Single-cell RNA sequencing integrated with bulk RNA sequencing analysis reveals the protective effects of lactate-mediated lactylation of microglia-related proteins on spinal cord injury.

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) results in significant neurological deficits, and microglia play the critical role in regulating the immune microenvironment and neurological recovery. Protein lactylation has been found to modulate the function of immune cells. Therefore, this study aimed to elucidate the effects of glycolysis-derived lactate on microglial function and its potential neuroprotective mechanisms via lactylation after SCI. METHODS: Single-cell RNA sequencing (scRNA-seq) data were obtained from figshare to analyze cellular and molecular alterations within the spinal cord post-SCI, further focusing on the expression of microglia-related genes for cell sub-clustering, trajectory analysis, and glycolysis function analysis. We also evaluated the expression of lactylation-related genes in microglia between day 7 after SCI and sham group. Additionally, we established the mice SCI model and performed the bulk RNA sequencing in a time-dependent manner. The expression of glycolysis- and lactylation-related genes was evaluated, as well as the immune infiltration analysis based on the lactylation-related genes. Then, we investigated the bio-effects of lactate on the inflammation and polarization phenotype of microglia. Finally, adult male C57BL/6 mice were subjected to exercise first to increase lactate level, before SCI surgery, aiming to evaluate the protective effects of lactate-mediated lactylation of microglia-related proteins on SCI. RESULTS: scRNA-seq identified a subcluster of microglia, recombinant chemokine C-X3-C-motif receptor 1+ (CX3CR1+) microglia, which is featured by M1-like phenotype and increased after SCI. KEGG analysis revealed the dysfunctional glycolysis in microglia after SCI surgery, and AUCell analysis suggested that the decreased glycolysis an increased oxidative phosphorylation in CX3CR1+ microglia. Differential gene analysis suggested that several lactylation-related genes (Fabp5, Lgals1, Vim, and Nefl) were downregulated in CX3CR1+ microglia at day 7 after SCI, further validated by the results from bulk RNA sequencing. Immunofluorescence staining indicated the expression of lactate dehydrogenase A (LDHA) in CX3CR1+ microglia also decreased at day 7 after SCI. Cellular experiments demonstrated that the administration of lactate could increase the lactylation level and inhibit the pro-inflammatory phenotype in microglia. Functionally, exercise-mediated lactate production resulted in improved locomotor recovery and decreased inflammatory markers in SCI mice compared to SCI alone. CONCLUSIONS: In the subacute phase of SCI, metabolic remodeling in microglia may be key therapeutic targets to promote nerve regeneration, and lactate contributed to neuroprotection after SCI by influencing microglial lactylation and inflammatory phenotype, which offered a novel approach for therapeutic intervention.

Enhanced Electrochemical Sensing of Oxalic Acid Based on VS2 Nanoflower-Decorated Glassy Carbon Electrode Prepared by Hydrothermal Method.

Oxalic acid (OA) is a predominant constituent in kidney stones, contributing to 70-80% of all cases. Rapid detection of OA is vital for the early diagnosis and treatment of kidney stone conditions. This work introduces a novel electrochemical sensing approach for OA, leveraging vanadium disulfide (VS2) nanoflowers synthesized via hydrothermal synthesis. These VS2 nanoflowers, known for their excellent electrocatalytic properties and large surface area, are used to modify glassy carbon electrodes for enhanced OA sensing. The proposed OA sensor exhibits high sensitivity and selectivity across a wide linear detection range of 0.2-20 µM, with an impressively low detection limit of 0.188 µM. The practicality of this sensor was validated through interference studies, offering a promising tool for the early diagnosis and monitoring of kidney stone diseases.

Modified Tracheal Traction Exercise Reduces the Incidence of Dysphagia in Patients with Multilevel Anterior Cervical Discectomy and Fusion.

