LncRNA Gas5 inhibits apoptosis and inflammation after spinal cord ischemia-reperfusion in rats. Brain Res Bull 2020; 168:110-119. [PMID: 33316370 DOI: 10.1016/j.brainresbull.2020.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/22/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022]
Abstract
Spinal cord ischemia-reperfusion injury(SCII)affects nerve function through many mechanisms, which are complex and not fully understood. Recently, accumulating evidence has indicated that long noncoding RNAs (lncRNAs) play an increasingly important role in SCII. We investigated the role of lncRNA growth arrest-specific 5(Gas5) in a rat SCII model, and its effects on apoptosis and inflammation possibly by modulating MMP-7, cleaved caspase-3 and IL-1β. LncRNA Gas5 and MMP-7 were knocked down by intrathecal siRNA injection. Neurological assessment and TUNEL assay were performed. The RNA and protein expression levels of lncRNA Gas5, MMP-7, cleaved caspase-3 and IL-1β were determined by PCR and Western blotting, respectively. MMP-7 localization was visualized by double-immunofluorescence. SCII induced functional impairment in the hind limb, and the expression of lncRNA Gas5 was highest at 24 h after SCII. LncRNA Gas5 downregulation inhibited the RNA and protein expression of MMP-7, as well as the protein expression of cleaved caspase-3 and IL-1β. LncRNA Gas5 downregulation reduced the number of TUNEL-positive and MMP-7-positive double-labeled cells. Therefore, lncRNA Gas5 downregulation alleviated hind limb functional impairment and improved neuronal apoptosis after SCII. MMP-7 downregulation also inhibited apoptosis and inflammation and alleviated damage. Pretreatment with intrathecal injection of si-lncRNA Gas5 and si-MMP-7 reduced the expression levels of cleaved caspase-3 and IL-1β, protecting nerve function after SCII. These results show that lncRNA Gas5 plays an important role in SCII, perhaps by inhibiting MMP-7, cleaved caspase-3 and IL-1β. LncRNA Gas5 downregulation could be a promising therapeutic approach in the SCII treatment.
Collapse
Affiliation(s)
- Zaili Zhang
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Xiaoqian Li
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Fengshou Chen
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Zhe Li
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Dan Wang
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Xiaoyan Ren
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Hong Ma
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| |
Collapse
|
|
46
|
Wu WD, Wang LH, Wei NX, Kong DH, Shao G, Zhang SR, Du YS. MicroRNA-15a inhibits inflammatory response and apoptosis after spinal cord injury via targeting STAT3. EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES 2020; 23:9189-9198. [PMID: 31773669 DOI: 10.26355/eurrev_201911_19409] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To clarify the function of microRNA-15a in the spinal cord injury (SCI) and its potential mechanism. PATIENTS AND METHODS The plasma levels of microRNA-15a and signal transducer and activator of transcription 3 (STAT3) in SCI patients were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlation between the expressions of microRNA-15a and STAT3 was analyzed. The in vitro SCI model was established in H2O2-induced C8-D1A and C8B4 cells, and in vivo SCI model was established in mice by hitting T10. The mRNA and protein expressions of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) were detected in the SCI model. The apoptosis was examined by flow cytometry or TUNEL staining, respectively. The motor function of mouse hindlimb was evaluated using the Basso Beattie Bresnahan (BBB) standard scale. The target gene of microRNA-15a was predicted by bioinformatics and further verified by dual-luciferase reporter gene assay. The expression changes of target genes in C8-D1A and C8B4 cells with microRNA-15a overexpression or knockdown were examined by qRT-PCR and Western blot. Finally, rescue experiments were performed to evaluate the regulatory effects of microRNA-15a and STAT3 on cell apoptosis. RESULTS MicroRNA-15a was lowly expressed in plasma of SCI patients, while STAT3 was highly expressed with a negative correlation to microRNA-15a. Identically, microRNA-15a was lowly expressed in H2O2-induced C8-D1A and C8B4 cells, and STAT3 was highly expressed. MicroRNA-15a overexpression downregulated mRNA and protein levels of TNF-α and IL-6 in C8-D1A and C8B4 cells. BBB score was markedly low in SCI mice relative to controls. SCI mice injected with microRNA-15a mimics had higher BBB score than those injected with negative control. Besides, SCI mice with microRNA-15a overexpression had downregulated expressions of STAT3, TNF-α, and IL-6 in the impaired spinal cord tissues, as well as lower apoptotic rate. Through bioinformatics, we found binding sites between STAT3 and microRNA-15a. Their binding conditions were further verified by dual-luciferase reporter gene assay. Moreover, STAT3 expression was negatively regulated by microRNA-15a. Finally, rescue experiments showed that STAT3 overexpression could reverse the regulatory effects of microRNA-15a on expressions of TNF-α and IL-6, as well as apoptosis. CONCLUSIONS MicroRNA-15a expression decreases in the SCI model, which participates in the process of SCI by regulating inflammatory response and cell apoptosis via targeting STAT3.
