Study Design. Prospective, randomized controlled trial (RCT). Objective. To directly compare the clinical and radiological outcomes of Unilateral Biportal Endoscopic Unilateral Laminotomy for Bilateral Decompression (UBE-ULBD) versus single-port Endoscopic Unilateral Laminectomy for Bilateral Decompression (Endo-ULBD) for single-level lumbar spinal stenosis (LSS). Summary of Background Data. While UBE-ULBD has emerged as an efficacious minimally invasive technique for degenerative LSS, the comparative efficacy and safety profile of Endo-ULBD remains comparatively underexplored. This study aims to bridge this knowledge gap by directly comparing these two endoscopic modalities. Methods. 110 patients with Schizas grade C/D LSS were randomized to UBE-ULBD or Endo-ULBD (55/group). Primary outcomes included VAS, ODI, and modified Macnab criteria. Radiological outcomes focused on dural sac cross-sectional area (DSCSA) and facet preservation. All procedures were performed by the same senior surgeon. Analysis was conducted per ITT and PP principles, with a 12-month follow-up. Results. Both groups demonstrated significant clinical improvement ( P <0.05). UBE-ULBD was associated with a shorter operative time ( P <0.01), largely attributable to the ergonomic advantages of the dual-portal system and the use of a high-speed drill. Notably, a trephine was utilized exclusively in the Endo-ULBD group. Conversely, Endo-ULBD was associated with a shorter postoperative hospital stay ( P <0.01), a difference potentially influenced by both technical and non-clinical factors. Radiological outcomes, including dural sac expansion and facet joint preservation rates, were comparable between groups ( P >0.05). No significant intergroup differences were observed in VAS, ODI, or modified Macnab satisfaction rates at the 12-month follow-up (ITT: 90.9% in UBE-ULBD vs. 89.1% in Endo-ULBD, P =0.92; PP: 98.0% in UBE-ULBD vs. 94.0% in Endo-ULBD, P =0.92). One dural tear occurred in the Endo-ULBD cohort. Conclusions. Both UBE-ULBD and Endo-ULBD proved safe and effective, yielding comparable clinical and radiological outcomes at the 12-month follow-up. Within the constraints of this study, both techniques represent viable options for minimally invasive decompression.

Background: Diabetic ulcer (DU) are severe complications of diabetes, characterized by persistent inflammation, oxidative stress, and impaired mitochondrial function. Verapamil, a calcium channel blocker, has shown potential in reducing oxidative stress and improving mitochondrial dysfunction, but its application in DU treatment remains unexplored. Methods: A dual-network QSAZ@VPH hydrogel was developed for local delivery and controlled release of verapamil. In vitro experiments evaluated its protective effects on HUVECs exposed to H2O2-induced mitochondrial dysfunction, including inflammatory marker expression, apoptosis inhibition, and angiogenesis promotion. In vivo studies used db/db mice and DU model rats to assess wound healing, granulation tissue formation, and neovascularization. Results: In vitro, QSAZ@VPH reduced mitochondrial dysfunction, lowered inflammatory markers, inhibited apoptosis, and promoted angiogenesis. In vivo, the hydrogel significantly improved wound healing in both models, reversing impaired healing and promoting granulation tissue formation and enhanced neovascularization. Conclusions: The QSAZ@VPH hydrogel presents a promising strategy for diabetic ulcer therapy by targeting mitochondrial dysfunction and promoting tissue regeneration.

Intervertebral disc degeneration (IVDD) is one of the most prevalent spinal degenerative disorders and imposes places heavy medical and economic burdens on individuals and society. Mechanical overloading applied to the intervertebral disc (IVD) has been widely recognized as an important cause of IVDD. Mechanical overloading-induced chondrocyte ferroptosis was reported, but the potential association between ferroptosis and mechanical overloading remains to be illustrated in nucleus pulposus (NP) cells. In this study, we discovered that excessive mechanical loading induced ferroptosis and endoplasmic reticulum (ER) stress, which were detected by mitochondria and associated markers, by increasing the intracellular free Ca2+ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free Ca2+ level elevation and the activation of ER stress are positive feedback processes that promote each other, consistent with the results that the level of ER stress in coccygeal discs of aged Piezo1-CKO mice were significantly lower than that of aged WT mice. Then, we confirmed that selenium supplementation decreased intracellular free Ca2+ level by mitigating ER stress through up-regulating Selenoprotein K (SelK) expression. Besides, ferroptosis caused by the impaired production and function of Glutathione peroxidase 4 (GPX4) due to mechanical overloading-induced calcium overload could be improved by selenium supplementation through Se-GPX4 axis and Se-SelK axis in vivo and in vitro, eventually presenting the stabilization of the extracellular matrix (ECM). Our findings reveal the important role of ferroptosis in mechanical overloading-induced IVDD, and selenium supplementation promotes significance to attenuate ferroptosis and thus alleviates IVDD, which might provide insights into potential therapeutic interventions for IVDD.

