Fisetin orchestrates neuroinflammation resolution and facilitates spinal cord injury recovery through enhanced autophagy in pro-inflammatory glial cells.

BACKGROUND: Neuroinflammation, a critical component of the secondary injury cascade post-spinal cord injury, involves the activation of pro-inflammatory cells and release of inflammatory mediators. Resolution of neuroinflammation is closely linked to cellular autophagy. This study investigates the potential of Fisetin, a natural anti-inflammatory compound, to ameliorate neuroinflammation and confer spinal cord injury protection through the regulation of autophagy in pro-inflammatory cells. METHODS: Utilizing a rat T10 spinal cord injury model with distinct treatment groups (Sham, Fisetin-treated, and Fisetin combined with autophagy inhibitor), alongside in vitro models involving lipopolysaccharide (LPS)-stimulated microglial cell activation and co-culture with neurons, we employed techniques such as transcriptomic sequencing, histological assessments (immunofluorescence staining, etc.), molecular analyses (PCR, WB, ELISA, etc.), and behavioral evaluations to discern differences in neuroinflammation, autophagy, neuronal apoptosis, and neurological function recovery. RESULTS: Fisetin significantly augmented autophagic activity in injured spinal cord tissue, crucially contributing to neurological function recovery in spinal cord-injured rats. Fisetin's autophagy-dependent effects were associated with a reduction in neuronal apoptosis at the injury site. The treatment reduced the population of CD68+ and iNOS+ cells, coupled with decreased pro-inflammatory cytokines IL-6 and TNF-α levels, through autophagy-dependent pathways. Fisetin pre-treatment attenuated LPS-induced pro-inflammatory polarization of microglial cells, with this protective effect partially blocked by autophagy inhibition. Fisetin-induced autophagy in the injured spinal cord and pro-inflammatory microglial cells was associated with significant activation of AMPK and inhibition of mTOR. CONCLUSION: Fisetin orchestrates enhanced autophagy in pro-inflammatory microglial cells through the AMPK-mTOR signaling pathway, thereby mitigating neuroinflammation and reducing the apoptotic effects of neuroinflammation on neurons. This mechanistic insight significantly contributes to the protection and recovery of neurological function following spinal cord injury, underscoring the vital nature of Fisetin as a potential therapeutic agent.

Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway.

Background: The JAK/STAT signaling pathway is the main inflammatory signal transduction pathway, whether JAK/STAT contributes the pathology of SCI and targeting the pathway will alleviate SCI needs to be addressed. Here, we explored the therapeutic effect of pan-JAK inhibitor tofacitinib (TOF) on secondary injury after SCI and explained the underlying mechanisms. Methods: SCI model in rat was established to evaluate the therapeutic effects of TOF treatment in vivo. Histological and behavioral analyses were performed at different time points after SCI. In vitro, the effects of TOF on pro-inflammatory activation of primary microglia and BV2 cells were analyzed by western blot analysis, fluorescent staining, qPCR and flow cytometry. The neuroprotection of TOF was detected using a co-culture system with primary neurons and microglia. Results: TOF can effectively improve motor dysfunction caused by spinal cord injury in rats. TOF administration in the early stage of inflammation can effectively inhibit neuronal apoptosis and scar tissue formation, and promote the repair of axons and nerve fibers. Further studies have demonstrated that TOF suppresses inflammation caused by spinal cord injury by inhibiting the activation of microglia to pro-inflammatory phenotype in vivo and in vitro. Additionally, an interesting phenomenon is revealed in our results that TOF exhibits superior neuronal protection during inflammation in vitro. Conclusions: Our study showed that TOF could regulate microglial activation via JAK / STAT pathway and promote the recovery of motor function after SCI, which is of great significance for the immunotherapy of SCI.

The association of rod curvature with postoperative outcomes in patients undergoing posterior lumbar interbody fusion for spinal stenosis: a retrospective case-control study.