OBJECTIVES: Dysphagia, an impairment in swallowing, is a frequent and debilitating complication for patients undergoing anterior cervical discectomy and fusion (ACDF), a common surgical treatment for degenerative cervical myelopathy (DCM). This retrospective study aimed to assess the efficacy of modified tracheal traction exercise (MTTE) in alleviating postoperative dysphagia and improving clinical outcomes for these patients. METHODS: A cohort of 143 patients underwent multilevel fusions, equally distributed between MTTE (n = 75) and traditional tracheal traction exercise (TTTE) (n = 68) groups. Demographic parity was observed in gender distribution, age averages (MTTE: 51.43 ± 11.25 years; TTTE: 52.35 ± 10.43 years), body mass index (BMI), comorbidities, fusion segments, and preoperative hospitalization days. Surgical duration differences were assessed. Clinical outcomes, dysphagia incidence, blood loss, postoperative complications, Cervical Japanese Orthopedic Association (c-JOA) scores, and functional outcome swallowing scale evaluations were conducted. Univariate and multivariate logistic regression analyses were used to explore factors influencing dysphagia. RESULTS: Modified tracheal traction exercise demonstrated advantages with a significantly lower dysphagia incidence (25.33% vs. 44.12%, p = 0.018), reduced blood loss (102.03 ± 17.04 vs. 113.46 ± 14.92, p < 0.001), shorter surgical durations (159.04 ± 9.82 vs. 164.41 ± 12.22 min, p = 0.004), and fewer postoperative complications (choking cough, cerebrospinal fluid leakage, and hoarseness). Postoperative c-JOA scores at 2 and 6 weeks favored MTTE, but no significant differences were observed at 12 and 24 weeks. Functional outcome swallowing scale evaluations favored MTTE with significantly higher percentages of "normal" and lower incidences of "mild" and "moderate dysphagia" at various postoperative intervals compared to TTTE. Factors significantly associated with dysphagia included MTTE, age, and BMI according to logistic regression analyses. CONCLUSION: Modified tracheal traction exercise demonstrates superior short-term outcomes in multilevel ACDF, showcasing reduced dysphagia incidence, blood loss, and specific postoperative complications. Notably, factors contributing to dysphagia, including operation technique and patient-related variables, emphasize the significance of MTTE and patient characteristics in optimizing postoperative outcomes in multilevel ACDF procedures.

A Novel "De-tension"-guided Anterior Decompression Strategy-Thoracic Anterior Controllable Antedisplacement Fusion (TACAF) for Multilevel Ossification of Posterior Longitudinal Ligament in Thoracic Spine: A Retrospective Study with at Least 2-Year Follow-Up.

OBJECTIVE: To propose a novel surgical strategy-thoracic anterior controllable antedisplacement fusion (TACAF) to treat multilevel thoracic ossification of the posterior longitudinal ligament (mT-OPLL), and investigate its safety and efficacy. METHODS: Between January 2019 and December 2021, a total of 49 patients with thoracic myelopathy due to mT-OPLL surgically treated with TACAF were retrospectively reviewed. Patients' demographic data, radiologic parameters, and surgery-related complications, modified Japanese Orthopedic Association (mJOA) and visual analog scale (VAS) scores, thoracic kyphosis (TK), kyphosis angle in fusion area (FSK), thoracic curvature, spinal cord curvature, and curvature of curved rod in surgical region, diameter, and area of the spinal cord at the most compressed level were included. RESULTS: All patients acquired satisfactory recovery of neurologic function and overall complication rate was low at the final follow up. The mean mJOA of the laminectomy+TACAF and Full Lamina Preservation +TACAF groups, respectively, was 3.74 ± 2.05, 3.67 ± 1.95 before surgery, and 9.97 ± 0.83, 9.80 ± 0.68 at the final followed up, with the recovery rate of 84.26% ± 14.20%, 82.79% ± 10.35%, as to VAS Scores. The mean FSK was 34.50 ± 4.46,35.33 ± 3.44 before surgery, and was restored to 20.97 ± 5.70, 22.93 ± 6.34 at the final followed up respectively, as to mean TK (P < 0.05). Spinal cord curvature was improved from 34.12 ± 3.59, 33.93 ± 3.45 before surgery to 19.47 ± 3.53, 18.80 ± 3.17 at the final follow-up respectively, as to thoracic curvature (P < 0.05). In addition, the area and diameter of the spinal cord was also significantly improved at the final follow up (all P < 0.05). The curvature of the thoracic pulp and thoracic vertebra is closely related to the curvature of the rod. There was no statistically significant difference in the incidence of the pelvis and the slope value of the sacrum. CONCLUSIONS: This strategy provides a novel solution for the treatment of mT-OPLL with favorable recovery of neurological function, the tension of spinal cord, and fewer complications.