Long-term use of glucocorticoids (GCs) is known to be a predominant cause of osteonecrosis of the femoral head (ONFH). Moreover, GCs can mediate apoptosis of various cell types by exaggerating oxidative stress. We have previously found that Cortistatin (CST) antagonizes oxidative stress and improves cell apoptosis in several conditions. In this study, we detected that the CST expression levels were diminished in patients with ONFH compared with femoral neck fracture (FNF). In addition, a GC-induced rat ONFH model was established, which impaired bone quality in the femoral head. Then, administration of CST attenuated these ONFH phenotypes. Furthermore, osteoblast and endothelial cells were cultured and stimulated with dexamethasone (Dex) in the presence or absence of recombinant CST. As a result, Dex induced impaired anabolic metabolism of osteoblasts and suppressed tube formation in endothelial cells, while additional treatment with CST reversed this damage to the cells. Moreover, blocking GHSR1a, a well-accepted receptor of CST, or blocking the AKT signaling pathway largely abolished the protective function of CST in Dex-induced disorder of the cells. Taken together, we indicate that CST has the capability to prevent GC-induced apoptosis and metabolic disorder of osteoblasts in the pathogenesis of ONFH via the GHSR1a/AKT signaling pathway.

Intervertebral disc degeneration (IVDD) is one of the most prevalent spinal degenerative disorders and imposes places heavy medical and economic burdens on individuals and society. Mechanical overloading applied to the intervertebral disc (IVD) has been widely recognized as an important cause of IVDD. Mechanical overloading-induced chondrocyte ferroptosis was reported, but the potential association between ferroptosis and mechanical overloading remains to be illustrated in nucleus pulposus (NP) cells. In this study, we discovered that excessive mechanical loading induced ferroptosis and endoplasmic reticulum (ER) stress, which were detected by mitochondria and associated markers, by increasing the intracellular free Ca2+ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free Ca2+ level elevation and the activation of ER stress are positive feedback processes that promote each other, consistent with the results that the level of ER stress in coccygeal discs of aged Piezo1-CKO mice were significantly lower than that of aged WT mice. Then, we confirmed that selenium supplementation decreased intracellular free Ca2+ level by mitigating ER stress through upregulating Selenoprotein K (SelK) expression. Besides, ferroptosis caused by the impaired production and function of Glutathione peroxidase 4 (GPX4) due to mechanical overloading-induced calcium overload could be improved by selenium supplementation through Se-GPX4 axis and Se-SelK axis in vivo and in vitro, eventually presenting the stabilization of the extracellular matrix (ECM). Our findings reveal the important role of ferroptosis in mechanical overloading-induced IVDD, and selenium supplementation promotes significance to attenuate ferroptosis and thus alleviates IVDD, which might provide insights into potential therapeutic interventions for IVDD.

BACKGROUND:Bone formation and resorption regulate bone homeostasis. Excessive osteoclastogenesis enhances bone resorption and causes osteoporosis. Although medicines targeting osteoclast have been developed, these drugs have several side effects. Natural compounds have advantages in safety and efficiency, making them potential candidates for osteoporosis treatment. PURPOSE:This study aims to elucidate the role of damascenone (Dama) in osteoclastogenesis and osteoporosis. STUDY DESIGN AND METHODS:To demonstrate the effect of Dama on osteoclast differentiation and function, we performed multiple in vitro experiments including TRAP staining, F-actin staining, bone slice resorption assay, real-time PCR, and western bolt. Further, ROS detection, network pharmacology, microscale thermophoresis assay, and ChIP assay were conducted to elucidate the underlying molecular mechanism. Finally, the in vivo effects of Dama were verified using an ovariectomy induced osteoporosis mice model. RESULTS:Dama inhibited RANKL-induced osteoclast differentiation and bone resorptive function in vitro. The expression of osteoclast-related genes and activation of MAPKs and NF-κB signaling in osteoclast were also attenuated by Dama. Meanwhile, Dama reduced intracellular ROS level via up-regulating Nrf2 expression. Network pharmacology demonstrated that HDAC2 is the potential direct target of Dama. Dama inhibited HDAC2 function and increased H3K27ac level of Nrf2, which induced Nrf2 expression and activated ROS scavenging enzymes. Inhibiting NRF2 or activating HDAC2 attenuated the effect of Dama on osteoclastogenesis. Finally, Dama injection suppressed in vivo osteoclastogenesis and ameliorated bone loss induced by OVX. CONCLUSION:Dama attenuates osteoclastogenesis by epigenetically modulating Nrf2 expression and ROS scavenge. This study provides evidence for Dama being a potential treatment for osteoporosis.

