Enhanced Transconjunctival Lower Blepharoplasty: A Novel Method for Intraorbital Fat Transposition and Stabilization.

BACKGROUND: The evolution of lower blepharoplasty has shifted from simply removing of orbital septum fat to smoothing of the lid-cheek junction through fat repositioning. This paper adopts a novel technique to transpose and stabilize intraorbital fat during transconjunctival lower blepharoplasty. The tear trough and nasal alar base were filled to correct the pouch while ensuring the blood supply of the fat flap. METHODS: Between September 2019 and June 2022, 104 patients aged between 22 and 49 who underwent bilateral fat flap transposition-nasal alar base filling lower blepharoplasty were selected. The surgical results were assessed by non-operative plastic surgeons according to the Hirmand grading system. Moreover, a self-satisfaction survey was conducted and patients were followed up for at least 6 months to evaluate any complications and surgical outcomes. A high-frequency ultrasound imaging system was used to assess the degree of filling of the tear trough and nasal alar base. RESULTS: All 104 patients were followed up for at least 6 months. The postoperative Hirmand grade was 0 for 96 out of 104 (92.3%) patients. In terms of self-satisfaction assessment, there were 92 out of 104 (88.5%) patients reported satisfaction. Dermatologic ultrasound showed no obvious gaps 6 months after surgery. CONCLUSION: Transconjunctival fat flap transposition combined with nasal alar base filling during lower blepharoplasty has been shown to have a positive postoperative effect and high patient satisfaction. This procedure can preserve the blood supply of the fat flap, reduce the rates of fat absorption and denaturation, and improve facial contour, resulting in a satisfactory repairing effect. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The need for thoracic magnetic resonance imaging before vertebral augmentation surgery in patients with lumbar vertebral fractures.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCFs) of the lumbar region may be accompanied by thoracic fractures. Treating only the lumbar fractures can lead to worsening of the thoracic fractures or unresolved postoperative symptoms. This study aims to investigate the need to perform thoracic MRI before vertebral augmentation (including percutaneous vertebroplasty and percutaneous kyphoplasty) in patients with lumbar OVCF. METHODS: This study retrospectively analyzed patients with lumbar OVCF who were scheduled for surgical treatment. All patients underwent thoracic and lumbar MRI before surgery. We evaluated the proportion of thoracic fractures accompanying lumbar fractures at each segment and identified the common locations of these accompanying fractures. Univariate and multivariate analyses were conducted to determine the risk factors and optimal thresholds for predicting accompanying thoracic fractures. RESULTS: The study recruited 700 patients, of whom 96 (13.71%) had new thoracic fractures along with lumbar fractures. The most common thoracic segments affected were T10 (22.50%), T9 (19.17%), T8 (26.67%), and T7 (20.83%). Univariate analysis showed significant differences in age and cause of injury between the thoracic fracture group and the control group. The bone density of the thoracic fracture group was significantly lower than that of the control group. Multivariate logistic regression analysis indicated that lifting heavy objects, sprains, and low bone density are risk factors for thoracic fractures in patients with lumbar OVCF. CONCLUSION: It is crucial to perform thoracic MRI before surgery in patients with lumbar OVCF. This helps to avoid missing thoracic fractures, prevent the worsening of injuries, and ensure better postoperative outcomes.

Surgical outcomes of robotic-assisted percutaneous fixation for thoracolumbar fractures in patients with ankylosing spondylitis.