Collapse
Affiliation(s)
- W-D Wu
- Anesthesiology Department, Danyang People's Hospital of Jiangsu Province & Danyang Hospital Affiliated to Nantong University, Danyang, Jiangsu, China.
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Ye J, Lin Y, Yu Y, Sun D. LncRNA NEAT1/microRNA-129-5p/SOCS2 axis regulates liver fibrosis in alcoholic steatohepatitis. J Transl Med 2020; 18:445. [PMID: 33228663 PMCID: PMC7686721 DOI: 10.1186/s12967-020-02577-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 10/24/2020] [Indexed: 02/07/2023] Open
Abstract
Background Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to play an essential role in non-alcoholic fatty liver disease. However, the role of NEAT1 in regulation of alcoholic steatohepatitis (ASH) remains largely unknown. This study aims to explore the role of NEAT1 in ASH by mediating microRNA-129-5p (miR-129-5p) targeting suppressor of cytokine signaling 2 (SOCS2). Methods NEAT1, miR-129-5p and SOCS2 expression in serum of ASH patients were assessed. In the in vitro cellular experiment, we transfected siRNAs, oligonucleotides or plasmids into ethanol-induced AML-12 mouse hepatocytes to alter NEAT1 and miR-129-5p expression, and inflammatory factors and lipid content were determined. In the in vivo animal experiment, we injected lentiviruses carrying siRNAs, oligonucleotides or plasmids onto ASH mice (ASH induced by feeding mice a Lieber-DeCarli ethanol diet) to alter NEAT1 and miR-129-5p expression through the tail vein. Serum liver function, blood lipids and inflammatory factors were detected; liver histopathology, liver cell apoptosis, and fibrosis were observed. The relationship between NEAT1 and miR-129-5p, or between miR-129-5p and SOCS2 was verified. Results MiR-129-5p was reduced while NEAT1 and SOCS2 were elevated in ASH. Inhibited NEAT1 or elevated miR-129-5p suppressed the elevated lipid metabolism and restrained inflammation reaction in ethanol-stimulated AML-12 cells. The promoted miR-129-5p and inhibited NEAT1 could improve the liver function and repress blood lipid, inflammation reaction, hepatocyte apoptosis and liver fibrosis in ethanol-induced ASH mice. Furthermore, NEAT1 could negatively regulate miR-129-5p to target SOCS2. Conclusion We have found that the inhibited NEAT1 could suppress liver fibrosis in ASH mice by promoting miR-129-5p and restraining SOCS2, thereby decelerating the development of ASH.
Collapse
Affiliation(s)
- Junfeng Ye
- Department of Hepato-Biliary-Pancreatic Surgery, First Hospital, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Yuanqiang Lin
- Department of Ultrasonography, China-Japan Union Hospital, Jilin University, Changchun , 130021, Jilin, People's Republic of China
| | - Ying Yu
- Department of Hepato-Biliary-Pancreatic Surgery, First Hospital, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Di Sun
- Department of Colorectal & Anal Surgery, First Hospital, Jilin University, No. 71 Xinmin street, Changchun, 130021, Jilin, People's Republic of China.