To describe a novel surgical technique note coined as anterior cervical tunnectomy and fusion (ACTF) which applying on removal of posterior vertebral bony protrusions or soft extrusions. Total twenty-three patients from January 2016 to January 2021 who experienced with spinal cord compression and performed by ACTF were retrospectively reviewed. Herein, relevant information including patient’s gender, age, BMI, intraoperative time, intraoperative blood loss, postoperative complications and postoperative hospitalized stay were collected. Furthermore, JOA and VAS score were both collected. Moreover, imaging parameters were measured and calculated on radiographs. Correlated data were analyzed by t test. Significance was considered when P < 0.05. All patients in this study were validated with favorable outcomes and none of postoperative complications. The Nurick grade of patients dramatically deceased postoperation (P < 0.001). And postoperative VAS score of patients (P < 0.001), as well as JOA score (P < 0.001), was given dramatical significance comparing to preoperation. Furthermore, occupying rate (OR) (P < 0.001) was obviously reduced while space available cord (SAC) (P < 0.001) and diameter of spinal cord (P < 0.001) was significantly increased postoperation. Meanwhile, disc height of involved segment, C2–7 SVA, and C2–C7 Cobb angle were measured on sagittal plane of lateral radiograph. Postoperative disc height of involved segment (P < 0.001) significantly elevated comparing to preoperation. However, there were no significance on C2–7 SVA (P = 0.460) and C2–C7 Cobb angle (P = 0.097). The novel surgical technique coined by ACTF is a practicable approach during taking charge of bony and soft narrowing behind vertebral space.

Wear debris-induced osteolysis, especially titanium (Ti) particles-induced osteolysis, is the most common cause of arthroplasty failure with no effective therapy. Previous studies have suggested that inflammation and impaired osteogenesis are associated with Ti particles -induced osteolysis. Selenium (Se) is an essential trace element in the human body, which forms selenomethionine (Se-Met) in nature, and selenoproteins has strong anti-inflammatory and antioxidant stress effects. In this study, the effects of Se-Met on Ti particles-induced osteolysis were observed and the potential mechanism was explored. We found that exogenous Se-Met relieved osteolysis induced by Ti particles in two animal models and MC3T3-E1 cells. We found that the addition of Se-Met effectively inhibited Ti particle-induced inflammation by regulating reactive oxygen species-dependent (ROS-dependent) NOD-like receptor protein 3 (NLRP3) inflammasome activation. These therapeutic effects were abrogated in MC3T3-E1 cells that had received a β-catenin antagonist, suggesting that Se-Met alleviates inflammatory osteolysis via the β-catenin signaling pathway. Collectively, these findings indicated that Se-Met may serve as a potential therapeutic agent for treating Ti particle-induced osteolysis.

Intervertebral disc degeneration (IVDD) demonstrates a gradually increased incidence and has developed into a major health problem worldwide. The nucleus pulposus is characterized by the hypoxic and avascular environment, in which hypoxia-inducible factor-1α (HIF-1α) has an important role through its participation in extracellular matrix synthesis, energy metabolism, cellular adaptation to stresses and genesis. In this study, the effects of HIF-1α on mouse primary nucleus pulposus cells (MNPCs) exposed to TNF-α were observed, the potential mechanism was explored and a rabbit IVDD model was established to verify the protective role of HIF-1α on IVDD. In vitro results demonstrated that HIF-1α could attenuate the inflammation, apoptosis and mitochondrial dysfunction induced by TNF-α in MNPCs; promote cellular anabolism; and inhibit cellular catabolism. In vivo results demonstrated that after establishment of IVDD model in rabbit, disc height and IVD extracellular matrix were decreased in a time-dependent manner, MRI analysis showed a tendency for decreased T2 values in a time-dependent manner and supplementation of HIF-1α improved histological and imaginative IVDD while downregulation of HIF-1α exacerbated this degeneration. In summary, HIF-1α protected against IVDD, possibly through reducing ROS production in the mitochondria and consequent inhibition of inflammation, metabolism disorders and apoptosis of MNPCs, which provided a potential therapeutic instrument for the treatment of IVDD diseases.

IntroductionsExcessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated.ObjectivesTo identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis.MethodsChondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested.ResultsHuman cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium.ConclusionsOur findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

Background Hepatocellular carcinoma (HCC) is characterized by widespread epidemiology and extraordinary heterogeneity, with challenging prognosis prediction. Ferroptosis is a regulatory cell death driven by iron-dependent lipid peroxidation. The main aim of this study was to determine the predictive value of ferroptosis-related genes (FRGs) in HCC. Methods Herein, the data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) public databases. In the ICGC cohort, a multigenic signature was constructed using the LASSO Cox regression model. Next, patients in the TCGA cohort were used to verify the reliability of the model. Results Results showed that 30.07% of the differentially expressed genes (DEGs) in the ICGC cohort were associated with ferroptosis. Among them, 35 genes were identified as intersected genes associated with overall survival in both cohorts. Moreover, an 8-gene signature for prediction of HCC patients was constructed and the patients were divided it into low-risk and high-risk groups. The results indicated that the overall survival (OS) of patients in the high-risk group was lower than OS of patients in the low-risk group (P < 0.001 in both cohorts). Multivariate Cox regression analysis indicated that the risk score was an independent predictor of OS (HR > 1, P < 0.001). Receiver operating curves (ROC) demonstrated the predictive power of the signature. Furthermore, functional enrichment analysis revealed the existence of significantly correlated immune-related pathways, and their immune states were different between groups. Conclusions In summary, the genetic signature described in this study was associated with ferroptosis and it can be used to predict the prognosis of HCC. Therefore, targeted treatment of ferroptosis may be an alternative treatment option for HCC.

Background: Intervertebral disc (IVD) degeneration is a common degenerative disease that can lead to collapse or herniation of the nucleus pulposus (NP) and result in radiculopathy in patients. Methods: NP tissue and cells were isolated from patients and mice, and the expression profile of cortistatin (CST) was analysed. In addition, ageing of the NP was compared between 6-month-old WT and CST-knockout (CST-/-) mice. Furthermore, NP tissues and cells were cultured to validate the role of CST in TNF-α-induced IVD degeneration. Moreover, in vitro and in vivo experiments were performed to identify the potential role of CST in mitochondrial dysfunction, mitochondrial ROS generation and activation of the NLRP3 inflammasome during IVD degeneration. In addition, NF-κB signalling pathway activity was tested in NP tissues and cells from CST-/- mice. Results: The expression of CST in NP cells was diminished in the ageing- and TNF-α-induced IVD degeneration process. In addition, compared with WT mice, aged CST-/- mice displayed accelerated metabolic imbalance and enhanced apoptosis, and these mice showed a disorganized NP tissue structure. Moreover, TNF-α-mediated catabolism and apoptosis were alleviated by exogenous CST treatment. Furthermore, CST inhibited mitochondrial dysfunction in NP cells through IVD degeneration and suppressed activation of the NLRP3 inflammasome. In vitro and ex vivo experiments indicated that increased NF-κB pathway activity might have been associated with the IVD degeneration observed in CST-/- mice. Conclusion: This study suggests the role of CST in mitochondrial ROS and activation of the NLRP3 inflammasome in IVD degeneration, which might shed light on therapeutic targets for IVD degeneration.

Aseptic loosening is a major complication of prosthetic joint surgery, in which exaggerated inflammation and impaired osteoblastogenesis are detected. Ghrelin is a recently discovered neuropeptide that is closely associated with inflammatory conditions and bone regeneration. Here, we report that titanium particles inhibited ghrelin expression in MC3T3-E1 cells. Furthermore, exogenous ghrelin effectively inhibited titanium particle-induced inflammation in vitro by interacting with its receptor GHSR1a; as an inhibitor of GHSR1a, Dlys repressed the function of ghrelin. Moreover, ghrelin attenuated the impairment of osteoblastogenesis and the exaggeration of osteolysis induced by titanium particles. Furthermore, the protective role of ghrelin in aseptic loosening might be associated with the Wnt/β-catenin signaling pathway. Collectively, these findings suggest that ghrelin might be a potential therapeutic target for wear-debris-induced inflammation and osteolysis.

