Pathogenesis Of Spinal Cord Injury Research Articles

Activation of the sigma-1 receptor ameliorates neuronal ferroptosis via IRE1α after spinal cord injury

Spinal Cord Injury (SCI) is a debilitating disease associated with a significant economic burden owing to its high level of disability; however, current treatment options have only limited efficacy. Past research has shown that iron-dependent programmed cell death, also known as ferroptosis, plays a critical role in the pathogenesis of SCI. The sigma-1 receptor (Sig-1R) is widely distributed in the central nervous system, and has been implicated in the pathophysiology of several neurological and psychiatric disorders. Several in vivo and ex vivo studies have shown that Sig-1R activation exerts unique neuroprotective effects. However, the underlying mechanisms remain unclear. To date, no study has yet demonstrated the association between Sig-1R activation and ferroptosis in patients with SCI. However, the present study found that Sig-1R activation effectively promoted the recovery of motor function in mice after spinal cord injury, attenuated neuronal apoptosis, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited ferroptosis in spinal cord tissues following SCI in mice. Ferroptosis and IRE1α were significantly upregulated after spinal cord injury, while sigma-1 receptor agonists were able to facilitate this result through the elimination of inositol-requiring enzyme-1 alpha (IRE1α)-mediated neuronal ferroptosis. Therefore, sigma-1 receptor activation could attenuate ferroptosis after SCI by reducing IRE1α and improving functional recovery after SCI, potentially representing a new therapeutic strategy for treating SCI.

The effects of hyaluronan and proteoglycan link protein 1 (HAPLN1) in ameliorating spinal cord injury mediated by Nrf2.

Excessive inflammatory response and oxidative stress (OS) play an important role in the pathogenesis of spinal cord injury (SCI). Balance of inflammation and prevention of OS have been considered an effective strategy for the treatment of SCI. Hyaluronan and proteoglycan link protein 1 (HAPLN1), also known as cartilage link protein, has displayed a wide range of biological and physiological functions in different types of tissues and cells. However, whether HAPLN1 regulates inflammation and OS during SCI is unknown. Therefore, we aimed to examine whether HAPLN1 can have a protective effect on SCI. In this study, both in vitro and in vivo SCI models were established. Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays were used. Western blotting and enzyme-linked immunosorbent assay were employed to assess the expression of proteins. Our results demonstrate that the administration of HAPLN1 promoted the recovery of motor neurons after SCI by increasing the Basso mouse scale score, increasing the numbers of motor neurons, and preventing apoptosis of spinal cord cells. Additionally, HAPLN1 mitigated OS in spinal cord tissue after SCI by increasing the content of superoxide dismutase SOD and the activity of glutathione peroxidase but reducing the levels of malondialdehyde. Importantly, we found that HAPLN1 stimulated the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and stimulated the expression of heme oxygenase-1 and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase-1, which mediated the attenuation of HAPLN1 in activation of the NOD-like receptor protein 3 (NLRP3) inflammasome by reducing the levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β. Correspondingly, in vitro experiments show that the presence of HAPLN1 suppressed the NLRP3 inflammasome and prevented cell injury against H2O2 in PC12 cells. These effects were mediated by the Nrf2/ARE pathway, and inhibition of Nrf2 with ML385 abolished the beneficial effects of HAPLN1. Based on these findings, we conclude that HAPLN1 inhibits the NLRP3 inflammasome through the stimulation of the Nrf2/ARE pathway, thereby suppressing neuroinflammation, enhancing motor neuronal survival, and improving the recovery of nerve function after SCI.