BACKGROUND: Restoration of sagittal balance is a crucial consideration in posterior lumbar interbody fusion (PLIF) surgery and adverse postoperative outcomes are associated with inadequate restoration of sagittal alignment. However, there remains a shortage of substantial evidence regarding the effect of rod curvature on both sagittal spinopelvic radiographic parameters and clinical outcomes. METHOD: A retrospective case-control study was conducted in this study. Patient demographics (age, gender, height, weight and BMI), surgical characteristics (number of fused levels, surgical time, blood loss and hospital stay) and radiographic parameters (lumbar lordosis [LL], sacral slope [SS], pelvic incidence [PI], pelvic tilt [PT], PI-LL, Cobb angle of fused segments [Cobb], rod curvature [RC], Posterior tangent angle of fused segments [PTA] and RC-PTA) were analyzed. RESULTS: Patients in the abnormal group had older mean age and suffered more blood loss than those in the normal group. In addition, RC and RC-PTA were significantly lower in the abnormal group compared to the normal group. Multivariate regression analysis revealed that lower age (OR = 0.94; 95% CI: 0.89-0.99; P = 0.0187), lower PTA (OR = 0.91; 95% CI: 0.85-0.96; P = 0.0015) and higher RC (OR = 1.35; 95% CI: 1.20-1.51; P < 0.0001) were related to higher odds of better surgical outcomes. The receiver operating characteristic curve analysis showed that the ROC curve (AUC) for predicting outcomes of surgery by RC classifier was 0.851 (0.769-0.932). CONCLUSIONS: In patients who underwent PLIF surgery for lumbar spinal stenosis, those who had a satisfactory postoperative outcome tended to be younger, had lower blood loss, and higher values of RC and RC-PTA compared to those who had poor recovery and required revision surgery. Additionally, RC was found to be a reliable predictor of postoperative outcomes.

Biomechanical Evaluation of the Cross-link Usage and Position in the Single and Multiple Segment Posterior Lumbar Interbody Fusion.

OBJECTIVE: Previous studies have neither explored the usage of cross-links nor investigated the optimal position of the cross-links in posterior lumbar interbody fusion (PLIF). This study evaluates biomechanical properties of cross-links in terms of different fixation segments and optimal position in single- and multi-segment posterior lumbar interbody fusion. METHODS: Two finite element (FE) models of instrumented lumbosacral spine with single-(L4/5) and multi-segment (L3-S1) PLIF surgery were simulated. On the basis of the two models, the benefits of the usage of cross-links were assessed and compared with the status of no application of cross-links. Moreover, the effects of position of cross-links on multi-segment PLIF surgery were studied in Upper, Middle, and Lower positions. RESULTS: No significant difference was found in the range of motion (ROM), intersegmental rotational angle (IRA) of adjacent segments, and intradiscal pressure (IDP) regardless of the usage of cross-links in the single-segment PLIF surgery, while the cross-link increased the maximum von Mises stress in the fixation (MSF) under the axial rotation (53.65 MPa vs 41.42 MPa). In the multi-segment PLIF surgery, the usage of cross-links showed anti-rotational advantages indicated by ROM (Without Cross-link 2.35o , Upper, 2.24o ; Middle, 2.26o ; Lower, 2.30o ) and IRA (Without Cross-link 1.19o , Upper, 1.08o ; Middle, 1.09o ; Lower, 1.13o ). The greatest values of MSF were found in without cross-link case under the flexion, lateral bending, and axial rotation (37.48, 62.61, and 86.73 MPa). The application of cross-links at the Middle and Lower positions had lower values of MSF (48.79 and 69.62 MPa) under the lateral bending and axial rotation, respectively. CONCLUSION: The application of cross-links was not beneficial for the single-segment PLIF, while it was found highly advantageous for the multi-segment PLIF. Moreover, the usage of cross-links at the Middle or Lower positions resulted in a better biomechanical stability.

Inhibition of IL1R1 or CASP4 attenuates spinal cord injury through ameliorating NLRP3 inflammasome-induced pyroptosis.

Spinal cord injury (SCI) is a devastating trauma characterized by serious neuroinflammation and permanent neurological dysfunction. However, the molecular mechanism of SCI remains unclear, and few effective medical therapies are available at present. In this study, multiple bioinformatics methods were used to screen out novel targets for SCI, and the mechanism of these candidates during the progression of neuroinflammation as well as the therapeutic effects were both verified in a rat model of traumatic SCI. As a result, CASP4, IGSF6 and IL1R1 were identified as the potential diagnostic and therapeutic targets for SCI by computational analysis, which were enriched in NF-κB and IL6-JAK-STATA3 signaling pathways. In the injured spinal cord, these three signatures were up-regulated and closely correlated with NLRP3 inflammasome formation and gasdermin D (GSDMD) -induced pyroptosis. Intrathecal injection of inhibitors of IL1R1 or CASP4 improved the functional recovery of SCI rats and decreased the expression of these targets and inflammasome component proteins, such as NLRP3 and GSDMD. This treatment also inhibited the pp65 activation into the nucleus and apoptosis progression. In conclusion, our findings of the three targets shed new light on the pathogenesis of SCI, and the use of immunosuppressive agents targeting these proteins exerted anti-inflammatory effects against spinal cord inflammation by inhibiting NF-kB and NLRP3 inflammasome activation, thus blocking GSDMD -induced pyroptosis and immune activation.

