The role of extracellular vesicles in iron homeostasis and ferroptosis: Focus on musculoskeletal diseases.

Iron homeostasis is crucial for maintaining proper cellular function, and its disruption is considered one of the pathogenic mechanisms underlying musculoskeletal diseases. Under conditions of oxidative stress, the accumulation of cellular iron overload and lipid peroxidation can lead to ferroptosis. Extracellular vesicles (EVs), serving as mediators in the cell-to-cell communication, play an important role in regulating the outcome of cell ferroptosis. Growing evidence has proven that EV biogenesis and secretion are tightly associated with cellular iron export. Furthermore, different sources of EVs deliver diverse cargoes to bring about phenotypic changes in the recipient cells, either activating or inhibiting ferroptosis. Thus, delivering therapies targeting ferroptosis through EVs may hold significant potential for treating musculoskeletal diseases. This review aims to summarize current knowledge on the role of EVs in iron homeostasis and ferroptosis, as well as their therapeutic applications in musculoskeletal diseases, and thereby provide valuable insights for both research and clinical practice.

Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 modification.

Although cigarette smoking (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We have shown that excessive activation of mast cells (MCs) and their proteases play key roles in CS-associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation, and lung cancer. Previous studies have also shown that MCs and their proteases induce degenerative musculoskeletal disease. By using a custom-designed smoke-exposure mouse system, we demonstrated that CS results in intervertebral disc (IVD) degeneration and release of MC-restricted tetramer tryptases (TTs) in the IVDs. TTs were found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3' untranslated region (UTR) of the transcript that encodes dishevelled-axin (DIX) domain-containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of Dixdc1. DIXDC1 functionally interacts with disrupted in schizophrenia 1 (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.

Bioactive VS4-based sonosensitizer for robust chemodynamic, sonodynamic and osteogenic therapy of infected bone defects.

BACKGROUND: Most bone defects caused by bone disease or trauma are accompanied by infection, and there is a high risk of infection spread and defect expansion. Traditional clinical treatment plans often fail due to issues like antibiotic resistance and non-union of bones. Therefore, the treatment of infected bone defects requires a strategy that simultaneously achieves high antibacterial efficiency and promotes bone regeneration. RESULTS: In this study, an ultrasound responsive vanadium tetrasulfide-loaded MXene (VSM) Schottky junction is constructed for rapid methicillin-resistant staphylococcus aureus (MRSA) clearance and bone regeneration. Due to the peroxidase (POD)-like activity of VS4 and the abundant Schottky junctions, VSM has high electron-hole separation efficiency and a decreased band gap, exhibiting a strong chemodynamic and sonodynamic antibacterial efficiency of 94.03%. Under the stimulation of medical dose ultrasound, the steady release of vanadium element promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The in vivo application of VSM in infected tibial plateau bone defects of rats also has a great therapeutic effect, eliminating MRSA infection, then inhibiting inflammation and improving bone regeneration. CONCLUSION: The present work successfully develops an ultrasound responsive VS4-based versatile sonosensitizer for robust effective antibacterial and osteogenic therapy of infected bone defects.

Biomimetic bone-periosteum scaffold for spatiotemporal regulated innervated bone regeneration and therapy of osteosarcoma.

The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design often overlooks the crucial role of precisely regulating innervation in bone regeneration. Here, we develop a Germanium Selenium (GeSe) co-doped polylactic acid (PLA) nanofiber membrane-coated tricalcium phosphate bioceramic scaffold (TCP-PLA/GeSe) that mimics the bone-periosteum structure. This biomimetic scaffold offers a dual functionality, combining piezoelectric and photothermal conversion capabilities while remaining biodegradable. When subjected to ultrasound irradiation, the US-electric stimulation of TCP-PLA/GeSe enables spatiotemporal control of neurogenic differentiation. This feature supports early innervation during bone formation, promoting early neurogenic differentiation of Schwann cells (SCs) by increasing intracellular Ca2+ and subsequently activating the PI3K-Akt and Ras signaling pathways. The biomimetic scaffold also demonstrates exceptional osteogenic differentiation potential under ultrasound irradiation. In rabbit model of large segment bone defects, the TCP-PLA/GeSe demonstrates promoted osteogenesis and nerve fibre ingrowth. The combined attributes of high photothermal conversion capacity and the sustained release of anti-tumor selenium from the TCP-PLA/GeSe enable the synergistic eradication of osteosarcoma both in vitro and in vivo. This strategy provides new insights on designing advanced biomaterials of repairing large segment bone defect and osteosarcoma.