Identification of key autophagy-related genes and pathways in spinal cord injury

Spinal cord injury (SCI) can cause a range of functional impairments, and patients with SCI have limited potential for functional recovery. Previous studies have demonstrated that autophagy plays a role in the pathological process of SCI, but the specific mechanism of autophagy in this context remains unclear. Therefore, we explored the role of autophagy in SCI by identifying key autophagy-related genes and pathways. This study utilized the GSE132242 expression profile dataset, which consists of four control samples and four SCI samples; autophagy-related genes were sourced from GeneCards. R software was used to screen differentially expressed genes (DEGs) in the GSE132242 dataset, which were then intersected with autophagy-related genes to identify autophagy-related DEGs in SCI. Subsequently, the expression levels of these genes were confirmed and analyzed with gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein–protein interaction (PPI) analysis was conducted to identify interaction genes, and the resulting network was visualized with Cytoscape. The MCODE plug-in was used to build gene cluster modules, and the cytoHubba plug-in was applied to screen for hub genes. Finally, the GSE5296 dataset was used to verify the reliability of the hub genes. We screened 129 autophagy-related DEGs, including 126 up-regulated and 3 down-regulated genes. GO and KEGG pathway enrichment analysis showed that these 129 genes were mainly involved in the process of cell apoptosis, angiogenesis, IL-1 production, and inflammatory reactions, the TNF signaling pathway and the p53 signaling pathway. PPI identified 10 hub genes, including CCL2, TGFB1, PTGS2, FN1, HGF, MYC, IGF1, CD44, CXCR4, and SERPINEL1. The GSE5296 dataset revealed that the control group exhibited lower expression levels than the SCI group, although only CD44 and TGFB1 showed significant differences. This study identified 129 autophagy-related genes that might play a role in SCI. CD44 and TGFB1 were identified as potentially important genes in the autophagy process after SCI. These findings provide new targets for future research and offer new perspectives on the pathogenesis of SCI.

Advancements and mechanisms of stem cell-based therapies for spinal cord injury in animals.

Spinal cord injury (SCI) is a neurodegenerative disorder of the central nervous system (CNS) that can lead to permanent loss of sensation and voluntary movement beyond the affected area. Extensive preclinical and clinical trials have been conducted to evaluate the safety and effectiveness of stem cells for the treatment of various CNS diseases or disorders, including SCI. However, several challenges hinder nerve cell regeneration in the injured spinal cord, such as extensive cell loss, limited neural cell regeneration capacity, axonal disruption, and the presence of growth-inhibiting molecules, particularly astroglial scarring or glial scars at the injury site in chronic cases. These obstacles pose significant challenges for physicians in restoring normal motor and sensory nerve function in both humans and animals following SCI. This review focuses on SCI pathogenesis, the mechanisms underlying the therapeutic potential of Mesenchymal Stem Cells (MSCs) in SCI, and the potential of stem cell-based therapies as promising avenues for treatment. This review article also included relevant preclinical and clinical data from animal studies.

Machine learning and experiments revealed a novel pyroptosis-based classification linked to diagnosis and immune landscape in spinal cord injury

BackgroundRising evidence indicates the development of pyroptosis in the initiation and pathogenesis of spinal cord injury (SCI). However, the associated effects of pyroptosis-related genes (PRGs) in SCI are unclear. MethodsWe obtained the gene expression profiles of SCI and normal samples in the GEO. DatabaseThe R package limma screened for differentially expressed (DE) PRGs and performed functional enrichment analysis. Mechanical learning and PPI analysis helped filter essential PRGs to diagnose SCI. Peripheral blood was collected for validation from ten SCI patients and eight healthy individuals. The association of essential PRGs with immune infiltration was evaluated, and pyroptosis subtypes were recognized in SCI patients by unsupervised cluster analysis. Besides, a SCI model was built for in vivo validation of essential PRGs. ResultWe identified 25 DE-PRGs between SCI and normal controls. Functional enrichment analysis revealed the principal involvement of DE-PRGs in pyroptosis, inflammasome complex, interleukin-1 beta production, etc. Subsequently, three essential PRGs were identified and validated, showing excellent diagnostic efficacy and significant correlation with immune cell infiltration. Additionally, we developed diagnostic nomograms to predict the occurrence of SCI. Two pyroptosis subtypes exhibited distinct biological functions and immune landscapes among SCI patients. Finally, the expression of these essential PRGswas verified in vivo. ConclusionThe current study described the vital effects of pyroptosis-related genes in SCI, providing a novel direction for effective assessment and management of SCI.

