scholarly journals miRNA-146a and miRNA-202-3p Attenuate Inflammatory Response by Inhibiting TLR4, IRAK1, and TRAF6 Expressions in Rats following Spinal Cord Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Feng Sun ◽  
Haiwei Zhang ◽  
Jianhui Shi ◽  
Tianwen Huang ◽  
Yansong Wang
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Rat Spinal Cord ◽  
Rat Serum ◽  
Inflammatory Reactions ◽  
Expression Levels ◽  
Tnf Α ◽  
Cord Injury ◽  
Anti Inflammatory

Spinal cord injury (SCI) is a catastrophic disease that induces a complex cascade of cellular reactions at the local lesion area, including secondary cell death and inflammatory reactions. Accumulating evidence has showed pro- and anti-inflammatory roles of microRNAs (miRNAs), a class of small RNAs, in SCI. The present study is aimed at investigating the effects of two miRNAs, miRNA-146a and miRNA-202-3p, on inflammatory response after SCI. Initially, we found that the expression levels of miRNA-146a and miRNA-202-3p were increased in the plasma samples of 32 SCI patients at days 3 and 7 after admission and the rat spinal cord at days 3 and 7 after SCI modeling compared with healthy controls and sham-operated rats, respectively. The expression levels of TLR4, IRAK1, and TRAF6 were declined in the rat spinal cord at days 1, 3, and 7 after SCI modeling compared with sham-operated rats. Injection of miRNA-146a mimic or miRNA-202-3p mimic decreased TLR4, IRAK1, and TRAF6 expressions in the rat spinal cord at days 1, 3, and 7 after SCI modeling, while injection of miRNA-146a antagomir or miRNA-202-3p antagomir produced opposed results. Subsequent results showed that the expression levels of tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-8 were upregulated in the rat serum at days 1, 3, and 7 after SCI modeling compared with sham-operated rats. Injection of miRNA-146a mimic or miRNA-202-3p mimic decreased TNF-α, IL-1β, IL-6, and IL-8 expression levels in the rat serum at days 1, 3, and 7 after SCI modeling, while injection of miRNA-146a antagomir or miRNA-202-3p antagomir yielded opposed results. The expression levels of TNF-α, IL-1β, IL-6, and IL-8 were higher in the supernatants of PC12 cells transfected with anti-miRNA-146a or anti-miRNA-202-3p than in those transfected with si-TLR4, si-IRAK1, or si-TRAF6. These findings support the notion that miRNA-146a/miRNA-202-3p exerts anti-inflammatory functions after SCI.

scholarly journals Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKβ/NF-κB signaling pathway

2018 ◽  
Vol 315 (1) ◽  
pp. C52-C61 ◽  
Author(s):  
Heng-Jun Zhou ◽  
Li-Qing Wang ◽  
Duan-Bu Wang ◽  
Jian-Bo Yu ◽  
Yu Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Tnf Α ◽  
Cord Injury

Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was widely recognized to be implicated in human cancer, vascular diseases, and neurological disorders. This study was to explore the role and underlying mechanism of MALAT1 in acute spinal cord injury (ASCI). ASCI models in adult rats were established and demonstrated by a numerical decrease in BBB scores. Expression profile of MALAT1 and miR-199b following ASCI in rats and in vitro was determined using quantitative real-time PCR. RNA pull-down assays combined with RIP assays were performed to explore the interaction between MALAT1 and miR-199b. In the present study, MALAT1 expression was significantly increased (2.4-fold that of control) in the spinal cord of the rat contusion epicenter accompanied by activation of IKKβ/NF-κB signaling pathway and an increase in the level of proinflammatory cytokines TNF-α and IL-1β. Upon treatment with LPS, MALAT1 expression dramatically increased in the microglia in vitro, but knockdown of MALAT1 attenuated LPS-induced activation of MGs and TNF-α and IL-1β production. Next, we confirmed that LPS-induced MALAT1 activated IKKβ/NF-κB signaling pathway and promoted the production of proinflammatory cytokines TNF-α and IL-1β through downregulating miR-199b. More importantly, MALAT1 knockdown gradually improved the hindlimb locomotor activity of ASCI rats as well as inhibited TNF-α, IL-1β levels, and Iba-1 protein, the marker of activated microglia in injured spinal cords. Our study demonstrated that MALAT1 was dysregulated in ASCI rats and in LPS-activated MGs, and MALAT1 knockdown was expected to attenuate ASCI through repressing inflammatory response of MGs.

