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.

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.

Development and Validation of a Novel Nomogram to Predict the Risk of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) has been a complex disorder resulted from genetic and environmental risk factors. The aim of this study was to identify the risk factors associated with IVDD in orthopaedic patients and develop a prediction model for predicting the risk of IVDD. A total of 309 patients were retrospectively included in the study and randomly divided into the training group and the validation group. The least absolute shrinkage and selection operator regression (LASSO) and the univariate logistic regression analysis were used to optimize factors selection for the IVDD risk model. Multivariable logistic regression analysis was used to establish a predicting nomogram model incorporating the factors. In addition, discrimination, calibration, and clinical usefulness of the nomogram model were evaluated via the C-index, receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA). Then, based on the results above, the relationship between IVDD and angiotensin II (AngII) level in peripheral blood was examined prospectively. The predictors of the nomogram include age, sex, hypertension, diabetes, gout, working posture, and exercising hours per week. The C-index values of the training and validation groups were 0.916 (95% CI, 0.876-0.956) and 0.949 (95% CI, 0.909-0.989), respectively, which indicated that the model displayed good discrimination. In addition, the area under the curve (AUC) values of the ROC curve of the training and the validation group were 0.815 (95% CI, 0.759-0.870) and 0.805 (95% CI, 0.718-0.892), respectively, revealing the satisfactory discrimination performance of the model. The prospective investigation showed that the average AngII level in the degenerated group (97.62 ± 44.02 pg/mL) was significantly higher than that in the nondegenerated group (52.91 ± 9.01 pg/mL) (p < 0.001). This present study explored the risk factors for IVDD and established a prediction model, which would effectively predict the risk of IVDD. In addition, based on the prediction model, AngII was revealed to be a potentially auxiliary clinical diagnostic marker for IVDD.

Vericiguat Modulates Osteoclast Differentiation and Bone Resorption via a Balance between VASP and NF-κB Pathways.

Bone homeostasis has been a dynamic equilibrium between osteoclasts (OCs) and osteoblasts (OBs). However, excessive activation of OCs could disturb the bone homeostasis. As a result, effective medical interventions for patients are greatly demanding. NO/guanylate cyclase (GC)/cGMP signaling cascade has been previously reported to regulate bone metabolism, and GC plays a significantly critical role. Vericiguat, as a novel oral soluble guanylate cyclase (sGC) stimulator, has been firstly reported in 2020 to treat patients with heart failure. Nevertheless, the biological effects of Vericiguat on the function of OCs have not yet been explored. In this present study, we found that Vericiguat with the concentration between 0 and 8 µM was noncytotoxic to bone marrow-derived monocyte-macrophage lineage (BMMs). Vericiguat could enhance the differentiation of OCs at concentration of 500 nM, whereas it inhibited OC differentiation at 8 µM. In addition, Vericiguat also showed dual effects on OC fusion and bone resorption in a dose-dependent manner. Furthermore, a molecular assay suggested that the dual regulatory effects of Vericiguat on OCs were mediated by the bidirectional activation of the IκB-α/NF-κB signaling pathway. Taken together, our present study demonstrated the dual effects of Vericiguat on the formation of functional OCs. The regulatory effects of Vericiguat on OCs were achieved by the bidirectional modulation of the IκB-α/NF-κB signaling pathway, and a potential balance between the IκB-α/NF-κB signaling pathway and sGC/cGMP/VASP may exist.

Urodynamic evaluation of bladder function in patients with urinary incontinence secondary to congenital tethered cord syndrome after homogeneous spinal-shortening axial decompression procedure.

OBJECTIVE: To evaluate the effect of homogeneous spinal-shortening axial decompression procedure (HSAD) on bladder function in patients with spina bifida tethered syndrome. METHODS AND MATERIALS: Patients with tethered spinal cord syndrome were collected prospectively, and all patients were treated with lumbar HSAD. Patients' urodynamic evaluation mainly included detrusor function, sphincter function, sphincter coordination (Ig TLR, ratio of tension and loose of urethral sphincter), and bladder compliance. Meanwhile, all patients were followed up with ICI-Q-SF, SF-12, and Rantala scores. RESULTS: Twenty-four patients were included, with the average age of 27 ± 16 years. At the final follow-up, patients' detrusor function, sphincter function, sphincter coordination, and bladder compliance, were all improved dramatically (all P < 0.01). The preoperative SF-12 score, ICQ, and Rantala score were [52.16 ± 5.64, 14.11 ± 5.25, 7.84 ± 4.87], whereas the postoperative mean was [33.53 ± 3.53, 9.05 ± 4.89, 15 ± 3.77] (P < 0.01, respectively). According to objective evaluation, 16.7% of them recovered to normal. According to the subjective evaluation, 25% of the patients returned to normal. Only one patient (4.2%) deteriorated. Limitations include none-randomized controlled design and limited patient samples. CONCLUSIONS: The HSAD can significantly restore the bladder function in patients with long-term urinary incontinence.

