Downregulation of Long Noncoding RNA TUG1 Attenuates MTDH-Mediated Inflammatory Damage via Targeting miR-29b-1-5p After Spinal Cord Ischemia Reperfusion

2020 ◽  
Author(s):  
Hui Jia ◽  
Zhe Li ◽  
Yi Chang ◽  
Bo Fang ◽  
Yongjian Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Noncoding Rna ◽  
Target Genes ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Specific Inhibitor ◽  
Direct Interaction ◽  
Luciferase Reporter ◽  
Inflammatory Damage

Abstract Long noncoding RNAs and microRNAs (miRNAs) play a vital role in spinal cord ischemia reperfusion (IR) injury. The aim of this study was to identify the potential interactions between taurine upregulated gene 1 (TUG1) and miRNA-29b-1-5p in a rat model of spinal cord IR. The IR injury was established by 14-minute occlusion of aortic arch. TUG1 and metadherin (MTDH) knockdown were induced by respective siRNAs, and miR-29b-1-5p expression was modulated using specific inhibitor or mimics. The interactions between TUG1, miR-29b-1-5p, and the target genes were determined using the dual-luciferase reporter assay. We found that IR respectively downregulated and upregulated miR-29b-1-5p and TUG1, and significantly increased MTDH expression. MTDH was predicted as a target of miR-29b-1-5p and its knockdown downregulated NF-κB and IL-1β levels. A direct interaction was observed between TUG1 and miR-29b-1-5p, and knocking down TUG1 upregulated the latter. Furthermore, overexpression of miR-29b-1-5p or knockdown of TUG1 alleviated blood-spinal cord barrier leakage and improved hind-limb motor function by suppressing MTDH and its downstream pro-inflammatory cytokines. Knocking down TUG1 also alleviated MTDH/NF-κB/IL-1β pathway-mediated inflammatory damage after IR by targeting miR-29b-1-5p, whereas blocking the latter reversed the neuroprotective effect of TUG1 knockdown and restored MTDH/NF-κB/IL-1β levels.

scholarly journals Downregulation of Long Noncoding RNA TUG1 Attenuate MTDH /NF-κB/IL-1β mediated inflammatory damage via Targeting miR-29b-1-5p After Spinal cord ischemia reperfusion in rats

2020 ◽  
Author(s):  
Hui Jia ◽  
Zhe Li ◽  
Bo Fang ◽  
Yi Chang ◽  
Yongjian Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Function ◽  
Noncoding Rna ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Luciferase Reporter ◽  
Inflammatory Damage ◽  
Blood Spinal Cord Barrier

Abstract Background: Spinal cord ischemia reperfusion (IR) is associated with an inflammatory response. The long non-coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) and microRNA-29b (miR-29b) family are frequently dysregulated in neuro-ischemic diseases. However, their potential roles in spinal cord IR injury (IR) are unknown. Methods: A spinal cord IR model was established in rats by14-minute occlusion of aortic arch. The aberrant miRNAs were identified by microarray analysis, and qRT-PCR was used to validate the lncRNA and microRNA levels. The motor function of the differentially-treated animals was assessed by Tarlov scores, and the leakage of Blood-spinal cord barrier (BSCB) was measured in terms of the extravasation of Evans blue (EB) dye. The expression levels of different proteins were analyzed by Western blotting and immunofluorescence. The interaction between TUG1 and miR-29b-1-5p, TRIL and miR-29b-1-5p, and MTDH and miR-29b-1-5p were determined using bioinformatics programs and the dual-luciferase reporter assay. Results: MiR-29b-1-5p was significantly downregulated and TUG1 was upregulated in the spinal cord of rats after IR. In addition, TRIL and MTDH protein levels were also significantly increased after IR. MTDH was predicted as a target of miR-29b-1-5p and its knockdown downregulated NF-κB and IL-1β levels. In addition, a direct interaction was observed between TUG1 and miR-29b-1-5p, and knocking down TUG1 upregulated the miRNA. Furthermore, overexpression of miR-29b-1-5p or TUG1 knockdown alleviated BSCB leakage and improved hind-limb motor function, and downregulated MTDH and its downstream pro-inflammatory cytokines. Suppression of miR-29b-1-5p reversed the neuroprotective effect of TUG1 knockdown, restored the levels of MTDH/ NF-κB/IL-1β and activated astrocytes. Conclusion: Downregulation of TUG1 alleviated MTDH/NF-κB/IL-1β pathway-mediated inflammatory damage after IR by targeting miR-29b-1-5p. Keywords: Spinal cord ischemia reperfusion injury, Neuroinflammation, Blood-spinal cord barrier, Astrocytes, TUG1, miR-29b-1-5p, MTDH

scholarly journals Downregulation of Long Noncoding RNA TUG1 Attenuate MTDH /NF-κB/IL-1β mediated inflammatory damage via Targeting miR-29b-1-5p After Spinal cord ischemia reperfusion in rats

2020 ◽  
Author(s):  
Hui Jia ◽  
Zhe Li ◽  
Bo Fang ◽  
Yi Chang ◽  
Yongjian Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Inflammatory Damage

Abstract The authors have withdrawn this preprint due to author disagreement.

