Search

Background: Depression is a common but often overlooked consequence in individuals with post‐traumatic brain injury (TBI). Circular RNAs (circRNAs) play essential roles in the nervous system, yet their involvement in the cell death mechanism known as cuproptosis and in TBI‐related depression remains unclear. Objectives: This study aimed to investigate the role of circRNA, specifically circSpna2, in the regulation of cuproptosis and its association with depression in TBI patients. Methods: RNA sequencing (RNA‐Seq) was used to assess the differential expression of circRNAs. Depression was evaluated using subjective and objective rating scales, and circSpna2 expression levels in plasma were measured. Further functional experiments were conducted in TBI mouse models, including knockdown and overexpression of circSpna2, to explore its impact on the Keap1‐Nrf2‐Atp7b pathway and cuproptosis. Results: TBI patients exhibited decreased levels of circSpna2, which correlated with depression (p < 0.0001). Knocking down circSpna2 in TBI mice aggravated depression‐like symptoms (p < 0.0001). Mechanistically, circSpna2 was found to bind ubiquitin ligase Keap1, modulating the Nrf2‐Atp7b signaling pathway and influencing cuproptosis (docking score: −331.88). Overexpression of circSpna2 alleviated cuproptosis after TBI through the Keap1/Nrf2/Atp7b axis. Conclusions: CircSpna2 plays a regulatory role in cuproptosis and may serve as a novel biomarker and therapeutic target for depression following TBI. Enhancing circSpna2 expression could mitigate depression after TBI by modulating the Keap1/Nrf2/Atp7b pathway. Key points: This study explores the role of circSpna2 in depression following traumatic brain injury (TBI). It was found that circSpna2 is significantly downregulated in TBI patients, and its expression levels correlate with depressive symptoms. In TBI mouse models, overexpression of circSpna2 alleviated depression‐like behaviours, while its knockdown exacerbated these symptoms, suggesting its potential as both a biomarker and a therapeutic target for post‐TBI depression. Mechanistically, circSpna2 regulates the Nrf2‐Atp7b signalling pathway by binding to the DGR domain of Keap1, which prevents Nrf2 ubiquitination and enhances Nrf2 activity. This in turn promotes the transcription of Atp7b, a copper transport protein, helping to maintain copper homeostasis and mitigate copper‐induced oxidative stress, a key protein of cell death (cuproptosis). The overexpression of circSpna2 also improved mitochondrial function and synaptic integrity, which are typically impaired by copper dysregulation. These findings highlight the therapeutic potential of circSpna2 in managing TBI‐related depression through the regulation of oxidative stress and copper homeostasis. [ABSTRACT FROM AUTHOR]

Up to now, the serine-arginine protein kinase 1 (SRPK1) has been suggested as an important signal mediator, which is implicated in the development of cancers. Unfortunately, some molecular pathways in SRPK1-mediated epithelial-mesenchymal transition (EMT) in human spinal glioblastoma have been not elucidated. In this work, we detected the expression of SRPK1 in human spinal glioblastoma tissues and GBM cell lines and analyzed the relevant molecular proteins using in vitro experiments, including RT-PCR, gene silencing, and Western blot. In this study, RT-PCR and Western blot revealed that the expression of SRPK1 mRNA and protein became higher in all six spinal glioblastoma specimens; however, its expression was low in matched normal specimens. We also demonstrated SRPK1 expression facilitated the proliferation of U87 and U251 cells and inhibited the apoptosis in U87 and U251 cells. Also, SRPK1 promoted the expression of EMT-regulating markers, involving N-cadherin, Snail, and MMP9 and decreased the expression of mesenchymal marker E-cadherin. Moreover, knockdown of SRPK1 significantly inhibited the expression levels of p-Akt rather than t-Akt. In conclusion, knockdown of SRPK1 inhibited glioblastoma cell proliferation, invasion, and EMT process via suppressing p-Akt signaling pathway. This study also lays a new foundation for the clinically biological treatment. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 5 (CDK5) and ataxia-telangiectasia mutated (ATM) are involved in normal human neurodevelopment and serves as a switch between neuronal survival and death. However, the molecular mechanisms underlying CDK5-ATM-induced neuronal injury caused by intracerebral hemorrhage (ICH) remain unclear. In this work, we used rat ICH models and thrombin-induced cell models to investigate the potential role of CDK5-ATM signals. Our findings revealed that CDK5 protein levels and kinase activities (p-histone H1 expression) were enforced in hematoma-surrounding neuron tissues following ICH. Besides, the expression of p25, p-ATM, and active caspase-3 protein was also upregulated after ICH. According to in vitro assays, the expression of CDK5, p-ATM, and active caspase-3 was all upregulated in cell viability-decreasing ICH cell models. However, blocking of either CDK5 or ATM suppressed the phosphorylation of ATM and the expression of active caspase-3, and attenuated the inhibition of neuronal survival. When p35/p25 was silenced, CDK5-ATM pathway was further inhibited, and cell viability was obviously ameliorated. In conclusion, this work suggested that ATM could be phosphorylated by CDK5 to induce the active caspase-3 and neuronal injury when intracerebral hemorrhage or ischemia occurred. Thus, the CDK5-AMT signal pathway has an important role in ICH process and may be a therapeutic target to prevent brain injury. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of blocking the activation of ERK pathway on the expression of matrix metalloproteinase-9 (MMP-9) and the formation of cerebral edema in SD rats after brain injury., Methods: Ninety SD rats were randomly divided into 3 equal groups, including a sham-operated group, modified Feeney's traumatic brain injury model group, and ERK inhibition group where the ERK inhibitor SCH772984 (500 μg/kg) was injected via the femoral vein 15 min before brain trauma. At 2 h and 2 days after brain trauma, the permeability of blood-brain barrier was assessed by Evans blue method, the water content of the brain tissue was determined, and the phosphorylation level of ERK and the expression level of MMP-9 mRNA and protein were measured by RT-PCR and Western blotting., Results: Compared with the sham-operated group, the rats with brain trauma exhibited significantly increased level of ERK phosphorylation at 2 h and significantly increased expression of MMP-9 mRNA and protein 2 days after the injury ( P &lt; 0.01). Treatment with the ERK inhibitor significantly decreased the phosphorylation level of ERK after the injury ( P &lt; 0.01), suppressed over-expression of MMP-9 mRNA and protein 2 days after the injury ( P &lt; 0.01). The permeability of blood-brain barrier increased significantly 2 h after brain trauma ( P &lt; 0.05) and increased further at 2 days ( P &lt; 0.01); the water content of the brain did not change significantly at 2 h ( P &gt; 0.05) but increased significantly 2 d after the injury ( P &lt; 0.01). Treatment with the ERK inhibitor significantly lowered the permeability of blood-brain barrier and brain water content after brain trauma ( P &lt; 0.01)., Conclusions: Blocking the activation of ERK pathway significantly reduced the over-expression of MMP-9 and alleviates the damage of blood-brain barrier and traumatic brain edema, suggesting that ERK signaling pathway plays an important role in traumatic brain edema by regulating the expression of MMP-9.