The clinical application of individualized three-dimensional printing guiding template for assisting scaphoid fracture fixation through dorsal approach.

The purpose is to introduce a novel scaphoid screw placement surgery based on a novel three-dimensional (3D) printing guiding template through dorsal approach, and to evaluate the clinical feasibility and accuracy. The diagnose of scaphoid fracture was confirmed by Computed Tomography (CT) scanning, and subsequently the CT scanning data was input into a three-dimension imaging system(Hongsong software, China). An individualized 3D skin surface template with a guiding hole was printed. We put the template to the correct position on patient's wrist. Fluoroscopy was used to confirm the accurate position after drilling of Kirschner wire according to the prefabricated holes of template. Finally, the hollow screw was inserted through the wire. The operations were performed successfully without incision and complications. The operation time was below 20 minutes and the blood loss was below 1ml. The intraoperative fluoroscopy demonstrated good position of the screws. Postoperative imaging showed that the screws were considered to be placed perpendicularly to the fracture plane in the scaphoid. Three months after the operation, the patients acquired good recovery of the motor function of their hands. This present study suggested that the computer-assisted 3D printing guiding template is effective, reliable, and minimally invasive for the treatment of type B scaphoid fracture through dorsal approach.

Clinical impact and imaging results after a modified procedure of ACDF: a prospective case-controlled study based on ninety cases with two-year follow-up.

STUDY DESIGN: This is a prospective case-controlled study. BACKGROUND: To analyze the postoperative axial pain and cage subsidence of patients presenting with cervical spondylotic myelopathy (CSM) after a modified procedure of ACDF (mACDF). METHODS: Ninety patients with CSM were prospectively collected from 2014 to 2018. The patients were divided into spread group and non-spread group (48:42 ratio) according to the cage placement with or without releasing the Caspar cervical retractor after decompression. Spread group received conventional ACDF and non-spread group received mACDF. Patients were followed-up for at least 24 months after surgery. Radiologic data, including height of intervertebral space and Cobb Angle, were collected. Nervous system function was obtained using JOA scores, and level of pain was assessed using VAS scores. RESULTS: A total of 90 patients were enrolled and the patients were divided into spread group (n = 48) and none-spread group(n = 42). Cage subsidence of (spread group vs none-spread group) was (0.82 ± 0.68 vs 0.58 ± 0.81) mm, (0.64 ± 0.77 vs 0.34 ± 0.46) mm, (0.48 ± 0.43 vs 0.25 ± 0.28) mm, and (0.45 ± 0.47 vs 0.17 ± 0.32) mm at 3 months, 6 months, 12 months and 24 months, respectively. The period exhibiting the most decrease of the height of intervertebral space was 3 months postoperatively. However, there was no statistical difference in the height of intervertebral space, JOA or VAS scores at the final follow-up between the two groups. CONCLUSIONS: The mACDF can avoid excessive distraction by releasing the Caspar Cervical retractor, restore the "natural height" of cervical vertebra, relieve immediate pain after surgery, and prevent rapid Cage subsidence and the loss of cervical curvature.

Expression of Nogo-A in dorsal root ganglion in rats with cauda equina injury.