The involvement of DDX3X in compression-induced nucleus pulposus pyroptosis.

OBJECTIVE: A study has been conducted to investigate the relationship between DDX3X and nucleus pulposus (NP) pyroptosis. METHODS: DDX3X and pyroptosis-related proteins (Caspase-1, Full-length GSDMD, Cleaved GSDMD) were measured in compression-induced human NP cells and tissue. DDX3X was overexpressed or knocked down by gene transfection. The expressions of NLRP3, ASC, and pyroptosis-related proteins were detected by Western blot assay. IL-1ß and IL-18 were detected by ELISA. HE staining and immunohistochemistry were used to observe the expression of DDX3X, NLRP3, and Caspase-1 in the rat model of compression-induced disc degeneration. RESULTS: DDX3X, NLRP3, and Caspase-1 were highly expressed in degenerated NP tissue. Overexpression of DDX3X induced pyroptosis in NP cells and increased levels of NLRP3, IL-1ß, IL-18, and pyroptosis-related proteins. Knockdown of DDX3X showed an opposite trend to overexpression of DDX3X. The NLRP3 inhibitor CY-09 effectively prevented the up-regulation of the expression of IL-1ß, IL-18, ASC, Pro-caspase-1, Full-length GSDMD, and Cleaved GSDMD. Increased expression of DDX3X, NLRP3, and Caspase-1 was observed in the rat model of compression-induced disc degeneration. CONCLUSION: Our study showed that DDX3X mediates pyroptosis of NP cells by upregulating NLRP3 expression, which ultimately leads to intervertebral disc degeneration (IDD). This discovery deepens the understanding of IDD pathogenesis and provides a promising and novel therapeutic target for IDD.

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage.

Poor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti-oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol-based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat-1, and Arrestin expressions of photoreceptors. RNA-sequencing, RT-qPCR, and Western blotting validate that mitochondrial DNA (mt-DNA)-encoded genes of the electron transport chain (ETC), such as mt-Nd4l, mt-Co1, mt-Cytb, and mt-Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n-DNA)-encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt-DNA and n-DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)-mediated mt-DNA cleavage and mt-DNA leakage via voltage-dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro-inflammatory cGAS-STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration.

BACKGROUND: Extracellular matrix stiffness is emerging as a crucial mechanical cue that drives the progression of various diseases, such as cancer, fibrosis, and inflammation. The matrix stiffness of the nucleus pulposus (NP) tissues increase gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In addition, mitochondrial dynamics play a key role in various cellular functions. An in-depth investigation of the pathogenesis of IDD can provide new insights for the development of effective therapies. In this study, we aim to investigate the effects of matrix stiffness on mitochondrial dynamics in IDD. METHODS: To build the gradient stiffness model, NP cells were cultured on polystyrene plates with different stiffness. Western blot analysis, and immunofluorescence staining were used to detect the expression of mitochondrial dynamics-related proteins. Flow cytometry was used to detect the mitochondrial membrane potential and intracellular Ca2+ levels. Apoptosis related proteins, ROS level, and TUNEL staining were performed to assess the effect of substrate stiffness on NP cells. RESULTS: Stiff substrate increased phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 by activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which promoted mitochondrial fission and apoptosis in NP cells. Furthermore, Piezo1 activation was involved in the regulation of the post-translational modifications of Drp1 and mitochondrial fission caused by matrix stiffness. Inhibition of Piezo1 and ERK1/2 can effectively reduce stiffness-induced ROS elevation and apoptosis in NP cells. CONCLUSIONS: Our results revealed that stiff substrate causes Piezo1 activation and Ca2+ influx, results in ERK1/2 activation and phosphorylation of Drp1 at S616, and finally leads to mitochondrial fission and apoptosis in NP cells. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for treating IDD.

Proton-Induced Defect-Rich Vanadium Oxides as Reversible Polysulfide Conversion Sites for High-Performance Lithium Sulfur Batteries.

Lithium-sulfur (Li-S) batteries have attracted attention due to their high theoretical energy density, natural abundance, and low cost. However, the diffusion of polysulfides decreases the utilization and further degrades the battery's life. We have successfully fabricated a defect-rich layered sodium vanadium oxide with proton doping (HNVO) nanobelt and used it as the functional interface layer on the separator in Li-S batteries. Benefiting from the abundant defects of NVO and the catalytic activity of metal vanadium in the electrochemical process, the shuttle of polysulfides was greatly decreased by reversible chemical adsorption. Moreover, the extra graphene layer contributes to accelerating the charge carrier at high current densities. Therefore, a Li-S battery with G@HNVO delivers a high capacity of 1494.8 mAh g-1 at 0.2 C and a superior cycling stability over 700 cycles at 1 C. This work provides an effective strategy for designing the electrode/separator interface layer to achieve high-performance Li-S batteries.