| |
Collapse
|
|
48
|
贺 亚, 孙 麟, 冯 皓, 李 季, 张 楠, 王 志. [Effect and mechanism of glycyrrhizin on glial scar formation after spinal cord injury in rats]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2020; 34:1298-1304. [PMID: 33063497 PMCID: PMC8171873 DOI: 10.7507/1002-1892.202002116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 06/13/2020] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To explore the effect and potential mechanism of glycyrrhizin (GL) by inhibiting high mobility group box 1 (HMGB1) on glial scar formation after spinal cord injury (SCI) in rats. METHODS Seventy-two female Sprague Dawley rats were randomly divided into sham group ( n=12), SCI model group (SCI group, n=36), GL intervention group (SCI+GL group, n=12), and nuclear factor κB (NF-κB) inhibitor [pynolidine dithiocarbamate (PDTC)] intervention group (SCI+PDTC group, n=12). The SCI models of SCI group, SCI+GL group, and SCI+PDTC group were made by modified Allen's method, the sham group was only exposed the spinal cord without any injury. First of all, Basso-Beattie-Bresnahan (BBB) score of hind limbs and slope test were performed in SCI group at 1, 2, and 3 weeks after operation; Western blot was used to detect the expressions of glial fibrillary acidic protein (GFAP) and HMGB1 proteins. Compared with the sham group, the most significant time point in the SCI group was selected for subsequent experiment, in which the most significant glial scar was formed. Then, behavioral tests (BBB score of hind limbs and slope test), histological observation of spinal cord tissue structure, Western blot detection of HMGB1, GFAP, and NF-κB proteins, and immunohistochemical staining observation of GFAP and chondroitin sulfate proteoglycan (CSPG) were used to explore the effect of GL on the formation of glial scar after SCI and its potential mechanism. RESULTS The BBB score and slope angle of the SCI group increased gradually with time, which were significantly lower than those of the sham group at each time point ( P<0.05). Western blot detection showed that the relative expressions of HMGB1 and GFAP proteins in the SCI group at 1, 2, and 3 weeks after operation were significantly higher than those in sham group ( P<0.05). The change was most obvious at 3 weeks after SCI, therefore the spinal cord tissue was selected for subsequent experiments at this time point. At 3 weeks after operation, compared with the SCI group, BBB score and slope angle of SCI+GL group significantly increased ( P<0.05); the relative expressions of HMGB1, GFAP, and NF-κB proteins detected by Western blot and the expressions of GFAP and CSPG proteins detected by immunohistochemical staining significantly decreased ( P<0.05); the disorder of spinal cord tissue by HE staining improved, inflammatory cell infiltration reduced, and glial scar formation decreased. At 3 weeks after operation, the expressions of NF-κB, GFAP, and CSPG proteins of the SCI+PDTC group significantly reduced when compared with the SCI group ( P<0.05); and the expression of NF-κB protein significantly decreased and the expressions of GFAP and CSPG proteins significantly increased when compared with the SCI+GL group ( P<0.05). CONCLUSION After SCI in rats, the application of GL to inhibit the expression of HMGB1 can reduce the expression of GFAP and CSPG in the injured spinal cord, then reduce the formation of glial scars and promote the recovery of motor function of the hind limbs, and GL may play a role in inhibiting glial scar through HMGB1/NF-κB pathway.