OBJECTIVE: To investigate the expression of Nogo-A in dorsal root ganglion (DRG) in rats with cauda equina injury and the therapeutic effects of blocking Nogo-A and its receptor. METHODS AND MATERIALS: Fifty-eight male Sprague-Dawley rats were divided randomly into either the sham operation group (n = 24) or the cauda equina compression (CEC) control group (n = 34). Behavioral, histological, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were conducted to assess the establishment of the model. The dynamic expression change of Nogo-A was evaluated using real time-qPCR. Immunofluorescence was used to evaluate the expression of Nogo-A in the DRG and cauda equina. Furthermore, 20 male Sprague-Dawley rats were equally divided into 4 groups, including the sham group, the CEC group, the NEP1-40 (the NgR antagonist peptide) treatment group, and the JTE-013 (the S1PR2 antagonist) treatment group. Behavioral assessments and western blotting were used to evaluate the therapeutic effect of cauda equina injury via blocking Nogo-A and its receptor. RESULTS: Tactile allodynia and heat hyperalgesia in the CEC model developed as soon as 1 day after surgery and recovered to normal at 7 days, which was followed by the downregulation of Nogo-A in DRG neurons. However, the locomotor function impairment in the CEC model showed a different prognosis from the sensory function, which was consistent with the expression change of Nogo-A in the spinal cord. Immunofluorescence results also demonstrated that Nogo A-positive/NF200-negative neurons and axons increased in the DRG and cauda equina 7 days after surgery. Surprisingly, Schwann cells, which myelinate axons in the PNS, also expressed considerable amounts of Nogo-A. Then, after blocking the Nogo-A/NgR signaling pathway by NEP1-40, significant improvement of mechanical allodynia was identified in the first 2 days after the surgery. Western blotting suggested the NEP1-40 treatment group had lower expression of cleaved caspase-3 than the CEC and JTE-013 treatment group. CONCLUSION: Neuronal Nogo-A in the DRG may be involved in regeneration and play a protective role in the CEC model. Whereas Nogo-A, released from the injured axons or expressed by Schwann cells, may act as an inhibiting factor in the process of CEC repairment. Thus, blocking the Nogo-A/NgR signaling pathway can alleviate mechanical allodynia by apoptosis inhibition.

Analysis of the spinal cord angle for severe cervical ossification of the posterior longitudinal ligament: comparison between anterior controllable antedisplacement and fusion (ACAF) and posterior laminectomy.

OBJECTIVE: To investigate the changes of spinal cord angle between anterior controllable antedisplacement and fusion (ACAF) and posterior laminectomy in treating severe ossification of the posterior longitudinal ligament (OPLL). PATIENTS AND METHODS: Seventy-one patients with cervical OPLL were enrolled. Patients in this study were divided into group A and group P. Japanese Orthopaedic Association (JOA) score was utilized to evaluate the neurological function. Radiological assessments included the spinal cord angle, Cobb angle, and area of the spinal cord. Surgery-related complications were also recorded. RESULTS: At the final follow-up, patients in group A had better recovery of local and whole cord angle, and the area of the cord than those in group P (all p < 0.05). A strong correlation between the change of local cord angle and the recovery of the spinal cord area was observed (r = - 0.867, p < 0.05). In addition, patients in group P had worse Cobb angle (9.15° ± 1.10°) than in group A (18.58° ± 0.73°) (p < 0.05). The final mean JOA score and its improvement rate were better in the group A than in group P (p < 0.05). During the follow-up, 15.15% patients in group P experienced surgery-related complications and 7.89% in group A. CONCLUSION: This present study revealed that ACAF can achieve better recovery of the expansion of the spinal cord, spinal cord alignment, and Cobb angle, with better postoperative JOA score and less complications, compared with posterior laminectomy in treating severe cervical OPLL. These slides can be retrieved under Electronic Supplementary Material.

Reliability and validity of multi-shot DWI in diagnosis of cervical spondylotic myelopathy: a study based on 3-T MRI.

OBJECTIVE: To investigate whether multi-shot diffusion-weighted imaging (ms-DWI) could be applied in diagnosis and quantitative evaluation of cervical spondylotic myelopathy (CSM). METHODS: Thirty-three normal volunteers and 78 patients with CSM were included in this study. The apparent diffusion coefficient (ADC) values were measured at C2-C7 levels on sagittal section ADC map. The intraclass correlation coefficient (ICC) and Bland and Altman plot and Spearman coefficient were used to quantify the reproducibility of test and retest and inter-rater reliability. Pearson correlations were calculated to compare lADC and rADC versus mJOA and NDI scores. Receiver operating characteristic curve and the area under the curve (AUC) were applied to evaluate the diagnostic reliability. RESULTS: There was no statistically significant difference between ADC values obtained from normal volunteers at C2-C7 levels (P < 0.05). The ICC and spearman coefficient of lADC and rADC indicated excellent test-retest and inter-rater reliability. The mean lADC and rADC were significantly higher from patients than that from volunteers (all P < 0.01). The lADC had moderate to good correlations with mJOA and NDI (all P < 0.0001). Moreover, rADC had good to excellent correlations with mJOA and NDI (all P < 0.0001). Comparing AUCs, rADC was significantly superior in diagnosis which participants were CSM than lADC (P = 0.0118). CONCLUSION: The ms-DWI could be applied in diagnosis and quantitive assessment of CSM according to lADC and rADC. A new parameter, rADC, could be served as a diagnostic indice for CSM, which may quantitively reflect the severity of CSM. These slides can be retrieved under Electronic Supplementary Material.