Molecular mechanism and therapeutic potential of HDAC9 in intervertebral disc degeneration.

BACKGROUND: Intervertebral disc degeneration (IVDD) is the major cause of low-back pain. Histone deacetylase 9 (HDAC9) was dramatically decreased in the degenerative nucleus pulposus (NP) samples of patients with intervertebral disc degeneration (IVDD) according to bioinformatics analysis of Gene Expression Omnibus (GEO) GSE56081 dataset. This study aims to investigate the role of HDAC9 in IVDD progression. METHODS: The contribution of HDAC9 to the progression of IVDD was assessed using HDAC9 knockout (HDAC9KO) mice and NP-targeted HDAC9-overexpressing mice by IVD injection of adenovirus-mediated HDAC9 under a Col2a1 promoter. Magnetic resonance imaging (MRI) and histological analysis were used to examine the degeneration of IVD. NP cells were isolated from mice to investigate the effects of HDAC9 on apoptosis and viability. mRNA-seq and coimmunoprecipitation/mass spectrometry (co-IP/MS) analysis were used to analyze the HDAC9-regulated factors in the primary cultured NP cells. RESULTS: HDAC9 was statistically decreased in the NP tissues in aged mice. HDAC9KO mice spontaneously developed age-related IVDD compared with wild-type (HDAC9WT) mice. In addition, overexpression of HDAC9 in NP cells alleviated IVDD symptoms in a surgically-induced IVDD mouse model. In an in vitro assay, knockdown of HDAC9 inhibited cell viability and promoted cell apoptosis of NP cells, and HDAC9 overexpression had the opposite effects in NP cells isolated from HDAC9KO mice. Results of mRNA-seq and co-IP/MS analysis revealed the possible proteins and signaling pathways regulated by HDAC9 in NP cells. RUNX family transcription factor 3 (RUNX3) was screened out for further study, and RUNX3 was found to be deacetylated and stabilized by HDAC9. Knockdown of RUNX3 restored the effects of HDAC9 silencing on NP cells by inhibiting apoptosis and increasing viability. CONCLUSION: Our results suggest that HDAC9 plays an important role in the development and progression of IVDD. It might be required to protect NP cells against the loss of cell viability and apoptosis by inhibiting RUNX3 acetylation and expression during IVDD. Together, our findings suggest that HDAC9 may be a potential therapeutic target in IVDD.

The contribution of preoperative balanced halo-pelvic traction to severe rigid spinal deformity correction.

PURPOSE: The aim of this study was to assess the clinical efficacy of balanced halo-pelvic traction (HPT) and evaluate its contribution to the correction surgery in treating adult severe rigid spinal deformity. METHODS: One hundred and eight adult patients with severe rigid spinal deformity who underwent preoperative HPT and correction surgery were reviewed. The main coronal curve, segmental kyphotic angle, coronal balance (CB), sagittal balance (SVA), and the length of spine were measured before HPT, after HPT, post-operatively, and at final follow-up. The HPT contribution rates to deformity correction were calculated. RESULTS: The pre-HPT main coronal curve was 103.4 ± 10.6°, improved to 61.0 ± 13.4° after traction and further improved to 44.2 ± 10.2° after surgical correction, and maintained at 50.3 ± 9.9° at final follow-up. CB started at 4.2 ± 4.8 cm, improved to 2.1 ± 2.5 cm after HPT, 0.8 ± 1.2 cm after operation, and 0.7 ± 0.9 cm at final follow-up. The pre-HPT sagittal segmental kyphotic angle was 67.3 ± 17.7°, was then improved to 42.2 ± 27.5° after traction and further improved to 34.9 ± 10.2° after surgery, and maintained at 35.4 ± 10.4° at final follow-up. The length of spine improved from 35.9 ± 5.9 to 42.6 ± 6.0 cm via HPT, reached up to 45.0 ± 6.0 cm after operation, and maintained at 44.3 ± 5.2 cm at final follow-up. CONCLUSION: HPT is effective for the treatment of severe rigid spinal deformity. Balanced HPT can dramatically improve coronal and sagittal deformity as well as spinal length before corrective surgery.