BACKGROUND: Spinal fractures in patients with ankylosing spondylitis (AS) mainly present as instability, involving all three columns of the spine, and surgical intervention is often considered necessary. However, in AS patients, the significant alterations in bony structure and anatomy result in a lack of identifiable landmarks, which increases the difficulty of pedicle screw implantation. Therefore, we present the clinical outcomes of robotic-assisted percutaneous fixation for thoracolumbar fractures in patients with AS. METHODS: A retrospective review was conducted on a series of 12 patients diagnosed with AS. All patients sustained thoracolumbar fractures between October 2018 and October 2022 and underwent posterior robotic-assisted percutaneous fixation procedures. Outcomes of interest included operative time, intra-operative blood loss, complications, duration of hospital stay and fracture union. The clinical outcomes were assessed using the visual analogue scale (VAS) and Oswestry Disability Index (ODI). To investigate the achieved operative correction, pre- and postoperative radiographs in the lateral plane were analyzed by measuring the Cobb angle. RESULTS: The 12 patients had a mean age of 62.8 ± 13.0 years and a mean follow-up duration of 32.7 ± 18.9 months. Mean hospital stay duration was 15 ± 8.0 days. The mean operative time was 119.6 ± 32.2 min, and the median blood loss was 50 (50, 250) ml. The VAS value improved from 6.8 ± 0.9 preoperatively to 1.3 ± 1.0 at the final follow-up (P < 0.05). The ODI value improved from 83.6 ± 6.1% preoperatively to 11.8 ± 6.6% at the latest follow-up (P < 0.05). The average Cobb angle changed from 15.2 ± 11.0 pre-operatively to 8.3 ± 7.1 at final follow-up (P < 0.05). Bone healing was consistently achieved, with an average healing time of 6 (5.3, 7.0) months. Of the 108 screws implanted, 2 (1.9%) were improperly positioned. One patient experienced delayed nerve injury after the operation, but the nerve function returned to normal upon discharge. CONCLUSION: Posterior robotic-assisted percutaneous internal fixation can be used as an ideal surgical treatment for thoracolumbar fractures in AS patients. However, while robot-assisted pedicle screw placement can enhance the accuracy of pedicle screw insertion, it should not be relied upon solely.

diABZI and poly(I:C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3.

Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate that IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor activities by inducing endogenous IFN-I and IFN-stimulated genes, their function in bone homeostasis still needs further exploration. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. First, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized -induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/-mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impairs the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway.

OCs are responsible for bone resorption, and their excessive differentiation and enhanced activity will lead to bone resorption diseases such as osteoporosis and osteolysis. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. IFN-I inducers suppress OC differentiation, and particularly diABZI alleviates bone loss in osteolysis and osteoporosis mouse models. Taken together, IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway. Our in-depth and comprehensive discovery of the IFN-I inducer would provide new insight into OC biology and therapeutic targets for osteoclastic bone resorption diseases.

Recent advances in the application of gasotransmitters in spinal cord injury.

Spinal Cord Injury (SCI) is a condition characterized by complete or incomplete motor and sensory impairment, as well as dysfunction of the autonomic nervous system, caused by factors such as trauma, tumors, or inflammation. Current treatment methods primarily include traditional approaches like spinal canal decompression and internal fixation surgery, steroid pulse therapy, as well as newer techniques such as stem cell transplantation and brain-spinal cord interfaces. However, the above methods have limited efficacy in promoting axonal and neuronal regeneration. The challenge in medical research today lies in promoting spinal cord neuron regeneration and regulating the disrupted microenvironment of the spinal cord. Studies have shown that gas molecular therapy is increasingly used in medical research, with gasotransmitters such as hydrogen sulfide, nitric oxide, carbon monoxide, oxygen, and hydrogen exhibiting neuroprotective effects in central nervous system diseases. The gas molecular protect against neuronal death and reshape the microenvironment of spinal cord injuries by regulating oxidative, inflammatory and apoptotic processes. At present, gas therapy mainly relies on inhalation for systemic administration, which cannot effectively enrich and release gas in the spinal cord injury area, making it difficult to achieve the expected effects. With the rapid development of nanotechnology, the use of nanocarriers to achieve targeted enrichment and precise control release of gas at Sites of injury has become one of the emerging research directions in SCI. It has shown promising therapeutic effects in preclinical studies and is expected to bring new hope and opportunities for the treatment of SCI. In this review, we will briefly outline the therapeutic effects and research progress of gasotransmitters and nanogas in the treatment of SCI.

G protein subunit alpha i2's pivotal role in angiogenesis.