The Neuroprotective Effect of Syringic Acid on Spinal Cord Ischemia/Reperfusion Injury in Rats

Inflammation ◽  
2015 ◽  
Vol 38 (5) ◽  
pp. 1969-1978 ◽  
Author(s):  
Mehmet Tokmak ◽  
Yasemin Yuksel ◽  
Muserref Hilal Sehitoglu ◽  
Mustafa Guven ◽  
Tarik Akman ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Syringic Acid

scholarly journals 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

2021 ◽  
Vol 9 ◽  
Author(s):  
Hua Fang ◽  
Hua-Feng Li ◽  
Qin Pan ◽  
Hon-Ling Jin ◽  
Miao Yang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Signaling Pathways ◽  
Ischemia Reperfusion ◽  
Quantitative Polymerase Chain Reaction ◽  
Spinal Cord Ischemia ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Jnk Signaling ◽  
M1 Polarization ◽  
Gene Assay

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.

Neuroprotective effect of alpha-lipoic acid and methylprednisolone on the spinal cord ischemia/reperfusion injury in rabbits

2014 ◽  
Vol 29 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Mehmet Gazi Boyaci ◽  
Olcay Eser ◽  
Cevdet Ugur Kocogullari ◽  
Ergun Karavelioglu ◽  
Cigdem Tokyol ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Reperfusion Injury ◽  
Lipoic Acid ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Alpha Lipoic Acid

scholarly journals Identification of key microRNAs and the underlying molecular mechanism in spinal cord ischemia-reperfusion injury in rats

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11454
Author(s):  
Fengshou Chen ◽  
Jie Han ◽  
Dan Wang
Keyword(s):  
Spinal Cord ◽  
Transcription Factor ◽  
Mirna Expression ◽  
Caspase 3 ◽  
Target Genes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Enrichment Analysis ◽  
Biological Processes

Spinal cord ischemia-reperfusion injury (SCII) is a pathological process with severe complications such as paraplegia and paralysis. Aberrant miRNA expression is involved in the development of SCII. Differences in the experimenters, filtering conditions, control selection, and sequencing platform may lead to different miRNA expression results. This study systematically analyzes the available SCII miRNA expression data to explore the key differently expressed miRNAs (DEmiRNAs) and the underlying molecular mechanism in SCII. A systematic bioinformatics analysis was performed on 23 representative rat SCII miRNA datasets from PubMed. The target genes of key DEmiRNAs were predicted on miRDB. The DAVID and TFactS databases were utilized for functional enrichment and transcription factor binding analyses. In this study, 19 key DEmiRNAs involved in SCII were identified, 9 of which were upregulated (miR-144-3p, miR-3568, miR-204, miR-30c, miR-34c-3p, miR-155-3p, miR-200b, miR-463, and miR-760-5p) and 10 downregulated (miR-28-5p, miR-21-5p, miR-702-3p, miR-291a-3p, miR-199a-3p, miR-352, miR-743b-3p, miR-125b-2-3p, miR-129-1-3p, and miR-136). KEGG enrichment analysis on the target genes of the upregulated DEmiRNAs revealed that the involved pathways were mainly the cGMP-PKG and cAMP signaling pathways. KEGG enrichment analysis on the target genes of the downregulated DEmiRNAs revealed that the involved pathways were mainly the Chemokine and MAPK signaling pathways. GO enrichment analysis indicated that the target genes of the upregulated DEmiRNAs were markedly enriched in biological processes such as brain development and the positive regulation of transcription from RNA polymerase II promoter. Target genes of the downregulated DEmiRNAs were mainly enriched in biological processes such as intracellular signal transduction and negative regulation of cell proliferation. According to the transcription factor analysis, the four transcription factors, including SP1, GLI1, GLI2, and FOXO3, had important regulatory effects on the target genes of the key DEmiRNAs. Among the upregulated DEmiRNAs, miR-3568 was especially interesting. While SCII causes severe neurological deficits of lower extremities, the anti-miRNA oligonucleotides (AMOs) of miR-3568 improve neurological function. Cleaved caspase-3 and Bax was markedly upregulated in SCII comparing to the sham group, and miR-3568 AMO reduced the upregulation. Bcl-2 expression levels showed a opposite trend as cleaved caspase-3. The expression of GATA6, GATA4, and RBPJ decreased after SCII and miR-3568 AMO attenuated this upregulation. In conclusion, 19 significant DEmiRNAs in the pathogenesis of SCII were identified, and the underlying molecular mechanisms were validated. The DEmiRNAs could serve as potential intervention targets for SCII. Moreover, inhibition of miR-3568 preserved hind limb function after SCII by reducing apoptosis, possibly through regulating GATA6, GATA4, and RBPJ in SCII.

scholarly journals MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sifei Yu ◽  
Lei Xie ◽  
Zhuochao Liu ◽  
Changwei Li ◽  
Yu Liang
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Sirtuin 1

Oxidative stress is a leading contributor to spinal cord ischemia-reperfusion (SCIR) injury. Recently, MLN4924, a potent and selective inhibitor of the NEDD8-activating enzyme, was shown to exert a neuroprotective effect against oxidative stress in vitro. However, it is unknown whether MLN4924 plays a protective role against SCIR injury. In the present study, we found that MLN4924 treatment significantly attenuated oxidative stress and neuronal cell death induced by H2O2 in SH-SY-5Y neural cells and during rat SCIR injury. Furthermore, MLN4924 administration restored neurological and motor functions in rats with SCIR injury. Mechanistically, we found that MLN4924 protects against H2O2- and SCIR injury-induced neurodegeneration by regulating sirtuin 1 (Sirt1) expression. Collectively, these findings demonstrate the neuroprotective role of MLN4924 against oxidative stress in SCIR injury via Sirt1.

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