A modified procedure of single-level transforaminal lumbar interbody fusion reduces immediate post-operative symptoms: a prospective case-controlled study based on two hundred and four cases.

STUDY DESIGN: This is a prospective case-controlled study. PURPOSE: The purpose of this study is to investigate the effect of a modified transforaminal lumbar interbody fusion (TLIF) on the immediate post-operative symptoms in patients with lumbar disc herniation (LDH) accompanied with stenosis. METHODS: A total of 204 LDH patients with single-level TLIF were enrolled. According to the sequence of the placement of rods and cage, patients were divided into group R (rod-prior-to-cage) and group C (cage-prior-to-rod). Neurological function was evaluated by the Japanese Orthopedic Association (JOA) score. Radiological assessment includes height of intervertebral space (HIS), foraminal height (FH), foraminal area (FA), and segmental lordosis (SL). Change of original symptoms (pain/numb) and new-onset symptoms (pain/numb) after surgery were also recorded. RESULTS: Patients in group R had less change of HIS at L3/4, L4/5, and L5/S1 levels compared with pre-operation (all p > 0.05), whereas group C had larger change (all p < 0.05). No statistical difference was found in FH between the two groups before and after surgery at L3/4, L4/5, and L5/S1, respectively (all p > 0.05). In terms of FA, patients in group R had better improvement after surgery than those in group C at L3/4 and L4/5 (both p < 0.05). Patients in both groups acquired good improvement of neurological function. However, there were fewer patients in group R who experienced post-operative leg pain or numb compared with those in group C (p < 0.05). CONCLUSION: The modified open TLIF can significantly reduce the incidence of immediate post-operative symptoms for patients with single-level lumbar disc herniation via installation of rods prior to insertion of cage and the "neural standard" should serve as the goal of decompression for spine surgeons to restore disc/foraminal height and to minimize nerve distraction.

A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability.

Shprintzen-Goldberg syndrome (SGS) is a rare systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations. It is associated with a significant risk of intellectual disability, a feature which distinguishes it from Marfan and Loeys-Dietz syndromes. SGS is mainly caused by mutations in the SKI gene, a repressor of TGF-ß activity. Most SKI mutations are found in exon 1 of the gene and are located in the R-SMAD domain, a proposed hotspot for de novo mutations. Here, we report on a de novo SKI mutation located in the DHD domain of SKI. By adding our finding to previously reported de novo SKI mutations, a new mutational hotspot in the DHD domain is proposed. Our patient presented with a lipomeningomyelocele, tethered cord, and spina bifida but with no SGS-related clinical findings apart from a marfanoid habitus and long slender fingers. Specifically, she did not have an intellectual disability, craniofacial, or cardiovascular abnormalities. By comparing the clinical findings on patients with mutations in the R-SMAD and DHD domains of SKI, we propose that mutations in those domains have different effects on TGF-ß activity during embryonic development with resulting phenotypic differences.

Skip corpectomy and fusion (SCF) versus anterior controllable antedisplacement and fusion (ACAF): which is better for patients with multilevel cervical OPLL?