Biomechanical and Clinical Study of Rod Curvature in Single-Segment Posterior Lumbar Interbody Fusion.

Objective: Pedicle screw fixation is a common technique used in posterior lumbar interbody fusion (PLIF) surgery for lumbar disorders. During operation, rod contouring is often subjective and not satisfactory, but only few studies focused on the rod-contouring issue previously. The aim of the study was to explore the effect of the rod contouring on the single-segment PLIF by the finite element (FE) method and retrospective study. Methods: A FE model of the lumbosacral vertebrae was first reconstructed, and subsequently single-segmental (L4/5) PLIF surgeries with four rod curvatures (RCs) were simulated. Herein, three RCs were designed by referring to centroid, Cobb, and posterior tangent methods applied in the lumbar lordosis measurement, and zero RC indicating straight rods was included as well. Clinical data of patients subjected to L4/5 segmental PLIF were also analyzed to verify the correlation between RCs and clinical outcome. Results: No difference was observed among the four RC models in the range of motion (ROM), intersegmental rotation angle (IRA), and intradiscal pressure (IDP) under four actions. The posterior tangent model had less maximum stress in fixation (MSF) in flexion, extension, and axial rotation than the other RC models. Patients with favorable prognosis had larger RC and positive RC minus posterior tangent angle (RC-PTA) of fused segments with respect to those who had poor prognosis and received revision surgery. Conclusion: All RC models had similar biomechanical behaviors under four actions. The posterior tangent-based RC model was superior in fixation stress distribution compared to centroid, Cobb, and straight models. The retrospective study demonstrated that moderate RC and positive RC-PTA were associated with better postoperative results.

Drug Discovery in Spinal Cord Injury With Ankylosing Spondylitis Identified by Text Mining and Biomedical Databases.

Spinal cord injury (SCI) and ankylosing spondylitis (AS) are common inflammatory diseases in spine surgery. However, it is a project where the relationship between the two diseases is ambiguous and the efficiency of drug discovery is limited. Therefore, the study aimed to investigate new drug therapies for SCI and AS. First, text mining was used to obtain the interacting genes related to SCI and AS, and then, the functional analysis was conducted. Protein-protein interaction (PPI) networks were constructed by STRING online and Cytoscape software to identify hub genes. Last, hub genes and potential drugs were performed after undergoing drug-gene interaction analysis, and MicroRNA and transcription factors regulatory networks were also analyzed. Two hundred five genes common to "SCI" and "AS" identified by text mining were enriched in inflammatory responses. PPI network analysis showed that 30 genes constructed two significant modules. Ultimately, nine (SST, VWF, IL1B, IL6, CXCR4, VEGFA, SERPINE1, FN1, and PROS1) out of 30 genes could be targetable by a total of 13 drugs. In conclusion, the novel core genes contribute to a novel insight for latent functional mechanisms and present potential prognostic indicators and therapeutic targets in SCI and AS.

Real-Time Evaluation of the Signal Processing of sEMG Used in Limb Exoskeleton Rehabilitation System.

As an important branch of medical robotics, a rehabilitation training robot for the hemiplegic upper limbs is a research hotspot of rehabilitation training. Based on the motion relearning program, rehabilitation technology, human anatomy, mechanics, computer science, robotics, and other fields of technology are covered. Based on an sEMG real-time training system for rehabilitation, the exoskeleton robot still has some problems that need to be solved in this field. Most of the existing rehabilitation exoskeleton robotic systems are heavy, and it is difficult to ensure the accuracy and real-time performance of sEMG signals. In this paper, we design a real-time training system for the upper limb exoskeleton robot based on the EMG signal. It has four main characteristics: light weight, portability, high precision, and low delay. This work includes the structure of the rehabilitation robotic system and the method of signal processing of the sEMG. An experiment on the accuracy and time delay of the sEMG signal processing has been done. In the experimental results, the recognition accuracy of the sEMG is 94%, and the average delay time is 300 ms, which meets the accuracy and real-time requirements.