Here we explored the potential role of Gαi2 (G protein subunit alpha i2) in endothelial cell function and angiogenesis. Methods: Genetic methodologies such as shRNA, CRISPR/Cas9, dominant negative mutation, and overexpression were utilized to modify Gαi2 expression or regulate its function. Their effects on endothelial cell functions were assessed in vitro. In vivo, the endothelial-specific Gαi2 shRNA adeno-associated virus (AAV) was utilized to silence Gαi2 expression. The impact of this suppression on retinal angiogenesis in control mice and streptozotocin (STZ)-induced diabetic retinopathy (DR) mice was analyzed. Results: Analysis of single-cell RNA sequencing data revealed Gαi2 (GNAI2) was predominantly expressed in retinal endothelial cells and expression was increased in retinal endothelial cells following oxygen-induced retinopathy (OIR) in mice. Moreover, transcriptome analysis linking Gαi2 to angiogenesis-related processes/pathways, supported by increased Gαi2 expression in experimental OIR mouse retinas, highlighted its possible role in angiogenesis. In various endothelial cell types, shRNA-induced silencing and CRISPR/Cas9-mediated knockout (KO) of Gαi2 resulted in substantial reductions in cell proliferation, migration, invasion, and capillary tube formation. Conversely, Gαi2 over-expression in endothelial cells induced pro-angiogenic activities, enhancing cell proliferation, migration, invasion, and capillary tube formation. Furthermore, our investigation revealed a crucial role of Gαi2 in NFAT (nuclear factor of activated T cells) activation, as evidenced by the down-regulation of NFAT-luciferase reporter activity and pro-angiogenesis NFAT-targeted genes (Egr3, CXCR7, and RND1) in Gαi2-silenced or -KO HUVECs, which were up-regulated in Gαi2-overexpressing endothelial cells. Expression of a dominant negative Gαi2 mutation (S48C) also down-regulated NFAT-targeted genes, slowing proliferation, migration, invasion, and capillary tube formation in HUVECs. Importantly, in vivo experiments revealed that endothelial Gαi2 knockdown inhibited retinal angiogenesis in mice, with a concomitant down-regulation of NFAT-targeted genes in mouse retinal tissue. In contrast, Gαi2 over-expression in endothelial cells enhanced retinal angiogenesis in mice. Single-cell RNA sequencing data confirmed increased levels of Gαi2 specifically in retinal endothelial cells of mice with streptozotocin (STZ)-induced diabetic retinopathy (DR). Importantly, endothelial Gαi2 silencing ameliorated retinal pathological angiogenesis in DR mice. Conclusion: Our study highlights a critical role for Gαi2 in NFAT activation, endothelial cell activation and angiogenesis, offering valuable insights into potential therapeutic strategies for modulating these processes.

Zinc-doped bioactive glass-functionalized polyetheretherketone to enhance the biological response in bone regeneration.

Polyether ether ketone (PEEK) is gaining recognition as a highly promising polymer for orthopedic implants, attributed to its exceptional biocompatibility, ease of processing, and radiation resistance. However, its long-term in vivo application faces challenges, primarily due to suboptimal osseointegration from postimplantation inflammation and immune reactions. Consequently, biofunctionalization of PEEK implant surfaces emerges as a strategic approach to enhance osseointegration and increase the overall success rates of these implants. In our research, we engineered a multifaceted PEEK implant through the in situ integration of chitosan-coated zinc-doped bioactive glass nanoparticles (Zn-BGNs). This novel fabrication imbues the implant with immunomodulatory capabilities while bolstering its osseointegration potential. The biofunctionalized PEEK composite elicited several advantageous responses; it facilitated M2 macrophage polarization, curtailed the production of inflammatory mediators, and augmented the osteogenic differentiation of bone marrow mesenchymal stem cells. The experimental findings underscore the vital and intricate role of biofunctionalized PEEK implants in preserving normal bone immunity and metabolism. This study posits that utilizing chitosan-BGNs represents a direct and effective method for creating multifunctional implants. These implants are designed to facilitate biomineralization and immunomodulation, making them especially apt for orthopedic applications.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promote the Recovery of Spinal Cord Injury and Inhibit Ferroptosis by Inactivating IL-17 Pathway.