Catalytic Nanodots-Driven Pyroptosis Suppression in Nucleus Pulposus for Antioxidant Intervention of Intervertebral Disc Degeneration.

Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.

A Clinical Classification of Cervical Ossification of the Posterior Longitudinal Ligament to Guide Surgical Strategy.

STUDY DESIGN: A clinical classification of cervical ossification of the posterior longitudinal ligament (COPLL) was developed based on imaging findings. OBJECTIVE: This study aimed to establish a clinical classification for COPLL and provide corresponding surgery strategies for each subtype. SUMMARY OF BACKGROUND DATA: A practical and reliable classification is needed to guide the treatment of COPLL. MATERIALS AND METHODS: This study retrospectively reviewed plain radiographs, computed tomography scans, and magnetic resonance images of patients diagnosed with COPLL between 2018 and 2022 at Shanghai Changzheng Hospital. The types of COPLL were classified according to the location, morphology, and canal-occupying ratio (OR) of the ossification mass. Interobserver and intraobserver reliability were evaluated using Cohen's kappa. RESULTS: A total of 1000 cases were included, which were classified into five types: focal type (F type), short-sequential type (S type), long-sequential type (L type), high type (H type), and mixed type (M type). In addition, each type could be classified into subtype 1 or subtype 2 according to the canal-OR. Then each type could be further classified into other subtypes according to location and morphology. The interobserver reliabilities in the first and second rounds were 0.853 and 0.887, respectively. The intraobserver reliability was 0.888. CONCLUSION: The authors classified COPLL into a system comprised of five types and several subtypes according to canal-OR, location, and morphology. Surgical strategies for each subtype are also suggested. This provides a theoretical guide for the description and surgical management of COPLL.

Sympathetic Neurotransmitter, VIP, Delays Intervertebral Disc Degeneration via FGF18/FGFR2-Mediated Activation of Akt Signaling Pathway.

Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and intervertebral disc (IVD) homeostasis remains unclear. Here, this study aimed to investigate the expression of postganglionic sympathetic nerve fiber-derived vasoactive intestinal peptide (VIP) system in human IVD tissue, and to assess the role of VIP-related neuromodulation in IVDD. Patient samples and in vitro cell experiments showed that the expression of receptors for VIP is negatively correlated with the severity of IVDD, and the administration of exogenous VIP can ameliorate interleukin 1ß-induced nucleus pulposus (NP) cell apoptosis and inflammation. Further mRNA-seq analysis revealed that fibroblast growth factor 18- (FGF18)-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway is involved in the protective effects of VIP on inflammation-induced NP cell degeneration. Further analysis identified VIP via its receptor vasoactive intestinal peptide receptor 2 can directly result in decreased expression of miR-15a-5p, which targeted FGF18. Finally, in vivo mice lumbar IVDD model confirmed that focally exogenous administration of VIP can effectively ameliorated the progression of IVDD, as shown by the radiological and histological analysis. In conclusion, these results indicated that sympathetic neurotransmitter, VIP, delayed IVDD via FGF18/FGFR2-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway, which will broaden the horizon concerning how the neuromodulation correlates with IVDD and shed new light on novel therapeutical alternatives to IVDD.

Liver-Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury.