The Role of Interleukin-10 in the Pathogenesis and Treatment of a Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating condition that often leads to severe and permanent neurological deficits. The complex pathophysiology of an SCI involves a cascade of events, including inflammation, oxidative stress, and secondary injury processes. Among the myriad of molecular players involved, interleukin-10 (IL-10) emerges as a key regulator with the potential to modulate both the inflammatory response and promote neuroprotection. This comprehensive review delves into the intricate interplay of IL-10 in the pathogenesis of an SCI and explores its therapeutic implications in the quest for effective treatments. IL-10 has been found to regulate inflammation, oxidative stress, neuronal apoptosis, and glial scars after an SCI. Its neuroprotective properties have been evaluated in a plethora of animal studies. IL-10 administration, either isolated or in combination with other molecules or biomaterials, has shown neuroprotective effects through a reduction in inflammation, the promotion of tissue repair and regeneration, the modulation of glial scar formation, and improved functional outcomes. In conclusion, IL-10 emerges as a pivotal player in the pathogenesis and treatment of SCIs. Its multifaceted role in modulating inflammation, oxidative stress, neuronal apoptosis, glial scars, and neuroprotection positions IL-10 as a promising therapeutic target. The ongoing research exploring various strategies for harnessing the potential of IL-10 offers hope for the development of effective treatments that could significantly improve outcomes for individuals suffering from spinal cord injuries. As our understanding of IL-10's intricacies deepens, it opens new avenues for innovative and targeted therapeutic interventions, bringing us closer to the goal of alleviating the profound impact of SCIs on patients' lives.

Mechanism Study of Polydatin in Treating Spinal Cord Injury by Modulating Mitochondrial Membrane Potential Based on Network Pharmacology and Molecular Docking.

Spinal cord injury (SCI) is one of the most devastating central lesions, and mitochondrial function plays an important role in secondary injury after SCI. Polydatin (PD) is a natural glycosylated precursor of resveratrol, showing mitochondrial preservation effects in the central nervous system. This study aimed to identify the hub target genes of PD on mitochondrial membrane potential (MMP) in SCI. A comprehensive analysis was performed on SCI-related genes, MMP-related genes, and PD targets screening from public databases. Differential expression analysis was conducted to identify differentially expressed genes (DEGs) in SCI. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were employed to assess pathway enrichment. Protein-protein interaction (PPI) network analysis and molecular docking were conducted to identify key genes and evaluate the binding affinity between PD and hub genes. A total of 16,958 SCI-related genes, 2,786 MMP-related genes, 318 PD-related target genes, and 7229 DEGs were identified. Intersection analysis revealed 46 genes common to all four categories. GSEA and GSVA analysis identified significant enrichment of pathways associated with suppressed and activated SCI biological processes. The PPI network analysis identified seven core hub genes: EGFR, SRC, VEGFA, STAT3, ERBB2, TP53, and RHOA. Molecular docking revealed strong binding affinities between PD and ERBB2, EGFR, and RHOA. The findings based on computational investigation from public databases suggest that PD may have therapeutic potential for SCI by modulating MMP. These results contribute to the understanding of SCI pathogenesis and the development of novel therapeutic strategies.