Mesenchymal stem cell (MSC)-derived exosomes are considered as alternative to cell therapy in various diseases. This study aimed to understand the effect of bone marrow MSC-derived exosomes (BMMSC-exos) on spinal cord injury (SCI) and to unveil its regulatory mechanism on ferroptosis. Exosomes were isolated from BMMSCs and the uptake of BMMSCs-exos by PC12 cells was determined using PKH67 staining. The effect of BMMSC-exos on SCI in rats was studied by evaluating pathological changes of spinal cord tissues, inflammatory cytokines, and ferroptosis-related proteins. Transcriptome sequencing was used to discover the differential expressed genes (DEGs) between SCI rats and BMMSC-exos-treated rats followed by functional enrichment analyses. The effect of BMMSC-exos on ferroptosis and interleukin 17 (IL-17) pathway was evaluated in SCI rats and oxygen-glucose deprivation (OGD)-treated PC12 cells. The results showed that particles extracted from BMMSCs were exosomes that could be taken up by PC12 cells. BMMSC-exos treatment ameliorated injuries of spinal cord, suppressed the accumulation of Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS), with the elevated glutathione (GSH). Also, BMMSC-exos downregulated the expression of acyl-CoA synthetase long chain family member 4 (ACSL4) and upregulated glutathione peroxidase 4 (GPX4) and cysteine/glutamate antiporter xCT. A total of 110 DEGs were discovered and they were mainly enriched in IL-17 signaling pathway. Further in vitro and in vivo experiments showed that BMMSC-exos inactivated IL-17 pathway. BMMSC-exos promote the recovery of SCI and inhibit ferroptosis by inhibiting the IL-17 pathway, which provides BMMSC-exos as an alternative to the management of SCI.

DNM3OS/miR-127-5p/CDH11, activates Wnt3a/ß-catenin/LEF-1 pathway to form a positive feedback and aggravate spine facet joint osteoarthritis.

Spinal facet joint osteoarthritis (FJOA) is an OA disease with pathogenesis and progression uncovered. Our present study was performed to elucidate the role of DNM3OS on spinal FJOA. In this study, spine facet joint tissue of patients were collected. In vitro and in vivo models were constructed with SW1353 cells and rats. Hematoxylin and eosin (HE) staining, Safranin O-fast Green, Alcian blue staining, and Tolueine blue O (TBO) staining were employed for histology analyses. Quantitative PCR, western blotting, and Immunofluorescence were performed to evaluate the expression of genes. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay analysis. Cell Counting Kit-8 and flow cytometry were used for cell activity and apoptosis evaluation. The targeting sites between microRNA (miR)-127-5p and cadherin 11 (CDH11) were predicted TargetScan and miRbase database and confirmed by Dual-luciferase reporter assays. CHIP and EMS assay were employed to confirm the binding of LEF1and DNM3OS promoter. Our results showed that DNM3OS was found to upregulated, while miR-127-5p was downregulated in severe FJOA patients and inflammation-induced chondrosarcoma SW1353 cells. DNM3OS reduced cell activity, induced cell apoptosis and extracellular matrix (ECM) degradation by sponging miR-127-5p in vitro. miR-127-5p targeted CDH11 and inhibited wnt3a/ß-catenin pathway to regulate OA in vitro. LEF1 promoted DNM3OS transcription to form a positively feedback in activated wnt3a/ß-catenin pathway. In vivo rat model also confirmed that DNM3OS aggravated FJOA. In summary, DNM3OS/miR-127-5p/CDH11 enhanced Wnt3a/ß-Catenin/LEF-1 pathway to form a positive feedback and aggravate spinal FJOA.

Clinical Observation of Posterior Approach for Surgical Treatment of Thoracolumbar Pseudarthrosis in Ankylosing Spinal Disorders.

OBJECTIVE: The objective of this study was to evaluate the surgical effectiveness of posterior procedure with long segment stabilization for treating thoracolumbar pseudarthrosis associated with ankylosing spinal disorders (ASDs) without anterior fusion or osteotomy. METHODS: Twelve patients with thoracolumbar pseudarthrosis in ASD were enrolled. All patients underwent posterior long-segment stabilization procedures. In some patients, the percutaneous technique or the aid of a robot or O-arm navigation was utilized for pedicle screw implantation. The clinical results were evaluated by means of the visual analog scale and Oswestry Disability Index. Radiological outcomes were evaluated for bone fusion, anterior column defect, local kyphotic correction, and position of the pedicle screws. RESULTS: All patients experienced effective bone fusion at the sites of pseudarthrosis. The mean operative time was 161.7 ± 57.1 minutes, and the average amount of blood loss was 305.8 ± 293.2 mL. For 6 patients who underwent surgery with the assistance of a robot or O-arm navigation, there was no statistically significant difference observed in terms of operative time and mean blood loss compared to those who used the freehand technique (P > 0.05). The visual analog scale score, Oswestry Disability Index value, and mean local kyphotic angle showed significant improvements at the final follow-up (P < 0.05). The accuracy of pedicle screw placement was 96%. CONCLUSIONS: Posterior surgery with long-segment fixation, without anterior fusion or osteotomy, can achieve satisfactory outcomes in ASD patients with thoracolumbar pseudarthrosis. The application of percutaneous techniques, as well as the assistance of robots or navigation technique may be a good choice for the treatment of pseudarthrosis in ASD patients.