The liver is the major ketogenic organ of the body, and ketones are reported to possess favorable neuroprotective effects. This study aims to elucidate whether ketone bodies generated from the liver play a critical role in bridging the liver and spinal cord. Mice model with a contusive spinal cord injury (SCI) surgery is established, and SCI induces significant histological changes in mice liver. mRNA-seq of liver tissue shows the temporal changes of ketone bodies-related genes, ß-hydroxybutyrate dehydrogenase (BDH1) and solute carrier family 16 (monocarboxylic acid transporters), member 6 (SLC16A6). Then, an activated ketogenesis model is created with adult C57BL/6 mice receiving the tail intravenous injection of GPAAV8-TBG-Mouse-Hmgcs2-CMV- mCherry -WPRE (HMGCS2liver ) and mice receiving equal AAV8-Null being the control group (Vectorliver ). Then, the mice undergo either a contusive SCI or sham surgery. The results show that overexpression of HMG-CoA synthase (Hmgcs2) in mice liver dramatically alleviates SCI-mediated pathological changes and promotes ketogenesis in the liver. Amazingly, liver-derived ketogenesis evidently alleviates neuron apoptosis and inflammatory microglia activation and improves the recovery of motor function of SCI mice. In conclusion, a liver-spinal cord axis can be bridged via ketone bodies, and enhancing the production of the ketone body within the liver has neuroprotective effects on traumatic SCI.

Lupenone improves motor dysfunction in spinal cord injury mice through inhibiting the inflammasome activation and pyroptosis in microglia via the nuclear factor kappa B pathway.

JOURNAL/nrgr/04.03/01300535-202408000-00034/figure1/v/2023-12-16T180322Z/r/image-tiff Spinal cord injury-induced motor dysfunction is associated with neuroinflammation. Studies have shown that the triterpenoid lupenone, a natural product found in various plants, has a remarkable anti-inflammatory effect in the context of chronic inflammation. However, the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown. In this study, we established an impact-induced mouse model of spinal cord injury, and then treated the injured mice with lupenone (8 mg/kg, twice a day) by intraperitoneal injection. We also treated BV2 cells with lipopolysaccharide and adenosine 5'-triphosphate to simulate the inflammatory response after spinal cord injury. Our results showed that lupenone reduced IκBα activation and p65 nuclear translocation, inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B, and enhanced the conversion of proinflammatory M1 microglial cells into anti-inflammatory M2 microglial cells. Furthermore, lupenone decreased NLRP3 inflammasome activation, NLRP3-induced microglial cell polarization, and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway. These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.

Valproic acid ameliorates cauda equina injury by suppressing HDAC2-mediated ferroptosis.

INTRODUCTION: Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive. METHODS: The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection. RESULTS: In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes. CONCLUSION: HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.

Effects of "fixation-fusion" sequence of lumbar surgery on surgical outcomes for patients with lumbar spinal stenosis: study protocol for a multicenter randomized controlled trial.

BACKGROUND: New-onset neurological symptoms such as numbness and pain in lower extremities might appear immediately after conventional lumbar interbody fusion (LIF) surgery performed in patients with lumbar spinal stenosis. METHODS AND ANALYSIS: This is a multicenter, randomized, open-label, parallel-group, active-controlled trial investigating the clinical outcomes of modified LIF sequence versus conventional LIF sequence in treating patients with lumbar spinal stenosis. A total of 254 eligible patients will be enrolled and randomized in a 1:1 ratio to either modified LIF sequence or conventional LIF sequence group. The primary outcome measure is the perioperative incidence of new-onset lower extremity neurological symptoms, including new adverse events of pain, numbness, and foot drop of any severity. Important secondary endpoints include visual analogue scale (VAS) pain score and lumbar Japanese Orthopaedic Association (JOA) recovery rate. Other safety endpoints will also be evaluated. The safety set used for safety data analysis by the actual surgical treatment received and the full analysis set for baseline and efficacy data analyses according to the intent-to-treat principle will be established as the two analysis populations in the study. CONCLUSION: This study is designed to investigate the clinical outcomes of modified LIF sequences in patients with lumbar spinal stenosis. It aims to provide clinical evidence that the modified "fixation-fusion" sequence of LIF surgery is effective in treating lumbar spinal stenosis. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx ID: ChiCTR2100048507.