Temporal profiling and validation of oxidative stress-related genes in spinal cord injury

Oxidative stress (OS) plays a pivotal role in the pathogenesis of spinal cord injury (SCI), yet its underlying mechanisms remain elusive. In this study, we explored the OS phenotype in a rat model of SCI. Subsequently, comprehensive bioinformatic analyses were conducted on microarray data pertaining to SCI (GSE45006). Notably, KEGG enrichment analysis revealed a pronounced enrichment of pivotal pathways, namely MAPK, FoxO, Apoptosis, NF-κB, TNF, HIF-1, and Chemokine across distinct phases of SCI. Furthermore, GO enrichment analysis highlighted the significance of biological processes including response to hypoxia, response to decrease oxygen levels, response to reactive oxygen species, cellular response to oxidative stress, reactive oxygen species metabolic process, and regulation of neuron death in the context of OS following SCI. Notably, our study underscores the prominence of nine genes, namely Itgb1, Itgam, Fn1, Icam1, Cd44, Cxcr4, Ptprc, Tlr4, and Tlr2 as OS key genes in SCI, consistently expressed in both the acute phase (1, 3, 7 days) and sub-acute phase (14 days). Subsequently, the relative mRNA expression of these key genes in different time points (1, 3, 7, 14 days) post-SCI. Finally, leveraging the DsigDB database, we predicted ten potential compounds potentially targeting OS and facilitating the repair of SCI, thus providing novel insights into the mechanisms underlying OS and identifying potential therapeutic targets for SCI.

PD-1 deficiency aggravates spinal cord injury by regulating the reprogramming of NG2 glia and activating the NgR/RhoA/ROCK signaling pathway

Spinal cord injury (SCI) is a devastating disorder and a leading cause of disability in adults worldwide. Multiple studies have reported the upregulation of programmed cell death 1 (PD-1) following SCI. However, the underlying mechanism of PD-1 deficiency in SCI is not well established. Therefore, we aimed to investigate the role and potential mechanism of PD-1 in SCI pathogenesis. PD-1 Knockout (KO) SCI mouse model was established, and PD-1 expression was evaluated in tissue samples by western blot assay. We then used a series of function gain-and-loss assays to determine the role of PD-1 in SCI pathogenesis. Moreover, mechanistic assays were performed to explore the association between PD-1, neuron-glia antigen-2 (NG2) glia cells, and miR-23b-5p and then investigated the involved signaling pathway. Results illustrated that PD-1 deficiency enhanced the inflammatory response, neuron loss, and functional impairment induced by SCI. We found that NG2 glia depletion aggravated inflammation, reduced neural survival, and suppressed locomotor recovery in murine SCI model. Further analysis indicated that NG2+ cells were increased in the spinal cord of SCI mice, and PD-1 deficiency increased the number of NG2+ cells by activating the Nogo receptor/ras homolog family member A/Rho kinase (NgR/RhoA/ROCK) signaling. Mechanistically, miR-23b-5p was identified as the negative regulator of PD-1 in NG2 glia. MiR-23b-5p deficiency reduced the expression of inflammatory cytokines, enhanced neural survival, and promoted locomotor recovery in SCI mice, which was counteracted by PD-1 deficiency. In conclusion, PD-1 deficiency exacerbates SCI in vivo by regulating reprogramming of NG2 glia and activating the NgR/RhoA/ROCK signaling.

VIRMA promotes neuron apoptosis via inducing m6A methylation of STK10 in spinal cord injury animal models.

Spinal cord injury (SCI) occurs as a devastating neuropathic disease. The role of serine-threonine kinase 10 (STK10) in the development of SCI remains unclear. This study aimed to investigate the action of m6A methylation on STK10 in the apoptosis of spinal cord neurons in the pathogenesis of SCI and the possible underlying mechanisms. Rat model of SCI was established and subsequently evaluated for motor function, pathological conditions, and apoptosis of spinal cord neurons. And the effects of overexpression of STK10 on neuronal cells in animal models of spinal cord injury and glyoxylate deprivation (OGD) cell models were evaluated. m6A2Target database and SRAMP database were used to predict the m6A methylation sites of STK10. The methylation kits were used to detect overall m6A methylation. Finally, the interaction between STK10 and vir like m6A methyltransferase associated (VIRMA) was explored in animal and cellular models. STK10 is markedly decreased in spinal cord injury models and overexpression of STK10 inhibits neuronal apoptosis. VIRMA can induce m6A methylation of STK10. VIRMA is over-expressed in spinal cord injury models and negatively regulates the expression of STK10. m6A methylation and apoptosis of neuronal cells are reduced by the knockdown of VIRMA and STK10 shRNA have shown the opposite effects. VIRMA promotes neuronal apoptosis in spinal cord injury by regulating STK10 m6A methylation.

