scholarly journals GAS5 knockdown alleviates spinal cord injury by reducing VAV1 expression via RNA binding protein CELF2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dan Wang ◽  
Xiaoxiao Xu ◽  
Junwei Pan ◽  
Shixin Zhao ◽  
Yu Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Cell Injury ◽  
Glucose Deprivation ◽  
Nucleotide Exchange ◽  
Coding Region ◽  
Cord Injury

AbstractLong non-coding RNA growth arrest specific transcript 5 (GAS5) has been found to be implicated in the pathogenesis of central nervous diseases and to be a contributor to hypoxic brain injury. However, the roles and molecular mechanisms of GAS5 in spinal cord injury (SCI) have not thoroughly investigated. Here, we reported that GAS5 knockdown improved rat locomotor function and alleviated pathological damage of spinal cord tissues by reducing oxidative stress, caspase-3 activity and vav guanine nucleotide exchange factor 1 (VAV1) expression in SCI rat models. GAS5 knockdown inhibited the increase of malondialdehyde (MDA) level and cell apoptotic rate induced by oxygen–glucose deprivation (OGD) and weakened the inhibitory effects of OGD on superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and cell viability in RN-Sc cells, suggesting that GAS5 loss mitigated OGD-triggered oxidative stress and cell injury in RN-Sc cells. Molecular mechanism explorations revealed that GAS5 recruited CUGBP, Elav-like family member 2 (CELF2) to the coding region of VAV1 mRNA, resulting in the increase of VAV1 mRNA stability and expression levels. VAV1 knockdown weakened OGD-induced oxidative stress and cell injury in RN-Sc cells. VAV1 loss alleviated GAS5-induced oxidative stress and cell injury in OGD-treated RN-Sc cells. As a conclusion, our findings suggested that GAS5 aggravated SCI by increasing VAV1 expression via binding with CELF2, deepening our understanding on function and molecular basis of GAS5 in SCI.

scholarly journals Ryanodine Receptor 2 Plays a Critical Role in Spinal Cord Injury via Induction of Oxidative Stress

2016 ◽  
Vol 38 (3) ◽  
pp. 1129-1137 ◽  
Author(s):  
Bo Liao ◽  
Yong Zhang ◽  
Honghui Sun ◽  
Baoan Ma ◽  
Jixian Qian
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Ros Generation ◽  
Lesion Volume ◽  
Activating Transcription Factor 3 ◽  
Cord Injury

Background/Aims: Spinal cord injury (SCI) is a severe health problem worldwide. Ryanodine receptors (RyRs) are a class of intracellular calcium channels in various excitable tissues such as muscles and nervous tissues. The current study was designed to investigate the possible role of RyR2 upregulation in SCI and to elucidate the possible molecular mechanisms. Methods: Rats were injected with LVshRNAi- RyR2 and then exposed to spinal cord contusion injury. Results: The results showed that knockdown of RyR2 significantly promoted the recovery of structural and functional injury in spinal cord, as evidenced by reduction of lesion volume and increase of Basso, Beattie and Bresnahan (BBB) and combined behavioral score (CBS) scores. Knockdown of RyR2 inhibited the increase of proinflammatory cytokines, including IL-1β and TNFα. Moreover, downregulation of RyR2 increased oxygen consumption rate and decreased the expression of glucose-regulated protein 78 (GRP78), activating transcription factor 3 (ATF3) and ATF6, indicating the improvement of mitochondrial dysfunction and endoplasmic reticulum stress after SCI. Furthermore, silence of RyR2 reduced oxidative stress, as reflected by decrease of TBARS and GSSG content and increase of GSH level. The expression of NADPH oxidase 2 (NOX2), NOX4 and p66shc were increased in SCI rats. Knockdown of RyR2 significantly decreased NOX2 expression, but had no evident effect on NOX4 and p66shc expression. These results indicated NOX2 may be involved in RyR2-induced ROS generation which mediated contusion-induced spinal cord injury. Conclusion: The data provide novel insights into the mechanism of RyR2-mediated injury and the potential therapeutic targets for injury in spinal cord.

scholarly journals pH-responsive delivery of H2 through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

2021 ◽  
Author(s):  
Yi Liu ◽  
Yeying Wang ◽  
Bing Xiao ◽  
Guoke Tang ◽  
Jiangming Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Ammonia Borane ◽  
Neural Regeneration ◽  
Dependent Manner ◽  
Cord Injury

Abstract Imbalance of oxidative and inflammatory regulation is the main contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury (SCI). As an emerging biosafe strategy for protecting against oxidative and inflammatory damage, hydrogen (H2) therapy is a promising approach for improving the microenvironment to allow neural regeneration. However, achieving release of H2 at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H2. Thus, we assembled SiO2@mSiO2 mesoporous silica nanoparticles and loaded them with ammonia borane (AB), which has abundant capacity and allows controllable release of H2 in an acid-dependent manner. The release of H2 from AB/SiO2@mSiO2 was satisfactory at pH 6.6, which is approximately equal to the microenvironmental acidity after SCI. After AB/SiO2@mSiO2 were intrathecally administered to rat models of SCI, continuous release of H2 from these nanoparticles synergistically enhanced neurofunctional recovery, reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction. Furthermore, in the subacute phase of SCI, microglia were markedly polarized toward the M2 phenotype by H2 via inhibition of TLR9 expression in astrocytes. In conclusion, H2 delivery through AB/SiO2@mSiO2 has the potential to efficiently treat SCI through comprehensive modulation of the oxidative and inflammatory imbalance in the microenvironment.

Protective role of β-carotene against oxidative stress and neuroinflammation in a rat model of spinal cord injury

2018 ◽  
Vol 61 ◽  
pp. 92-99 ◽  
Author(s):  
Lihui Zhou ◽  
Lian Ouyang ◽  
Shuangzhi Lin ◽  
Song Chen ◽  
YingJie Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Rat Model ◽  
Protective Role ◽  
Cord Injury ◽  
Β Carotene

Activation of SIRT1 by Hyperbaric  Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

2020 ◽  
Author(s):  
Huiqiang Chen ◽  
Mengyu Yao ◽  
Zhibo Li ◽  
Ranran Xing ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Inflammatory Cascade ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

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