Strontium Ranelate Ameliorates Intervertebral Disc Degeneration via Regulating TGF-ß1/NF-κB Axis.

Intervertebral disc degeneration (IVDD) is a prevalent and debilitating condition characterized by chronic back pain and reduced quality of life. Strontium ranelate (SRR) is a compound traditionally used for treating osteoporosis via activating TGF-ß1 signaling pathway. Recent studies have proved the anti-inflammatory effect of SRR on chondrocytes. Although the exact mechanism of IVDD remains unclear, accumulating evidences have emphasized the involvement of multifactorial pathogenesis including inflammation, oxidative stress damage, and etc. However, the biological effect of SRR on IVDD and its molecular mechanism has not been investigated. Firstly, this study proved the decreased expression of Transforming Growth Factor-beta 1(TGF-ß1) in degenerated human intervertebral disc tissues. Subsequently, we confirmed for the first time that SRR could promote cell proliferation, mitigate inflammation and oxidative stress in human nucleus pulposus cells in vitro via increasing the expression of TGF-ß1 and suppressing the Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) pathway. The molecular docking result proved the interaction between SRR and TGF-ß1 protein. To further verify this interaction, gain- and loss- of function experiments were conducted. We discovered that both TGF-ß1 knockdown and overexpression influenced the activation of the NF-κB pathway. Taken together, SRR could mitigate IL-1ß induced-cell dysfunction in human nucleus pulposus cells by regulating TGF-ß1/NF-κB axis in vitro. Finally, the in vivo therapeutic effect of SRR on IVDD was confirmed. Our findings may contribute to the understanding of the complex interplay between inflammation and degenerative processes in the intervertebral disc and provide valuable insights into the development of targeted treatment-based therapeutics for IVDD.

Exploring the role and mechanism of Fuzi decoction in the treatment of osteoporosis by integrating network pharmacology and experimental verification.

BACKGROUND: Fuzi decoction (FZD), a traditional Chinese medicine formula, was used to treat musculoskeletal diseases by warming channels, strengthening yang and dispelling pathogenic cold and dampness. In clinical practice, FZD has been used to treat rheumatoid arthritis and osteoarthritis. It alleviated osteoarticular disorders through ameliorating the degradation of cartilage and improving meniscal damage in osteoarthritis, while its roles and mechanisms in the treatment of bone loss diseases remain unclear. This study aims to investigate the underlying mechanisms of FZD in treating osteoporosis using an integrative method of network pharmacology and experimental study. METHODS: In this study, network pharmacology was used to predict the core targets and potential pathways of the bioactive ingredients of FZD to attenuate osteoporosis. Molecular docking was performed to evaluate the interactions between core compounds and key targets. In addition, both cell and animal experiments were carried out to validate the role and potential mechanism in treating osteoporosis. RESULTS: In the present study, data revealed that kaempferol, beta-sitosterol, stigmasterol, fumarine, and (+)-catechin may be the primary bioactive ingredients of FZD in the treatment of osteoporosis, which were closely associated with the osteoporosis-related targets. And the KEGG results indicated that the NF-κB pathway was closely associated with the function of FZD in treating osteoporosis. In addition, in vivo demonstrated that FZD ameliorated osteoporosis. In vitro experiments showed that the pro-apoptotic factors indicators including CASP3 and BAX were decreased by FZD and the anti-apoptotic factor BCL2 was increased by FZD. In addition, FZD significantly suppressed the osteoclast differentiation in culture and the expression levels of osteoclast-related genes including TRAF6, CTSK, and MMP9. And the NF-κB pathway was confirmed, via in vitro experiment, to be involved in osteoclast differentiation. CONCLUSIONS: This study demonstrated that FZD played a pivotal role in suppressing the osteoclast differentiation via regulating the NF-κB pathway, indicating that FZD could be a promising antiosteoporosis drug and deserve further investigation.