The Role of Resveratrol on Spinal Cord Injury: from Bench to Bedside.

Spinal cord injury (SCI) is a severe and disabling injury of the central nervous system, with complex pathological mechanisms leading to sensory and motor dysfunction. Pathological processes, such as oxidative stress, inflammatory response, apoptosis, and glial scarring are important factors that aggravate SCI. Therefore, the inhibition of these pathological processes may contribute to the treatment of SCI. Currently, the pathogenesis of SCI remains under investigation as SCI treatment has not progressed considerably. Resveratrol, a natural polyphenol with anti-inflammatory and antioxidant properties, is considered a potential therapeutic drug for various diseases and plays a beneficial role in nerve damage. Preclinical studies have confirmed that signaling pathways are closely related to the pathological processes in SCI, and resveratrol is believed to exert therapeutic effects in SCI by activating the related signaling pathways. Based on current research on the pathways of resveratrol and its role in SCI, resveratrol may be a potentially effective treatment for SCI. This review summarizes the role of resveratrol in promoting the recovery of nerve function by regulating oxidative stress, inflammation, apoptosis, and glial scar formation in SCI through various mechanisms and pathways, as well as the deficiency of resveratrol in SCI research and the current and anticipated research trends of resveratrol. In addition, this review provides a background for further studies on the molecular mechanisms of SCI and the development of potential therapeutic agents. This information could also help clinicians understand the known mechanisms of action of resveratrol and provide better treatment options for patients with SCI.

Research progress of acupuncture-moxibustion in treatment of spinal cord injury through mediating inflammatory reaction

Inflammatory reaction after spinal cord injury (SCI) is the main obstacle to the recovery of neural function. In the occurrence and development of SCI, the complex regulatory mechanisms are involved in inflammatory reaction, including the activation of inflammatory cells (e.g.macrophages and microglia), and the release of cytokines (e.g. tumor necrosis factor, interleukin and chemokines). Acupuncture-moxibustion is significantly effective in clinical treatment of SCI, and its mechanism is related to adjusting the function of inflammatory cells after SCI, modulating the expression of cytokines and the activation of NLRP3 inflammatory bodies, as well as the expression of high mobility group protein B1 and calcitonin gene related peptide. This article summarizes the research progress of mechanism of inflammatory reaction after SCI and the effects of acupuncture-moxibustion intervention in recent years so that the new ideas can be provided to clarify the pathogenesis of SCI and the effect of acupuncture-moxibustion intervention.

Long-term changes of Th17 and regulatory T cells in peripheral blood of dogs with spinal cord injury after intervertebral disc herniation