Hesperidin improves motor disability in rat spinal cord injury through anti-inflammatory and antioxidant mechanism via Nrf-2/HO-1 pathway

2020 ◽  
Vol 715 ◽  
pp. 134619 ◽  
Author(s):  
Seung-Dam Heo ◽  
Jeongtae Kim ◽  
Yuna Choi ◽  
Poornima Ekanayake ◽  
Meejung Ahn ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Rat Spinal Cord ◽  
Motor Disability ◽  
Antioxidant Mechanism ◽  
Cord Injury ◽  
Anti Inflammatory

Effect of Electroacupuncture on Spinal Cord Injury in Mice: Inhibition Of Inflammatory Response and Oxidative Stress via ApoE and Nrf2

2020 ◽  
Author(s):  
Ni Dai ◽  
Chenglin Tang ◽  
Hongdi Zhao ◽  
Pan Dai ◽  
Siqin Huang
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Neuroprotective Effect ◽  
Related Factor ◽  
Cord Injury ◽  
Anti Inflammatory ◽  
And Oxidative Stress

Abstract Background: Spinal cord injury (SCI) is a catastrophic central nervous system disease. Inflammatory response and oxidative stress are two critical factors in the pathophysiological process of SCI and closely involved with Apolipoprotein E(ApoE) and Nuclear factor erythroid 2-related factor (Nrf2). Electroacupuncture (EA) has perfectly neuroprotective effect on SCI. However, the underlying mechanism by which EA mediates the inflammatory response and oxidative stress is not completely elucidated. In the present study, we investigated the signaling pathways that EA regulates inflammatory response and oxidative stress through elevation of ApoE and Nrf2 after SCI.Methods: C57BL/6 Wide Type (WT) mice and ApoE -/- mice were subjected to SCI model by a serrefine clamping. Neurological function was detected by BMS scores, ultrastructure of demyelinationed axons was observed by transmission electron microscopy. ApoE, pro- and anti- inflammatory cytokines, oxidative stress-relevant proteins were determined by histochemistry technology. Two-way ANOVA was applied to BMS scores. One-way ANOVA and Bonferroni's multiple comparison test were used to analyse differences among groups.Results: BMS scores were increased gradually and demyelinated axons were improved by EA gradually with the expression of ApoE. EA can inhibit inflammatory response by activation of ApoE, which decreased pro-inflammatory cytokines(TNF-α, IL-6, and IL-1β) expression and increased anti-inflammatory cytokines(IL-10 and TGF-β1).Meanwhile, EA can also inhibit oxidative stress by elevation of Nrf2,which induced HO-1 and NQO1 expression in WT and ApoE -/- mice.Conclusions: EA is a reliable treatment for promoting functional recovery of SCI. Thesynergisticrole of ApoE and Nrf2 in EA regulating inflammatory response and oxidative stress is decisiveto recovery after SCI.

scholarly journals Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue

2015 ◽  
Vol 32 (18) ◽  
pp. 1413-1421 ◽  
Author(s):  
April Cox ◽  
Abhay Varma ◽  
John Barry ◽  
Alexey Vertegel ◽  
Naren Banik
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cerebrospinal Fluid ◽  
Rat Spinal Cord ◽  
Cord Injury ◽  
Anti Inflammatory

scholarly journals Ultrasound stimulation improves inflammatory resolution, neuroprotection, and functional recovery after spinal cord injury