Objective: To explore the role of p38 signal pathway in regulating matrix metalloproteinase-9 (MMP-9) expression and brain edema formation in a rat model of traumatic brain injury (TBI)., Methods: A total of 130 adult male Sprague Dawley rats were randomly divided into 4 groups, namely the normal group (n=10), sham-operated group (n=40), TBI (induced by Feeney free falling methods) group (n=40), and SB group with intraperitoneal SB203580 treatment (10 µmol/L) 15 min before TBI (n=40). The rats were sacrificed 2 h and 2 days after TBI. The expressions of p38, p-p38, and MMP-9 mRNA and protein were detected by RT-PCR and Western blotting. The blood brain barrier permeability was detected by Evans Blue (EB) test, and the brain water content (BWC) was determined using a gravimetric technique., Results: The expression of p-p38 protein increased markedly 2 h after TBI (P<0.05), and was suppressed by SB203580 treatment (P<0.05). MMP-9 mRNA and protein showed no obvious increase at 2 h after TBI, but significantly increased at 2 days as compared with those in the sham-operated group (P<0.05). MMP-9 mRNA and protein were much lower in SB group than in TBI group 2 days after TBI (P<0.05). The blood brain barrier permeability significantly increased 2 h after TBI (P<0.05) and kept increasing until 2 days (P<0.05), but was reduced significantly by SB203580 (P<0.05). BWC increased obviously 2 days after TBI (P<0.05) and was lessened by SB203580 (P<0.05)., Conclusion: Blocking p38 signal pathway can attenuate MMP-9 upregulation and brain edema after TBI, suggesting the important role of p38 in regulating MMP-9 expression to affect traumatic brain edema.

Objective: To explore the role of P38 signaling pathway in neonatal rat astrocyte swelling and the expression of aquaporin-4 (AQP4) after oxygen-glucose deprivation (OGD) and recovery (OGD/R)., Methods: Primarily cultured neonatal rat astrocytes were subject to OGD for 5 h followed by oxygen-glucose recovery in the presence or absence of the P38 inhibitor SB203580 (10 µmol/L). The astrocytes were investigated at 0.5, 2, 8 and 24 h after oxygen-glucose recovery for morphological changes and cell injuries using lactate dehydrogenase (LDH) assay. The expressions of P38, P-P38, and AQP4 mRNAs and proteins in the astrocytes were detected using RT-PCR and Western blotting., Results: OGD/R caused significantly enhanced expression of P-P38 protein, and this effect was blocked by SB203580. AQP4 mRNA and protein expression declined transiently at 0.5 h after OGD and increased gradually to reach the peak level at 8 h (P<0.05). Application of the SB203580 significantly lowered OGD-induced AQP4 mRNA and protein up-regulation (P<0.05). Astrocyte swelling occurred after OGD/R but was obviously lessened by SB203580. LDH release increased markedly after OGD/R, and was attenuated by treatment with SB203580 (P<0.01)., Conclusion: P38 signaling pathway participates in astrocyte swelling after OGD/R, and blocking this pathway can attenuate AQP4 up-regulation and ameliorate the cell swelling.