BackgroundIntervertebral disc herniation (IVDH) is one of the most common causes of spinal cord injury (SCI) in dogs. As a result of acute SCI, a complex inflammatory response occurs in the spinal cord. Th17 cells (Th17) produce pro-inflammatory cytokines, while regulatory T cells (Treg) have opposite effects producing anti-inflammatory cytokines. Therefore, the aim of this study was to determine whether Th17- and Treg cells are involved in the pathogenesis of SCI or whether cellular changes occur due to coexisting inflammatory diseases. We hypothesized that chronic alterations in the Th17/Treg ratio are associated with a worse outcome after SCI.MethodsTwenty-six paretic or plegic dogs with IVDH with and without coexisting inflammatory disease were investigated in the acute stage of the disease and after recovery of SCI. In addition, a healthy control group was included (n = 14). Quantification of Th17 and Treg cells, from peripheral blood samples, was performed by multicolor flow cytometry and IL17 was measured using an enzyme-linked immunosorbent assay (ELISA).ResultsAfter recovery significantly higher levels of Th17 (p = 0.0265) and Treg cells (p = 0.00025) were detected compared to acute IVDH but Th17/Treg ratio did not differ significantly. Recovered dogs and the control group did not differ significantly from each other. No association between an imbalance in the ratio and neurologic severity or underlying inflammatory diseases was found.ConclusionThis study demonstrated that altered Th17 and Treg levels in peripheral blood are altered in the acute stage of IVDH, preexisting inflammatory diseases seem not to influence these cell populations. Th17 and Treg cells could be considered when evaluating new treatment strategies for SCI.

Inhibition of TANK-binding kinase1 attenuates the astrocyte-mediated neuroinflammatory response through YAP signaling after spinal cord injury.

TANK-binding kinase 1 (TBK1) is involved in regulating the pathological process of a variety of inflammatory diseases in the central nervous system. However, its role and underlying molecular mechanisms in spinal cord injury (SCI) remain largely unknown. We employed the TBK1 inhibitor amlexanox (ALX) to address this question. An in vivo clip-compressive SCI model and in vitro lipopolysaccharide (LPS)-induced astrocyte inflammation model were established to examine the effects of TBK1 inhibition on the expression of proinflammatory cytokines. In this study, we found that TBK1 and TBK1-medicated innate immune pathways, such as TBK1/IRF3 and noncanonical NF-κB signaling, were activated in astrocytes and neurons after SCI. Furthermore, inhibition of TBK1 by ALX alleviated neuroinflammation response, reduced the loss of motor neurons, and improved the functional recovery after SCI. Mechanistically, inhibition of TBK1 activity promoted the activation of the noncanonical NF-κB signaling pathway and inhibited p-IRF3 activity in LPS-induced astrocytes, and the TBK1 activity was required for astrocytic activation through yes-associated protein (YAP) signaling after SCI and in LPS-induced astrocytes inflammation model. TBK1-medicated innate immune pathway in astrocytes through YAP signaling plays an important role in the pathogenesis of SCI and inhibition of TBK1 may be a potential therapeutic drug for SCI.

CK2 inhibitor DMAT ameliorates spinal cord injury by increasing autophagy and inducing anti-inflammatory microglial polarization

Spinal cord injury (SCI) is a destructive and disabling nerve injury from which complete recovery has not yet been achieved due to complex pathology. Casein kinase II (CK2) is a pleiotropic serine/threonine protein kinase that plays an essential role in the nervous system. This study aimed to investigate the role of CK2 in SCI to understand the pathogenesis of SCI and explore new therapeutic methods. The SCI rat model of C5 unilateral clamp was established by modified clamp method in male adult SD rats. Then, CK2 inhibitor DMAT was used to treat SCI rats, and the behaviour, pathological changes in the spinal cord and microglial polarization were analysed. Additionally, the effects of DMAT on the polarization and autophagy of microglial BV-2 cells were investigated in vitro, and the effects of BV-2 polarization on spinal cord neuronal cells were analysed by Transwell coculture. Results showed that DMAT significantly increased the BBB score, improved histopathological injury, decreased the expression of inflammatory cytokines, and promoted M2 polarization of microglia in SCI rats. In vitro experiments further confirmed that DMAT could promote the polarization of BV-2 to the M2 type, promote autophagy, and reverse the LPS-induced decline in cell viability and increase in apoptosis of neuronal cells. The use of 3-MA confirmed that autophagy plays an important role in DMAT promoting M2 polarization of BV-2 to improve neuronal cell viability. In conclusion, CK2 inhibitor DMAT improved SCI by inducing anti-inflammatory polarization of microglia through autophagy and is a potential therapeutic target for SCI.