The deubiquitinase USP11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3.

Increasing studies have reported that intervertebral disc degeneration (IVDD) is the main contributor and independent risk factor for low back pain (LBP), it would be, therefore, enlightening that investigating the exact pathogenesis of IVDD and developing target-specific molecular drugs in the future. Ferroptosis is a new form of programmed cell death characterized by glutathione (GSH) depletion, and inactivation of the regulatory core of the antioxidant system (glutathione system) GPX4. The close relationship of oxidative stress and ferroptosis has been studied in various of diseases, but the crosstalk between of oxidative stress and ferroptosis has not been explored in IVDD. At the beginning of the current study, we proved that Sirt3 decreases and ferroptosis occurs after IVDD. Next, we found that knockout of Sirt3 (Sirt3-/-) promoted IVDD and poor pain-related behavioral scores via increasing oxidative stress-induced ferroptosis. The (immunoprecipitation coupled with mass spectrometry) IP/MS and co-IP demonstrated that USP11 was identified to stabilize Sirt3 via directly binding to Sirt3 and deubiquitinating Sirt3. Overexpression of USP11 significantly ameliorate oxidative stress-induced ferroptosis, thus relieving IVDD by increasing Sirt3. Moreover, knockout of USP11 in vivo (USP11-/-) resulted in exacerbated IVDD and poor pain-related behavioral scores, which could be reversed by overexpression of Sirt3 in intervertebral disc. In conclusion, the current study emphasized the importance of the interaction of USP11 and Sirt3 in the pathological process of IVDD via regulating oxidative stress-induced ferroptosis, and USP11-mediated oxidative stress-induced ferroptosis is identified as a promising target for treating IVDD.

Hesperidin mitigates oxidative stress-induced ferroptosis in nucleus pulposus cells via Nrf2/NF-κB axis to protect intervertebral disc from degeneration.

Intervertebral disc degeneration (IVDD), a widely known contributor to low back pain (LBP), has been proved to be a global health challenging conundrum. Hesperidin (hesperetin-7-O-rutinoside, HRD) is a flavanone glycoside that belongs to the subgroup of citrus flavonoids with therapeutic effect on various diseases due to its anti-inflammatory, antioxidant properties. However, the effect of HRD on IVDD remains elusive. The human nucleus pulposus tissues were harvested for isolating human nucleus pulposus (HNP) cells to verify the expression of Nrf2. The biological effect of HRD on HNP cells were assessed in vitro, and the in vivo therapeutic effects of HRD were assessed in mice. Firstly, we found that the expression of Nrf2 was decreased with the progression of degeneration in degenerated human nucleus pulposus tissue. Subsequently, we confirmed that HRD could mitigate oxidative stress-induced ferroptosis in nucleus pulposus cells via enhancing the expression of Nrf2 axis and suppressing the NF-κB pathway to protect intervertebral disc from degeneration in vitro. Finally, the therapeutic effects of HRD were confirmed in vivo. The current study proved for the first time that HRD may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-κB pathway. The evidence will provide a possible basis for future targeted treatment for IVDD.

The Gantry Crane Technique: A Novel Technique for Treating Severe Thoracic Spinal Stenosis and Myelopathy Caused by Ossification of the Ligamentum Flavum and Preliminary Clinical Results.