Collapse
Affiliation(s)
- 亚军 贺
- 山西医科大学附属白求恩医院骨科（太原 030032）Department of Orthopaedics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan Shanxi, 030032, P.R.China
| | - 麟 孙
- 山西医科大学附属白求恩医院骨科（太原 030032）Department of Orthopaedics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan Shanxi, 030032, P.R.China
| | - 皓宇 冯
- 山西医科大学附属白求恩医院骨科（太原 030032）Department of Orthopaedics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan Shanxi, 030032, P.R.China
| | - 季声 李
- 山西医科大学附属白求恩医院骨科（太原 030032）Department of Orthopaedics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan Shanxi, 030032, P.R.China
| | - 楠 张
- 山西医科大学附属白求恩医院骨科（太原 030032）Department of Orthopaedics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan Shanxi, 030032, P.R.China
- 山西医科大学公共卫生学院（太原 030000）School of Public Health, Shanxi Medical University, Taiyuan Shanxi, 030000, P.R.China
| | - 志强 王
- 山西医科大学附属白求恩医院骨科（太原 030032）Department of Orthopaedics, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan Shanxi, 030032, P.R.China
| |
Collapse
|
|
49
|
Shomali N, Mahmoodpoor A, Abbas Abad AN, Marofi F, Akbari M, Xu H, Sandoghchian Shotorbani S. The Relationship between Extracellular/intracellular microRNAs and TLRs May Be Used as a Diagnostic and Therapeutic Approach in Sepsis. Immunol Invest 2020; 51:154-169. [PMID: 33054447 DOI: 10.1080/08820139.2020.1817067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
One of the leading causes of death in the intensive care unit (ICU) is sepsis. Different studies have been performed on different markers to determine the cause of sepsis. microRNAs (miRNAs) are non-coding RNAs that can be released both inside and outside the cell and regulate the target gene expression by binding to the 3' untranslated region (3'UTR) of the target genes. TLRs play an important role in innate immunity that can be modulated by biological markers such as microRNAs. In this study, we summarized the recent progress on the role of extracellular and intracellular microRNAs in sepsis. It has also been focused on the association of TLRs with extracellular and intracellular micro RNAs in the regulation of sepsis. In conclusion, this study has provided new insight into the role of microRNAs as a regulator of the TLRs which may lead to the aberrant inflammatory response in sepsis. Therefore, it suggests that both intracellular and extracellular microRNAs may play a therapeutic role in the treatment of sepsis via regulating TLRs. However, yet sepsis and septic shock are medical emergencies and further studies are needed to specify the exact role of microRNAs and TLRs in sepsis.
Collapse
Affiliation(s)
- Navid Shomali
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Huaxi Xu
- Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Jiangsu University, Zhenjiang, China
| |
Collapse
|
|
50
|
Li J, He W, Wang Y, Zhao J, Zhao X. miR-103a-3p alleviates oxidative stress, apoptosis, and immune disorder in oxygen-glucose deprivation-treated BV2 microglial cells and rats with cerebral ischemia-reperfusion injury by targeting high mobility group box 1. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1296. [PMID: 33209876 PMCID: PMC7661898 DOI: 10.21037/atm-20-5856] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Cerebral ischemia-reperfusion injury (CI/R) is among the most common diseases affecting the central nervous system. Due to the poor efficacy and adverse side effects of the drugs used to treat CI/R in clinical trials, a new treatment strategy is urgently needed. In this study, we aimed to investigate whether miR-103a-3p alleviates CI/R in vivo and vitro and to explore the relevant mechanisms. Methods BV2 microglial cells underwent oxygen-glucose deprivation (OGD) treatment to imitate the pathophysiology of CI/R in vitro. A middle cerebral artery occlusion (MCAO) rat model was established to imitate the pathophysiology of CI/R in vivo. The expression levels of miR-103a-3p and HMGB1 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, enzyme-linked immunosorbent assay (ELISA), and hematoxylin and eosin (H&E) and Nissl staining were used to evaluated apoptosis, oxidative stress, inflammatory response, and histopathology, respectively. Results OGD-stimulated BV2 microglial cells and brain tissues with CI/R had low expression of miR-103a-3p but high expression of high mobility group box 1 (HMGB1). As expected, miR-103a-3p and HMGB1 had a targeting relationship. Overexpression of HMGB1 enhanced the the levels of interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA), but reduced the content of superoxide dismutase (SOD), IL-4, and IL-10, in vitro. Moreover, high expression of HMGB1 aggravated the brain injury of the model rats, and increased the secretion of inflammatory factors, exacerbated oxidative stress, and further induced tissue apoptosis in the brain tissue. Importantly, these effects of HMGB1 overexpression were partly reversed by miR-103a-3p overexpression on HMGB1 interference. Conclusions HMGB1 is targeted by miR-103a-3p, which may be a new strategy in the treatment of CI/R.
Collapse
Affiliation(s)
- Jianshe Li
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Wenlong He
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Yan Wang
- Department of Neurology, The Third Affiliated Hospital of Xinxiang Medical College, Xinxiang, China
| | - Jianting Zhao
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Xinli Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, China
| |
Collapse
|