CircSmox knockdown alleviates PC12 cell apoptosis and inflammation in spinal cord injury by miR‐340‐5p/Smurf1 axis

Spinal cord injury (SCI) is a traumatic central nervous system disorder that leads to irreversible neurological dysfunction. Emerging evidence has shown that differentially expressed circular RNAs (circRNAs) after SCI is closely associated with the pathophysiological process. Herein, the potential function of circRNA spermine oxidase (circSmox) in functional recovery after SCI was investigated. Differentiated PC12 cells stimulated with lipopolysaccharide (LPS) were employed as an in vitro model for neurotoxicity research. Levels of genes and proteins were detected by quantitative real-time PCR and Western blot analysis. Cell viability and apoptosis were determined by CCK-8 assay and flow cytometry. Western blot analysis was used to detect the protein level of apoptosis-related markers. The levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Dual-luciferase reporter, RIP, and pull-down assays were used to confirm the target relationship between miR-340-5p and circSmox or Smurf1 (SMAD Specific E3 Ubiquitin Protein Ligase 1). LPS elevated the levels of circSmox and Smurf1, but decreased the levels of miR-340-5p in PC12 cells in a dose-dependent manner. Functionally, circSmox silencing alleviated LPS-induced apoptosis and inflammation in PC12 cells in vitro. Mechanistically, circSmox directly sponged miR-340-5p, which targeted Smurf1. Rescue experiments showed that miR-340-5p inhibition attenuated the neuroprotective effect of circSmox siRNA in PC12 cells. Moreover, miR-340-5p suppressed LPS-triggered neurotoxicity in PC12 cells, which was reversed by Smurf1 overexpression. CircSmox enhances LPS-induced apoptosis and inflammation via miR-340-5p/Smurf1 axis, providing an exciting view of the potential involvement of circSmox in SCI pathogenesis.

Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury.

Maintaining the integrity of the blood-spinal cord barrier is critical for the recovery of spinal cord injury. Ferroptosis contributes to the pathogenesis of spinal cord injury. We hypothesized that ferroptosis is involved in disruption of the blood-spinal cord barrier. In this study, we administered the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal cord injury in rats. Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord injury. Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein. Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury, as shown by the immunofluorescence of an endothelial cell marker (rat endothelium cell antigen-1, RECA-1) and ferroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Liproxstatin-1 reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Furthermore, inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment. In summary, liproxstatin-1 improved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-spinal cord barrier integrity.

The gut microbiota and metabolite profiles are altered in patients with spinal cord injury

BackgroundMetabolites secreted by the gut microbiota may play an essential role in microbiota–gut–central nervous system crosstalk. In this study, we explored the changes occurring in the gut microbiota and their metabolites in patients with spinal cord injury (SCI) and analyzed the correlations among them.MethodsThe structure and composition of the gut microbiota derived from fecal samples collected from patients with SCI (n = 11) and matched control individuals (n = 10) were evaluated using 16S rRNA gene sequencing. Additionally, an untargeted metabolomics approach was used to compare the serum metabolite profiles of both groups. Meanwhile, the association among serum metabolites, the gut microbiota, and clinical parameters (including injury duration and neurological grade) was also analyzed. Finally, metabolites with the potential for use in the treatment of SCI were identified based on the differential metabolite abundance analysis.ResultsThe composition of the gut microbiota was different between patients with SCI and healthy controls. At the genus level, compared with the control group, the abundance of UBA1819, Anaerostignum, Eggerthella, and Enterococcus was significantly increased in the SCI group, whereas that of Faecalibacterium, Blautia, Escherichia–Shigella, Agathobacter, Collinsella, Dorea, Ruminococcus, Fusicatenibacter, and Eubacterium was decreased. Forty-one named metabolites displayed significant differential abundance between SCI patients and healthy controls, including 18 that were upregulated and 23 that were downregulated. Correlation analysis further indicated that the variation in gut microbiota abundance was associated with changes in serum metabolite levels, suggesting that gut dysbiosis is an important cause of metabolic disorders in SCI. Finally, gut dysbiosis and serum metabolite dysregulation was found to be associated with injury duration and severity of motor dysfunction after SCI.ConclusionsWe present a comprehensive landscape of the gut microbiota and metabolite profiles in patients with SCI and provide evidence that their interaction plays a role in the pathogenesis of SCI. Furthermore, our findings suggested that uridine, hypoxanthine, PC(18:2/0:0), and kojic acid may be important therapeutic targets for the treatment of this condition.