2021 ◽  
Author(s):  
Yu-ri Hong ◽  
Eun-hee Lee ◽  
Ki-su Park ◽  
Mun Han ◽  
Kyoung-Tae Kim ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Motor Function ◽  
Functional Recovery ◽  
Rat Model ◽  
Inflammatory Responses ◽  
Injury Site ◽  
Cord Injury ◽  
Anti Inflammatory

Abstract Spinal cord injury (SCI) is associated with limited functional recovery. Despite advances in neuroscience, realistic therapeutic treatments for SCI remain unavailable. In this study, the effects of non-invasive ultrasound (US) treatment on behavior and inflammatory responses were evaluated in a rat model of SCI. Adult female Sprague–Dawley rats were subjected to spinal cord contusion injury. Two different US parameters (SCIU5: 5% and SCIU40: 40% duty cycle) were applied, and their effects on behavioral recovery after SCI were quantified. Tissue and neuronal responses were detected. Immunofluorescence was used to detect inflammatory markers. In the rat model of SCI, motor function was more effectively restored, and the lesion cavity area was smaller in the SCIU5 group. Furthermore, the SCIU5 protocol elicited an anti-inflammatory response at the injury site by reducing degenerative FJC-labeled neurons, macrophage/microglia activation, and infiltration. Thus, the lesion area decreased, and tissue density increased. Meanwhile, the SCIU40 protocol did not improve motor function or induce an anti-inflammatory response at the injury site. The SCIU5 protocol effectively accelerated the rate of improved exercise performance in the rat model while reducing inflammation. Accordingly, appropriate US stimulation may represent a promising treatment modality for SCI with beneficial anti-inflammatory effects.

Neonatal Rats Exhibit a Predominantly Anti-Inflammatory Response following Spinal Cord Injury

2021 ◽  
pp. 1-9
Author(s):  
Theresa C. Sutherland ◽  
Alison Ricafrente ◽  
Katarina Gomola ◽  
Bronwyn A. O’Brien ◽  
Catherine A. Gorrie
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Neonatal Rats ◽  
Adult Rats ◽  
Lesion Effect ◽  
Cord Injury ◽  
Th1 Cytokine ◽  
Anti Inflammatory

It has been reported that children may respond better than adults to a spinal cord injury (SCI) of similar severity. There are known biomechanical differences in the developing spinal cord that may contribute to this “infant lesion effect,” but the underlying mechanisms are unknown. Using immunohistochemistry, we have previously demonstrated a different injury progression and immune cell response after a mild thoracic contusion SCI in infant rats, as compared to adult rats. Here, we investigated the acute inflammatory responses using flow cytometry and ELISA at 1 h, 24 h, and 1 week after SCI in neonatal (P7) and adult (9 weeks) rats, and locomotor recovery was examined for 6 weeks after injury. Adult rats exhibited a pronounced pro-inflammatory response characterized by neutrophils and M1-like macrophage infiltration and Th1 cytokine secretion. Neonatal rats exhibited a decreased pro-inflammatory response characterized by a higher proportion of M2-like macrophages and reduced Th1 cytokine responses, as compared to adults. These results suggest that the initial inflammatory response to SCI is predominantly anti-inflammatory in very young animals.

scholarly journals EZH2 Mediates miR-146a-5p/HIF-1α to Alleviate Inflammation and Glycolysis after Acute Spinal Cord Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Shuangfei Ni ◽  
Bo Yang ◽  
Lei Xia ◽  
Huafeng Zhang
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cerebrospinal Fluid ◽  
Underlying Mechanism ◽  
Acute Spinal Cord Injury ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Expression Levels ◽  
Tnf Α ◽  
Cord Injury