STUDY DESIGN: Retrospective single-arm study. OBJECTIVE: To propose a novel technique named the gantry crane technique for treating severe thoracic spinal stenosis and myelopathy caused by thoracic ossification of the ligamentum flavum (TOLF) and investigate its clinical results. METHODS: From June 2017 to January 2019, 18 patients presenting with severe spinal stenosis and myelopathy caused by TOLF were included in our study. All patients were treated with gantry crane technique, pre-operative JOA score, as well as 3 days-, 3 months-, 6 months-, 12 months-, 24 months after operation, and Hirabayashi recovery rate were reported. Pre- and post-operative image were utilized for the assessment of post-operative effect. Peri-operative complications were recorded to assess the safety of the gantry crane technique. RESULTS: The JOA score increased from 10.56 ± 3.76 preoperatively to 12.94 ± 3.33, 13.56 ± 3.48, 13.94 ± 3.32, 14.17 ± 3.70 and 14.06 ± 3.54 in 3 days, 3 months, 6 months, 12 months and 24 months after surgery, respectively. The post-operative JOA scores were improved with statistical significance at the level of P < 0.05. The recovery rate was (39.09 ± 33.85) %, (51.35 ± 42.60) %, (55.79 ± 36.10) %, (64.98 ± 29.24) % and (60.98 ± 35.96) % for 3 days, 3 months, 6 months, 12 months and 24 months after surgery, respectively. There were 2 cases of SSI (surgical site infection), 1 case of NI (neurovascular injury) and 1 case of cerebrospinal fluid (CSF) leakage. CONCLUSIONS: This study highlights a safe and effective technique, the gantry crane technique, for treating severe thoracic spinal stenosis and myelopathy caused by TOLF.

Comparison of Surgical Results of the Bridge Crane Technique Versus Laminectomy for the Treatment of Thoracic Myelopathy Caused by Ossification of the Ligamentum Flavum.

STUDY DESIGN: A retrospective study. OBJECTIVES: This study aimed to evaluate the safety and effectiveness of the bridge crane technique versus laminectomy for the treatment of thoracic myelopathy caused by ossification of the ligamentum flavum (OLF). METHODS: Totally 41 patients who underwent surgical decompression due to thoracic OLF from May 2017 to June 2018 in our institution were enrolled in this study and were divided into group BG (bridge crane technique, n = 19) and group L (laminoectomy, n = 22). Demographic data was collected from medical records and the modified Japanese Orthopaedic Association (JOA) scoring system was used to evaluate the neurological outcomes during the follow-up. Surgery-related complications were analyzed. RESULTS: The mean duration of follow-up was comparable between group BG (19.4 ± 1.5 months) and group L (19.6 ± 1.4 months). No statistical differences were observed between two groups in terms of gender, age, duration of symptoms, preoperative occupying rate, involved levels, operation time, intraoperative blood loss, and complications. The JOA score significantly increased at the final follow-up in both groups. However, patients in group BG had higher JOA score and recovery rate (P < 0.05). Four patients in group L experienced complications, including 3 cerebrospinal fluid (CSF) leakage and one postoperative hematoma. Only one patient in group BG had CSF leakage. CONCLUSION: The results of this study suggested that bridge crane technique may be relatively safe and effective for patients with symptomatic thoracic OLF with more satisfactory clinical improvement. However, high-quality studies are still required to validate the results of this study.

The effect of K-line classification in different cervical dynamic position on surgical outcomes in patients with ossification of the posterior longitudinal ligament after anterior controllable antedisplacement and fusion.

Purpose: To investigate whether the K-line classification in different cervical dynamic position of patients with Ossification of the Posterior Longitudinal Ligament (OPLL) affects clinical outcome after Anterior Controllable Antedisplacement and Fusion (ACAF) surgery. Methods: A total of 93 patients who suffered from cervical spondylosis caused by OPLL underwent ACAF surgery between June 2015 and December 2017 in a single institution. Neutral, neck-flexed and neck-extended cervical radiographs were obtained from every patient. Subsequently they were classified into K-line (+) and K-line (-) with reference to the K-line classification criteria. Clinical outcomes were assessed by the JOA score, improvement rate (IR) and visual analogue scale (VAS). Radiological assessment included Cobb angle and occupation ratio (OR) of OPLL. Correlations between the long-term surgical outcomes and classification of K-line in different dynamic position were analyzed by one-way analysis of variance. Results: Significant improvements were shown in all postoperative clinical and radiographic assessments (P < 0.05). There were no differences in IR, Cobb angle and VAS among flexion K-line (-), flexion K-line (+), extension K-line (-) and extension K-line (+) at the 2-year follow-up (P > 0.05). However, the OR of extension K-line (-) (16.13% ± 11.58%) was higher than that of extension K-line (+) (9.00% ± 10.27%) and flexion K-line (+) subgroup (9.47% ± 9.97%) (P < 0.05). Conclusion: The ACAF procedure has shown satisfactory surgical outcomes in various K-line classifications in different dynamic position.