Cell Development Enhanced Bionic Silk Hydrogel on Remodeling Immune Pathogenesis of Spinal Cord Injury via M2 Polarization of Microglial

AbstractDue to the complex spatial‐temporal pathophysiology of spinal cord injury (SCI), effective modulation of SCI‐specific inflammatory pathogenesis to achieve desirable therapeutic effects on functional recovery still remains challenging. Herein, cell‐enhanced photocrosslinked silk fibroin hydrogels with extracellular matrix‐mimicking cues of mechanical properties and RGD (Arg‐Gly‐Asp) signals are gelled in situ to fill the lesion site to modulate injury‐induced neuroinflammation and promote neurite regrowth after SCI. The bionic hydrogel system provides biomimetic mechanical cues to promote neuronal differentiation of neural stem/progenitor cells (NPCs) and neurite growth by activating YAP nuclear expression. Importantly, favored by the strong capacity of silk fibroin hydrogels on macrophage/microglia recruitment, NPCs encapsulated hydrogel (NPCs@SFRGD0.1) effectively promotes recruited macrophages/microglia to M2 polarization in the lesion site by releasing S100A4 and thereby remodels the inflammatory microenvironment after SCI. Moreover, NPCs@SFRGD0.1 successfully reduces glial scar formation and accelerates corticospinal tract axon regrowth to improve locomotor recovery. Overall, this work contributes to illustrating the therapeutic mechanism of NPCs development based biomaterial therapies on modulating inflammatory microenvironment and this NPCs enhanced silk fibroin hydrogel provides a promising therapeutic strategy for SCI.

Circulating exosomal lncRNA contributes to the pathogenesis of spinal cord injury in rats.

Exosome-derived long non-coding RNAs (lncRNAs) are extensively engaged in recovery and repair of the injured spinal cord, through different mechanisms. However, to date no study has systematically evaluated the differentially expressed lncRNAs involved in the development of spinal cord injury. Thus, the aim of this study was to identify key circulating exosome-derived lncRNAs in a rat model of spinal cord injury and investigate their potential actions. To this end, we established a rat model of spinal cord hemisection. Circulating exosomes were extracted from blood samples from spinal cord injury and control (sham) rats and further identified through Western blotting and electron microscopy. RNA was isolated from the exosomes and sequenced. The enrichment analysis demonstrated that there were distinctively different lncRNA and mRNA expression patterns between the two groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional analysis were performed to determine the possible involvements of upregulated and downregulated lncRNAs in various pathways and different biological processes, as well as their cellular locations and molecular functions. Furthermore, quantitative reverse transcription-polymerase chain reaction showed that the expression of five lncRNAs--ENSRN0T00000067908, XR_590093, XR_591455, XR_360081, and XR_346933--was increased, whereas the expression of XR_351404, XR_591426, XR_353833, XR_590076, and XR_590719 was decreased. Of note, these 10 lncRNAs were at the center of the lncRNA-miRNA-mRNA coexpression network, which also included 198 mRNAs and 41 miRNAs. Taken together, our findings show that several circulating exosomal lncRNAs are differentially expressed after spinal cord injury, suggesting that they may be involved in spinal cord injury pathology and pathogenesis. These lncRNAs could potentially serve as targets for the clinical diagnosis and treatment of spinal cord injury.