Acute spinal cord injury (ASCI) is a severe traumatic disease of the central nervous system, the underlying mechanism of which is unclear. This study was intended to study the role of EZH2 and miR-146a-5p/HIF-1α in inflammation and glycolysis after ASCI, providing reference and basis for the clinical treatment and prognosis of ASCI injury. We used lipopolysaccharide (LPS) to induce inflammation of microglia, and we constructed the ASCI animal model. qRT-PCR detected the relative expression levels of EZH2, HIF-1α, miR-146a-5p, IL-6, TNF-α, IL-17, PKM2, GLUT1, and HK2 in cells and tissues. Western blot was performed to detect the expression levels of EZH2, HIF-1α, H3K27me3, IL-6, TNF-α, IL-17, PKM2, GLUT1, and HK2. ChIP verified the enrichment of H3K27me3 in the miR-146a-5p promoter region. Bioinformatics predicted the binding sites of HIF-1α and miR-146a-5p, and dual-luciferase reporter assay verified the binding of HIF-1α and miR-146a-5p. ELISA detects the levels of inflammatory factors IL-6, TNF-α, and IL-17 in the cerebrospinal fluid of rats. The GC-TOFMS was used to detect the changes of glycolytic metabolites in the cerebrospinal fluid of rats. EZH2 could mediate inflammation and glycolysis of microglia. EZH2 regulates inflammation and glycolysis through HIF-1α. EZH2 indirectly regulated the HIF-1α expression by mediating miR-146a-5p. EZH2 mediates miR-146a-5p/HIF-1α to alleviate inflammation and glycolysis in ASCI rats. In the present study, our results demonstrated that EZH2 could mediate miR-146a-5p/HIF-1α to alleviate the inflammation and glycolysis after ASCI. Therefore, EZH2/miR-146a-5p/HIF-1α might be a novel potential target for treating ASCI.

scholarly journals miRNA-221 Regulates Spinal Cord Injury-Induced Inflammatory Response through Targeting TNF-α Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Feng Sun ◽  
Haiwei Zhang ◽  
Tianwen Huang ◽  
Jianhui Shi ◽  
Tianli Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Luciferase Reporter ◽  
Spinal Cord Tissue ◽  
Tnf Α ◽  
Cord Injury ◽  
And Oxidative Stress

Objectives. To investigate the roles of miR-221 in spinal cord injury (SCI) as well as the underlying mechanism. Methods. A mouse model of SCI was generated and used to examine dynamic changes in grip strength of the mouse upper and lower limbs. The expression of miR-221 and tumor necrosis factor-α (TNF-α) was detected by RT-qPCR and Western blot. Levels of inflammation and oxidative stress in microglia cells of the injured mice overexpressing miR-221 were then measured by ELISA. Bioinformatics analysis and dual-luciferase reporter assay were conducted to identify the miR-221 target. Results. We successfully constructed SCI mouse model. The results of qRT-PCR showed that miR-221 was gradually upregulated in the spinal cord tissue of mice in the SCI group with the prolonged injury time. At the same time, the mRNA and protein of TNF-α gradually decreased. We further confirmed through cell experiments that the inflammatory factors TNF-α and IL-6, as well as iNOS and eROS, were upregulated in spinal cord microglia cells of SCI mice, and upregulation of miR-122 can inhibit their expression. Finally, the luciferase reporter experiment confirmed that miR-122 targeted TNF-α. Conclusions. We present evidence that miR-221 promotes functional recovery of the injured spinal cord through targeting TNF-α, while alleviating inflammatory response and oxidative stress.