Initial experience of 3-dimensional exoscope in decompression of massive lumbar disc herniation.

OBJECTIVES: To investigate the effect of a three-dimensional (3D) exoscope for decompression of single-segment massive lumbar disc herniation (LDH). METHODS: The study included 56 consecutive patients with single segment massive LDH who underwent decompression assisted by a 3D exoscope from October 2019 to October 2022 at a university hospital. The analysis was based on comparison of perioperative metrics including decompression time, estimated blood loss (EBL) during decompression and postoperative length of stay (PLS); clinical outcomes including assessment using the visual analogue scale (VAS) and the Oswestry disability index (ODI); and incidence of reoperation and complications. RESULTS: The mean decompression time was 28.35 ± 8.93 min (lumbar interbody fusion (LIF)) and 15.50 ± 5.84 min (fenestration discectomy (LOVE surgery)), the mean EBL during decompression was 42.65 ± 12.42 ml (LIF) and 24.32 ± 8.61 ml (LOVE surgery), and the mean PLS was 4.56 ± 0.82 days (LIF) and 2.00 ± 0.65 days (LOVE surgery). There were no complications such as cerebrospinal fluid leakage, nerve root injury and epidural hematoma. All patients who underwent decompression assisted by a 3D exoscope were followed up for 6 months. At the last follow-up, the VAS and ODI scores were significantly improved from the preoperative period to the last follow-up (P < 0.05). CONCLUSIONS: A 3D exoscope provides a visually detailed, deep and clear surgical field, which makes decompression safer and more effective and reduces short-term complications. A 3D exoscope may be a good assistance tool during decompression for single-segment massive LDH.

A novel mini-open transforaminal lumbar interbody fusion for lumbar degenerative diseases: technical note and preliminary results.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) is an effective and popular surgical procedure for the management of various spinal pathologies, especially degenerative diseases. Surgeons have been pursuing minimally invasive technology as soon as TLIF was appeared. Currently, TLIF can be performed with transforaminal approaches by open surgery, minimally invasive surgery or percutaneous endoscope. We provide a detailed description of a new modified open TLIF with percutaneous pedicle screws, which we refer to as mini-open TLIF. The objective of this study was to present feasibility of this procedure and the preliminary results. METHODS: The study is a prospective study. From January 2021 to March 2022, 96 patients (43 males and 53 females) with neurological symptoms due to degenerative lumbar spine diseases were enrolled. Operation time, blood loss, ambulatory time, hematocrit and complications were recorded during perioperative period. Clinical symptoms were evaluated 1 week, 3 months and 12 months after surgery. Visual analogue scale (VAS) scores for lower back pain and leg pain and Oswestry disability index (ODI) were assessed. Magnetic resonance imaging was performed preoperatively and 12 months postoperatively to emulate cross-sectional area of paraspinal muscles. The lumbar interbody fusion rate was evaluated by CT scanning. RESULTS: The mean operation time of single level was 112.6 min, and the mean operation time of multilevel was 140.1 min. Intraoperative blood loss of single level was 64.5 ml and was 116.3 ml of multilevel. The VAS and ODI scores before and after surgery were significantly different (P < 0.0001) and reached minimal clinically important difference. Atrophy rate of paraspinal muscles was 2.5% for symptomatic side and 1.2% for asymptomatic side. The cross-sectional area before and after the operation and atrophy rate had no statistically significant difference (P > 0.05). CONCLUSION: Mini-open TLIF is effective and feasible for the treatment of lumbar degenerative diseases especially in multilevel disease, with minor damage to muscle and shorter operation time. TRIAL REGISTRATION: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Second Affiliated Hospital of Soochow University (No. JD-LK2023045-I01).

Macrophage Membrane-Reversibly Cloaked Nanotherapeutics for the Anti-Inflammatory and Antioxidant Treatment of Rheumatoid Arthritis.