Sequential correction of severe and rigid kyphoscoliosis: a new technical note and preliminary results.

OBJECTIVE: The present study is to evaluate the clinical outcomes of the sequential correction of severe and rigid kyphoscoliosis. METHODS: Between January 2014 and December 2020, 27 adults with severe and rigid kyphoscoliosis underwent sequential correction combined with posterior grade 4 or grade 5 spinal osteotomy. Radiological parameters, including the major curve Cobb angle, kyphotic angle, coronal imbalance, and sagittal vertical axis (SVA), were compared. Patient self-reported health-related quality of life (HRQOL) scores were used to evaluate clinical outcomes. RESULTS: The mean major curve Cobb angle improved from 134.30 ± 13.24° to 44.48 ± 9.34° immediately after surgery and to 46.11 ± 8.94° at the final follow-up. The mean kyphotic angle improved from 112.15 ± 20.28° to 38.63 ± 15.00° immediately after surgery and to 39.85 ± 14.92° at the final follow-up. The mean preoperative major curve Cobb angle of grade 5 spinal osteotomy group was higher than that of grade 4 spinal osteotomy group. Coronal imbalance and SVA slightly improved. The patient self-reported HRQOL scores improved postoperatively and at the final follow-up. Activity, appearance and total scores of the SRS-22 of the grade 5 spinal osteotomy group at the final follow-up were significantly better than those of the grade 4 spinal osteotomy group. CONCLUSIONS: Sequential correction combined with posterior grade 4 or grade 5 spinal osteotomies is an excellent and safe treatment for severe and rigid kyphoscoliosis in adults. Sequential correction combined with posterior grade 5 spinal osteotomies can be used to correct severe and rigid kyphoscoliosis with higher major curve Cobb angle.

Total en bloc spondylectomy of thoracic giant cell tumor with secondary aneurysmal bone cyst: case reports and review of literature.

Spinal giant cell tumor (GCT) combined with secondary aneurysmal bone cyst (ABC) is a locally aggressive primary bone tumor. Total en bloc spondylectomy has never been reported to treat thoracic GCT combined with secondary ABC. We retrospectively reviewed two cases of spinal GCT combined with secondary ABC. A 41-year-old male patient was presented with back pain due to irregular expansive bone destruction involving the T6 vertebral body and intraspinal space-occupying lesion. Total en bloc spondylectomy of T6 vertebra was performed with good neurological status after the surgery. A 29-year-old female patient was presented with right scapular region pain due to irregular expansive bone destruction involving the T5 vertebral body and intraspinal space-occupying lesion. Total en bloc spondylectomy of T5 vertebra was performed with good neurological status after the surgery. Adjuvant radiation therapy was applied after the surgery without local recurrence at the 12-month or 24-month follow-up. Spinal GCT combined with secondary ABC appears to have a high local recurrence rate. Therefore, total en bloc spondylectomy should be applied to treat thoracic GCT combined with secondary ABC.

Global realignment after posterior vertebral column resection in severe thoracolumbar post-tubercular kyphosis: correlation with patient-reported outcomes.

PURPOSE: To investigate spinal realignment in patients with severe post-tubercular kyphosis (PTK) who underwent posterior vertebral column resection (PVCR) and its correlation with patient-reported outcomes (PROs). METHODS: Eighty-two patients were included in this study. Spinopelvic parameters (focal scoliosis (FS), coronal balance (CB), sagittal vertical axis (SVA), focal kyphosis (FK), C2-7 lordosis (CL), thoracic kyphosis (TK), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), and pelvic incidence minus lumbar lordosis (PI-LL)) and PROs (Visual Analog Scale (VAS) and Oswestry Disability Index (ODI)) were analyzed. The correlation between spinopelvic parameters and PROs was evaluated. RESULTS: FK, FS, CL, TK, LL, and PI-LL significantly changed after surgery. FK decreased from pre-operative 108.5 ± 16.4° to 31.8 ± 4.5° at three months after surgery and increased to 38.7 ± 6.6° at final follow-up (P < 0.001). FS decreased from pre-operative 20.9 ± 2.2° to 5.1 ± 2.2° at final follow-up (P < 0.001). CL decreased from pre-operative 7.2 ± 7.3° to 3.3 ± 8.3° at final follow-up (P = 0.002). TK improved from pre-operative - 5.6 ± 7.1° to 12.9 ± 8.2° at final follow-up (P < 0.001). LL decreased from pre-operative 75.5 ± 12.6° to 45.5 ± 7.9° at final follow-up (P < 0.001). PI-LL improved from pre-operative - 24.8 ± 13.4° to 4.8 ± 9.9° at final follow-up (P < 0.001). The improvement of PROs was found to be significantly correlated with the variations of FK, CL, TK, LL, and PI-LL. The multiple regression analysis revealed that FK was an independent predictor for the improvement of VAS and ODI. CONCLUSIONS: PVCR is effective in treating severe PTK, which can significantly improve patients' clinical and radiographic outcomes. Spine surgeons should pay more attention to reducing the residual kyphosis.