Contact dermatitis and psoriasis are skin disorders caused by immune dysregulation, yet much remains unknown about their underlying mechanisms. Ghrelin, a recently discovered novel peptide and potential endogenous anti-inflammatory factor expressed in the epidermis, is involved in skin repair and disease. In this study, we investigated the expression pattern and therapeutic effect of ghrelin in both contact dermatitis and psoriasis mouse models induced by oxazolone (OXA) and imiquimod (IMQ), respectively, and in TNF-α-stimulated RAW264.7 macrophages, NHEKs and skin fibroblasts. Ghrelin expression was reduced in both the OXA-induced contact dermatitis and IMQ-induced psoriasis mouse models. Furthermore, treatment with ghrelin attenuated skin inflammation in both the contact dermatitis and psoriasis mouse models. Mice administered PBS after OXA- or IMQ-induced model generation exhibited typical skin inflammation, whereas ghrelin treatment in these mouse models substantially decreased the dermatitis phenotype. In addition, exogenous ghrelin attenuated the inflammatory reaction induced by TNF-α in RAW264.7 cells. Moreover, ghrelin administration limited activation of NF-κB signaling. In summary, ghrelin may represent a potential molecular target for the prevention and treatment of inflammatory skin diseases, including contact dermatitis and psoriasis.

Background: Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-alpha) is known to play a critical role in OA. Cortistatin (CST) is a neuropeptide discovered over 20 years ago, which plays a vital role in inflammatory reactions. However, it is unknownwhether CST is involved in cartilage degeneration and OA development. Methods: The interaction between CST and TNF-alpha receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase binding assay. Western blot, Real-time PCR, ELISA, immunofluorescence staining, nitrite production assay andDMMB assay ofGAGwere performed for the primary chondrocyte experiments. Surgically induced and spontaneous OA models were established and western blot, flow cytometry, Real-time PCR, ELISA, immunohistochemistry and fluorescence in vivo imaging were performed for in vivo experiments. Findings: CST competitively bound to TNFR1 aswell as TNFR2. CST suppressed proinflammatory function of TNF alpha. Both spontaneous and surgically induced OA models indicated that deficiency of CST led to an accelerated OA-like phenotype, while exogenous CST attenuated OA development in vivo. Additionally, TNFR1- and TNFR2-knockout mice were used for analysis and indicated that TNFRs might be involved in the protective role of CST in OA. CST inhibited activation of the NF-kappa B signaling pathway in OA. Interpretation: This study provides new insight into the pathogenesis and therapeutic strategy of cartilage degenerative diseases, including OA. Fund: The National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province, Key Research andDevelopment Projects of Shandong Province and the Cross-disciplinary Fund of Shandong University. (c) 2019 The Authors. Published by Elsevier B. V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND: A retrospective comparative study was conducted to evaluate the clinical efficacy of platelet-rich plasma (PRP) application in total hip arthroplasty. METHODS: A total of 50 patients with severe hip injuries who underwent hip replacement surgeries in our hospital from February 2015 to March 2016 were collected, including 30 males and 20 females, with an average age of 75.5 +/- 6.5 years. Among them, 35 cases (PRP group) received PRP application, and 15 cases (control group) were without. The operation time, intraoperative and postoperative bleeding, score of Harris joint function, postoperative complications, and lengths of hospitalization days were recorded. RESULTS: Results showed that there was no significant difference in operative time, intraoperative and postoperative bleeding, and complications between the two groups (P>0.05) but there was trend toward less hospitalization days in the PRP group (P<0.05). The score of Harris joint function was higher in PRP than control (P=0.01). CONCLUSIONS: Application of PRP has a strong clinical efficacy in hip arthroplasty.

A 64-year-old man presented with severe weakness of the lower limbs after falling 3 meters 3 days earlier. Physical examination showed hypoesthesia below the arch rib, grade 1 weakness of the lower limbs, absent deep tendon reflexes, and a negative Babinski sign. Radiographs (Fig. 1A), computed tomography reconstruction images (Fig. 1B and C), and magnetic resonance imaging (Fig. 1D) revealed kyphosis with a Cobb angle of 180 and associated rotational deformity. T10 and T11 were the top vertebrae and there was spinal stenosis at T8–L1 with spinal cord compression. The patient was treated with decompression of the spinal canal on T10 and T11 and screw internal fixation (Fig. 2). Sensory and motor deficits were unchanged at 3 months' follow-up. Fig. 2X-ray radiographs after treatment. View Large Image Figure Viewer Download Hi-res image