During rheumatoid arthritis (RA) development, over-produced proinflammatory cytokines represented by tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) represented by H2 O2 form a self-promoted cycle to exacerbate the synovial inflammation and tissue damage. Herein, biomimetic nanocomplexes (NCs) reversibly cloaked with macrophage membrane (RM) are developed for effective RA management via dual scavenging of TNF-α and ROS. To construct the NCs, membrane-penetrating, helical polypeptide first condenses TNF-α siRNA (siTNF-α) and forms the cationic inner core, which further adsorbs catalase (CAT) via electrostatic interaction followed by surface coating with RM. The membrane-coated NCs enable prolonged blood circulation and active joint accumulation after systemic administration in Zymosan A-induced arthritis mice. In the oxidative microenvironment of joints, CAT degrades H2 O2 to produce O2 bubbles, which shed off the outer membrane layer to expose the positively charged inner core, thus facilitating effective intracellular delivery into macrophages. siRNA-mediated TNF-α silencing and CAT-mediated H2 O2 scavenging then cooperate to inhibit inflammation and alleviate oxidative stress, remodeling the osteomicroenvironment and fostering tissue repair. This study provides an enlightened strategy to resolve the blood circulation/cell internalization dilemma of cell membrane-coated nanosystems, and it renders a promising modality for RA treatment.

Ultrasmall iron-quercetin metal natural product nanocomplex with antioxidant and macrophage regulation in rheumatoid arthritis.

Oxidative stress, due to the disruption of the balance between reactive oxygen species (ROS) generation and the antioxidant defense system, plays an important role in the pathogenesis of rheumatoid arthritis (RA). Excessive ROS leads to the loss of biological molecules and cellular functions, release of many inflammatory mediators, stimulate the polarization of macrophages, and aggravate the inflammatory response, thus promoting osteoclasts and bone damage. Therefore, foreign antioxidants would effectively treat RA. Herein, ultrasmall iron-quercetin natural coordination nanoparticles (Fe-Qur NCNs) with excellent anti-inflammatory and antioxidant properties were constructed to effectively treat RA. Fe-Qur NCNs obtained by simple mixing retain the inherent ability to remove ROS of quercetin and have a better water-solubility and biocompatibility. In vitro experiments showed that Fe-Qur NCNs could effectively remove excess ROS, avoid cell apoptosis, and inhibit the polarization of inflammatory macrophages by reducing the activation of the nuclear factor-κ-gene binding (NF-κB) pathways. In vivo experiments showed that the swollen joints of mice with rheumatoid arthritis treated with Fe-Qur NCNs significantly improved, with Fe-Qur NCNs largely reducing inflammatory cell infiltration, increasing anti-inflammatory macrophage phenotypes, and thus inhibiting osteoclasts, which led to bone erosion. This study demonstrated that the new metal-natural coordination nanoparticles could be an effective therapeutic agent for the prevention of RA and other diseases associated with oxidative stress.

SCF/c-Kit-activated signaling and angiogenesis require Gαi1 and Gαi3.

The stem cell factor (SCF) binds to c-Kit in endothelial cells, thus activating downstream signaling and angiogenesis. Herein, we examined the role of G protein subunit alpha inhibitory (Gαi) proteins in this process. In MEFs and HUVECs, Gαi1/3 was associated with SCF-activated c-Kit, promoting c-Kit endocytosis, and binding of key adaptor proteins, subsequently transducing downstream signaling. SCF-induced Akt-mTOR and Erk activation was robustly attenuated by Gαi1/3 silencing or knockout (KO), or due to dominant negative mutations but was strengthened substantially following ectopic overexpression of Gαi1/3. SCF-induced HUVEC proliferation, migration, and capillary tube formation were suppressed after Gαi1/3 silencing or KO, or due to dominant negative mutations. In vivo, endothelial knockdown of Gαi1/3 by intravitreous injection of endothelial-specific shRNA adeno-associated virus (AAV) potently reduced SCF-induced signaling and retinal angiogenesis in mice. Moreover, mRNA and protein expressions of SCF increased significantly in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. SCF silencing, through intravitreous injection of SCF shRNA AAV, inhibited pathological retinal angiogenesis and degeneration of retinal ganglion cells in DR mice. Finally, the expression of SCF and c-Kit increased in proliferative retinal tissues of human patients with proliferative DR. Taken together, Gαi1/3 mediate SCF/c-Kit-activated signaling and angiogenesis.