Ultrasonic Interfacial Engineering of MoS2 -Modified Zn Single-Atom Catalysts for Efficient Osteomyelitis Sonodynamic Ion Therapy.

Osteomyelitis is considered as the most serious bone infection, which can lead to the bone destruction or fatal sepsis. Clinical treatments through frequent antibiotics administration and surgical debridement bring inevitable side effects including drug-resistance and disfigurements. It is urgent to develop an antibiotics-free and rapid strategy to treat osteomyelitis. Herein, a bifunctional sonosensitizer that consists of porphyrin-like Zn single-atom catalysts (g-ZnN4 ) and MoS2 quantum dots is developed, which exhibits excellent sonodynamic antibacterial efficiency and osteogenic ability. It is found that the construction of heterogeneous interfaces of g-ZnN4 -MoS2 fully activates the adsorbed O2 due to the increased interface charge transfer, enhanced spin-flip, and reduced activation energy of O2 . The generated 1 O2 can kill methicillin-resistant Staphylococcus aureus (MRSA) with an antibacterial efficiency of 99.58% under 20 min of ultrasound (US) irradiation. The Zn single atoms immobilized in g-ZnN4 can be released steadily in the form of Zn2+ for 28 days within safe concentration, realizing the great osteoinductive ability of such a sonosensitizer. For the treatment of MRSA-infected osteomyelitis, the inflammation and bone loss can be significantly suppressed through sonodynamic ion therapy. This work provides another strategy for developing high efficiency sonosensitizer through ultrasound interfacial engineering.

Bone Repairment via Mechanosensation of Piezo1 Using Wearable Pulsed Triboelectric Nanogenerator.

Bone repair in real time is a challenging medical issue for elderly patients; this is mainly because aged bone marrow mesenchymal stem cells (BMSCs) possess limited osteogenesis potential and repair capacity. In this study, triboelectric stimulation technology is used to achieve bone repair via mechanosensation of Piezo1 by fabricating a wearable pulsed triboelectric nanogenerator (WP-TENG) driven by human body movement. A peak value of 30 µA has the optimal effects to rejuvenate aged BMSCs, enhance their osteogenic differentiation, and promote human umbilical vein endothelial cell tube formation. Further, previous studies demonstrate that triboelectric stimulation of a WP-TENG can reinforce osteogenesis of BMSCs and promote the angiogenesis of human umbilical vein endothelial cells (HUVECs). Mechanistically, aged BMSCs are rejuvenated by triboelectric stimulation via the mechanosensitive ion channel Piezo1. Thus, the osteogenesis potential of BMSCs is enhanced and the tube formation capacity of HUVECs is improved, which is further confirmed by augmented bone repair and regeneration in in vivo investigations. This study provides a potential signal transduction mechanism for rejuvenating aged BMSCs and a theoretical basis for bone regeneration using triboelectric stimulation generated by a WP-TENG.

Synergistic Poly(lactic acid) Antibacterial Surface Combining Superhydrophobicity for Antiadhesion and Chlorophyll for Photodynamic Therapy.

The problem of nosocomial infections caused by bacterial growth on material surfaces is an urgent threat to public health. Although numerous materials and methods have been explored to fight against infections, the methods are complicated and the materials are slightly toxic. It is highly desirable to develop an antibacterial strategy that kills bacteria effectively without drug resistance and cytotoxicity. Herein, we present a synergistic antibacterial polylactic acid (PLA) surface with superhydrophobic antibacterial adhesion and photodynamic bactericidal activity. Initially, the surface displayed low-adhesion superhydrophobicity and resisted most bacterial adhesion. Furthermore, completely non-toxic chlorophyll possessed excellent photodynamic bactericidal properties under non-toxic visible light, which was incorporated into micro-/nanoscale PLA surfaces. We achieved efficient antibacterial activity using completely non-toxic materials and a facile non-solvent-induced phase separation process. This non-toxic, simple, good biocompatible, and no drug-resistant strategy has great advantages in combating bacterial infections.