Electroacupuncture Alleviates the Inflammatory Response via Effects on M1 and M2 Macrophages after Spinal Cord Injury

2017 ◽  
Vol 35 (3) ◽  
pp. 224-230 ◽  
Author(s):  
Jiagui Zhao ◽  
Likui Wang ◽  
Yuanhai Li
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Control Group ◽  
Acupuncture Points ◽  
Functional Evaluation ◽  
M2 Macrophages ◽  
Tnf Α ◽  
Cord Injury

Background Macrophages/microglia are important effector cells at the site of spinal cord injury (SCI). M1-type macrophages facilitate innate immunity to remove foreign microbes and wound debris from the injury site. M2-type macrophages exhibit tissue repair properties and attenuate production of pro-inflammatory cytokines. Regulation of the polarisation of M1/M2 macrophages may affect the inflammatory response in SCI and may be related to neurotrophin-3 (NT-3). Electroacupuncture (EA) at GV acupuncture points can be used as an adjuvant therapy for SCI. Aim To investigate the effects of EA on Basso, Beattie and Bresnahan (BBB) functional evaluation and inflammatory cytokines (tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10), and on the proportions of M1/M2 macrophages, and to provide a greater understanding of the mechanisms underlying the potential clinical treatment of SCI. Methods A rat SCI model was induced by spinal segment transection at T10 in 16 Sprague-Dawley rats. A further eight rats were included as a Control group. Ten surviving SCI model rats were divided into two groups (n=5 each): an SCI group that remained untreated; and an SCI+EA group that received EA at GV6 and GV9. Results EA improved BBB scores, inhibited the proportion of M1 macrophages and TNF-α, IL-1β and IL-6 levels, and downregulated the M1 marker CD86. By contrast, EA enhanced IL-10, the proportion of M2 macrophages and upregulated the M2 marker CD206 and NT-3 expression. Conclusions EA had a positive impact on SCI model rats. This may be related to the neuroprotective effect of NT-3, which may increase the polarisation of M2 microglia/macrophages.

scholarly journals miR-136-5p Regulates the Inflammatory Response by Targeting the IKKβ/NF-κB/A20 Pathway After Spinal Cord Injury

2018 ◽  
Vol 50 (2) ◽  
pp. 512-524 ◽  
Author(s):  
Guiying Deng ◽  
Yunbing Gao ◽  
Zhongxi Cen ◽  
Jichen He ◽  
Baichuan Cao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Rat Model ◽  
Inflammatory Cell ◽  
Luciferase Activity ◽  
Inflammatory Cell Infiltration ◽  
Tnf Α ◽  
Cord Injury

Background/Aims: miR-136-5p participates in recovery after spinal cord injury (SCI) via an unknown mechanism. We investigated the mechanism underlying the involvement of miR-136-5p in the inflammatory response in a rat model of SCI. Methods: Sprague-Dawley rat astrocytes were cultured in vitro to construct a reporter plasmid. Luciferase assays were used to detect the ability of miR-136-5p to target the IKKβ and A20 genes. Next, recombinant lentiviral vectors were constructed, which either overexpressed miR-136-5p or inhibited its expression. The influence of miR-136-5p overexpression and miR-136-5p silencing on inflammation was observed in vivo in an SCI rat model. The expression of IL-1β, IL-6, TNF-α, IFN-α, and related proteins (A20, IKKβ, and NF-κB) was detected. Results: In vitro studies showed that luciferase activity was significantly activated in the presence of the 3’ untranslated region (UTR) region of the IKKβ gene after stimulation of cells with miR-136-5p. However, luciferase activity was significantly inhibited in the presence of the 3’UTR region of the A20 gene. Thus, miR-136-5p may act directly on the 3’UTR regions of the IKKβ and A20 genes to regulate their expression. miR-136-5p overexpression promoted the production of related cytokines and NF-κB in SCI rats and inhibited the expression of A20 protein. Conclusion: Overexpression of miR-136-5p promotes the generation of IL-1β, IL-6, TNF-α, IFN-α, IKKβ, and NF-κB in SCI rats but inhibits the expression of A20. Under these conditions, inflammatory cell infiltration into the rat spinal cord increases and injury is significantly aggravated. Silencing of miR-136-5p significantly reduces the protein expression results described after miR-136-5p overexpression and ameliorates the inflammatory cell infiltration and damage to the spinal cord. Therefore, miR-136-5p might be a new target for the treatment of SCI.

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