BACKGROUND: The aim of this study was to compare the clinical efficacy and radiological outcomes of skip corpectomy and fusion (SCF) with anterior controllable antedisplacement and fusion (ACAF) for treating multilevel ossification of the posterior longitudinal ligament (OPLL). METHODS: 62 patients with multilevel OPLL who had undergone SCF or ACAF were analyzed retrospectively. Types of OPLL, occupying ratio (OR), Japanese Orthopaedic Association (JOA) score, Recovery Rate (RR), Neck Disability Index (NDI) score, Cobb's angles of C2-C7, operation time, blood loss, hospital stay, ratings for fusion assessment and complications were recorded and assessed. RESULTS: Postoperative C2-C7 Cobb's angle (11.1 ± 3.2° vs. 13.7 ± 2.5°; P < 0.05), NDI scores at final follow-up (14.3 ± 1.6 vs. 13.3 ± 1.3; P < 0.05), and rate of cerebral fluid (CSF) leakage (5, 16.7% vs. 0,0%; P < 0.05) were significantly better in the ACAF group. At 6 months, bone graft fusion rate was significantly greater in the ACAF group (24.75% vs. 15.50%; P < 0.05). CONCLUSIONS: Surgical treatment of multilevel OPLL by SCF or ACAF showed no significant differences in clinical outcomes, with the exception of better NDI scores at final follow-up in ACAF. In addition, ACAF is better than SCF in terms of early bone graft fusion rate, lordotic curvature improvement, risk of CSF leakage.

Placement of Titanium Mesh in Hybrid Decompression Surgery to Avoid Graft Subsidence in Treatment of Three-Level Cervical Spondylotic Myelopathy: Cephalad or Caudal?

BACKGROUND Hybrid decompression has been used to treat patients with cervical spondylotic myelopathy (CSM). However, no published study has investigated the effect of titanium mesh (TM) located cephalad or caudal in hybrid decompression surgery on the graft subsidence in treatment of three-level CSM. MATERIAL AND METHODS Forty-eight cases with three-level CSM who underwent the procedure of hybrid decompression from Jan 2014 to Jan 2017 were retrospectively reviewed. Radiological outcomes immediately postoperatively and at the final follow-up were compared between cases from group A (TM located cephalad, n=21) and group B (TM located caudal, n=27). RESULTS No differences were observed in the 2 groups in terms of number, sex, or duration of follow-up. The average follow-up was 4.38±0.439 months in group A and 4.81±0.509 months in group B (p>0.05). The index loss of anterior (AIBH), middle (MIBH), and posterior interbody height (PIBH) in group A were 0.857±0.448/1.00±0.525/1.33±0.608, respectively, which were all lower than that in group B (P<0.05), as was the occurrence of TM subsidence. However, there was no significance difference in height loss of adjacent intervertebral space between groups. All angles were decreased at the final follow-up in both groups (p<0.05). More decrease of C2-C7 angle occurred in group B (p>0.05), and segmental angle in group A decreased more than in group B (p>0.05). CONCLUSIONS TM inferior to intervertebral cage (IC) in hybrid decompression has a higher risk for developing subsidence, and when the choice of the position of TM is available in hybrid decompression surgery, TM located cephalad was recommend to alleviate TM subsidence.

The bridge crane technique for the treatment of the severe thoracic ossification of the ligamentum flavum with myelopathy.

PURPOSE: This study aims to investigate the clinical effect and complications of a novel technique named bridge crane for the treatment of the severe thoracic ossification of the ligamentum flavum (TOLF) with myelopathy. METHOD: A patient diagnosed as TOLF (T9-T11) was treated with the bridge crane technique and the outcomes were reported. The main surgical procedures include installation of pedicle screws, rods and transverse connectors; preparation of stay prolene sutures passing through the laminae-OLF complex (LOC); en bloc isolation of the LOC; tightening of the sutures to achieve posterior suspension of the LOC; and fixation of the LOC to the transverse connectors. The modified Japanese Orthopaedic Association (mJOA) scale was studied. The pre- and postoperative radiological parameters and surgical complications were also investigated. RESULTS: Postoperative CT and MRI showed a sufficient decompression of spinal cord by the technique of bridge crane. The ratio of spinal canal encroachment improved significantly. At the final follow-up assessment, no specific complications were identified. Imaging information suggested that the bone graft was fused and the "bridge" was in good position. The mJOA score was 9 with a recovery rate of 75% at the final follow-up. CONCLUSIONS: The technique of bridge crane is feasible and may be relatively safe and effective for the treatment of severe TOLF with myelopathy. However, further studies with large-scale cases and control groups are required to reveal the generalizability and safety of the bridge crane technique in the future. These slides can be retrieved under Electronic Supplementary Material.

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.

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.

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.

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.