Is HFPO-DA (GenX) a suitable substitute for PFOA? A comprehensive degradation comparison of PFOA and GenX via electrooxidation.

Due to the potential hazard of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA, GenX) has become a typical alternative since 2009. However, GenX has recently been reported to have equal or even greater toxicity and bioaccumulation than PFOA. Considering the suitability of alternatives, it is quite essential to study and compare the degradation degree between PFOA and GenX in water. Therefore, in the present study, a comprehensive degradation comparison between them via electrooxidation with a titanium suboxide membrane anode was conducted. The degradation rate decreased throughout for PFOA, while it first increased and then decreased for GenX when the permeate flux increased from 17.3 L to 100.3 L m-2·h-1. The different responses of PFOA and GenX to flux might be attributed to their different solubilities. In addition, the higher kobs of PFOA demonstrated that it had a better degradability than GenX by 2.4-fold in a mixed solution. The fluorinated byproduct perfluoropropanoic acid (PFPrA) was detected as a GenX intermediate, suggesting that ether bridge splitting was needed for GenX electrooxidation. This study provides a reference for assessing the degradability of GenX and PFOA and indicates that it is worth reconsidering whether GenX is a suitable alternative for PFOA from the point of view of environmental protection.

Vasorin-containing small extracellular vesicles retard intervertebral disc degeneration utilizing an injectable thermoresponsive delivery system.

Intervertebral disc degeneration (IDD) is the pathological reason of back pain and the therapeutic approaches are still unsatisfactory. Recently, mesenchymal stem cell-derived small extracellular vesicles (EVs) have emerged as the novel regenerative method for IDD. In this study, we intensively investigated the therapeutic mechanism of small EVs, and found that vasorin protein enriched in EVs promoted the proliferation and extracellular matrix anabolism of nucleus pulposus cells via the Notch1 signaling pathway. Then, we fabricated a thermoresponsive gel which composed of Pluronic F127 and decellularized extracellular matrix (FEC) for the delivery and sustained release of EVs. Besides, ex vivo and in vivo results showed that EVs embedded in FEC (EVs@FEC) ameliorate the disc degeneration efficiently and achieve better therapeutic effects than one-off EVs delivery. Collectively, these findings deepen the understanding of EVs mechanism in treating intervertebral disc degeneration, and also illustrate the promising capacity of sustained EVs release system for intervertebral disc regeneration.

RETREG1-mediated ER-phagy activation induced by glucose deprivation alleviates nucleus pulposus cell damage via ER stress pathway.

Accumulating evidence indicates that ER-phagy serves as a key adaptive regulatory mechanism in response to various stress conditions. However, the exact mechanisms underlying ER-phagy in the pathogenesis of intervertebral disc degeneration remain largely unclear. In the present study, we demonstrated that RETREG1-mediated ER-phagy is induced by glucose deprivation (GD) treatment, along with ER stress activation and cell function decline. Importantly, ER-phagy was shown to be crucial for cell survival under GD conditions. Furthermore, ER stress was suggested as an upstream event of ER-phagy upon GD treatment and upregulation of ER-phagy could counteract the ER stress response. Therefore, our findings indicate that RETREG1-mediated ER-phagy activation protects against GD treatment-induced cell injury via modulating ER stress in human nucleus pulposus cells.

Preoperative management and postoperative complications associated with transoral decompression for the upper cervical spine.

PURPOSE: This review aimed to describe the preoperative management and postoperative complications associated with transoral decompression of the upper cervical spine, and to clarify the risk factors, related issues and complication management. METHODS: Studies on transoral decompression for the upper cervical spine were reviewed systematically. The preoperative management and postoperative complications associated with transoral decompression for upper cervical deformities were analyzed. RESULTS: Evidence suggests that preoperative management in patients undergoing transoral decompression for the upper cervical spine is closely related to the occurrence of postoperative complications. Hence, preoperative surgical planning, preoperative preparation, and oral nursing care should be seriously considered in these patients. Moreover, while being established as an effective and safe method, transoral decompression is associated with several postoperative complications, which could be prevented by elaborate preoperative management, improved surgical skills, and appropriate precautionary measures. CONCLUSIONS: The effectiveness and safety of transoral decompression has been improved by the constant development of operative techniques and advanced auxiliary diagnostic and therapeutic methods, with the understanding of the anatomical structure of the craniocervical joint. Therefore, the incidence rates of postoperative complications have decreased. The application of individualized anterior implants and less-invasive endoscopic endonasal approach has improved the effectiveness of transoral decompression and reduced the associated complications.