The Effect of Diabetes Mellitus on the Neurological Function of Patients with Cervical Spondylotic Myelopathy.

OBJECTIVE: To evaluate the clinical value of diabetes mellitus for diagnosis and postoperative prognosis in patients with cervical spondylotic myelopathy undergoing anterior decompression and fusion. METHODS: A total of 84 Patients (50 males and 34 females) who underwent anterior decompression and fusion were reviewed in this single-center retrospective study. The patients were divided into two groups (44 patients in the diabetes mellitus group and 40 in the non-diabetic group). Clinical manifestations were evaluated, including characteristics baseline, clinical tests, MRI information, clinical scores, and complications. The predictive effect of diabetes mellitus on clinical scores were assessed via the receiver operating characteristic curve. The correlation between the severity of diabetes mellitus and neurological function recovery was estimated using the Pearson correlation coefficient. RESULTS: Patients with diabetes mellitus exhibited a higher ratio of hyperintensity of the spinal cord (P < 0.05) and worse preoperative clinical scores and neurological recovery (all P < 0.05). Receiver operating characteristic curve results indicated that diabetes mellitus could serve as a good indicator for preoperative evaluation of the Japanese Orthopedic Association (JOA) score (area under curve [AUC] = 0.639), visual analogue score (AUC = 0.642), and Nurick score (AUC = 0.740). In addition, analysis of JOA in isolation suggested that diabetes mellitus correlated closely with the sensory function in the upper and lower limbs (both P < 0.01). The Receiver operating characteristic curve also demonstrated that diabetes mellitus as a clinical test had a reasonable specificity for sensory function in the upper (AUC = 0.654) and lower limbs (AUC = 0.671). Both the level of HbA1c and the duration of diabetes mellitus were negatively correlated with the recovery rate of the JOA score. There was no significant difference between the perioperative complications between the two groups (P > 0.05). CONCLUSION: This present study revealed that the neurological impairment caused by diabetes mellitus in patients undergoing anterior decompression and fusion does not only affect postoperative functional recovery but also interferes with the preoperative clinical manifestations, especially the sensory function in the upper and lower limbs.

The role of nerve fibers and their neurotransmitters in regulating intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) has been the major contributor to chronic lower back pain (LBP). Abnormal apoptosis, senescence, and pyroptosis of IVD cells, extracellular matrix (ECM) degradation, and infiltration of immune cells are the major molecular alternations during IVDD. Changes at tissue level frequently occur at advanced IVD tissue. Ectopic ingrowth of nerves within inner annulus fibrosus (AF) and nucleus pulposus (NP) tissue has been considered as the primary cause for LBP. Innervation at IVD tissue mainly included sensory and sympathetic nerves, and many markers for these two types of nerves have been detected since 1940. In fact, in osteoarthritis (OA), beyond pain transmission, the direct regulation of neuropeptides on functions of chondrocytes have attracted researchers' great attention recently. Many physical and pathological similarities between joint and IVD have shed us the light on the neurogenic mechanism involved in IVDD. Here, an overview of the advances in the nervous system within IVD tissue will be performed, with a discussion on in the role of nerve fibers and their neurotransmitters in regulating IVDD. We hope this review can attract more research interest to address neuromodulation and IVDD itself, which will enhance our understanding of the contribution of neuromodulation to the structural changes within IVD tissue and inflammatory responses and will help identify novel therapeutic targets and enable the effective treatment of IVDD disease.