Size selection and placement of pedicle screws using robot-assisted versus fluoroscopy-guided techniques for thoracolumbar fractures: possible implications for the screw loosening rate.

BACKGROUND: There has been increased development of robotic technologies for the accuracy of percutaneous pedicle screw placement. However, it remains unclear whether the robot really optimize the selection of screw sizes and enhance screw stability. The purpose of this study is to compare the sizes (diameter and length), placement accuracy and the loosening rate of pedicle screws using robotic-assisted versus conventional fluoroscopy approaches for thoracolumbar fractures. METHODS: A retrospective cohort study was conducted to evaluate 70 consecutive patients [34 cases of robot-assisted percutaneous pedicle screw fixation (RAF) and 36 of conventional fluoroscopy-guided percutaneous pedicle screw fixation (FGF)]. Demographics, clinical characteristics, and radiological features were recorded. Pedicle screw length, diameter, and pedicle screw placement accuracy were assessed. The patients' sagittal kyphosis Cobb angles (KCA), anterior vertebral height ratios (VHA), and screw loosening rate were evaluated by radiographic data 1 year after surgery. RESULTS: There was no significant difference in the mean computed tomography (CT) Hounsfield unit (HU) values, operation duration, or length of hospital stay between the groups. Compared with the FGF group, the RAF group had a lower fluoroscopy frequency [14 (12-18) vs. 21 (16-25), P < 0.001] and a higher "grade A + B" pedicle screw placement rate (96.5% vs. 89.4%, P < 0.05). The mean screw diameter was 6.04 ± 0.55 mm in the RAF group and 5.78 ± 0.50 mm in the FGF group (P < 0.001). The mean screw length was 50.45 ± 4.37 mm in the RAF group and 48.63 ± 3.86 mm in the FGF group (P < 0.001). The correction loss of the KCA and VHR of the RAF group was less than that of the FGT group at the 1-year follow-up [(3.8 ± 1.8° vs. 4.9 ± 4.2°) and (5.5 ± 4.9% vs. 6.4 ± 5.7%)], and screw loosening occurred in 2 out of 34 patients (5.9%) in the RAF group, and 6 out of 36 patients (16.7%) in the FGF group, but there were no significant differences (P > 0.05). CONCLUSION: Compared with the fluoroscopy-guided technique, robotic-assisted spine surgery decreased radiation exposure and optimizes screw trajectories and dimensions intraoperatively. Although not statistically significant, the loosening rate of the RAF group was lower that of than the FGT group.

MiR-99a alleviates apoptosis and extracellular matrix degradation in experimentally induced spine osteoarthritis by targeting FZD8.

BACKGROUND: Our previous study identified miR-99a as a negative regulator of early chondrogenic differentiation. However, the functional role of miR-99a in the pathogenesis of osteoarthritis (OA) remains unclear. METHODS: We examined the levels of miR-99a and Frizzled 8 (FZD8) expression in tissue specimens. Human SW1353 chondrosarcoma cells were stimulated with IL-6 and TNF-α to construct an in vitro OA environment. A luciferase reporter assay was performed to analyze the relationship between miR-99a and FZD8. CCK-8 assays, flow cytometry, and ELISA assays were used to assess cell viability, apoptosis, and inflammatory molecule expression, respectively. Percutaneous intra-spinal injections of papain mixed solution were performed to create an OA Sprague-Dawley rat model. Alcian Blue staining, Safranin O Fast Green staining, and Toluidine Blue O staining were performed to detect the degrees of cartilage injury. RESULTS: MiR-99a expression was downregulated in the severe spine OA patients when compared with the mild spine OA patients, and was also decreased in the experimentally induced in vitro OA environment when compared with the control environment. Functionally, overexpression of miR-99a significantly suppressed cell apoptosis and extracellular matrix degradation stimulated by IL-6 and TNF-α. FZD8 was identified as a target gene of miR-99a. Furthermore, the suppressive effects of miR-99a on cell injury induced by IL-6 and TNF-α were reversed by FZD8 overexpression. Moreover, the levels of miR-99a expression were also reduced in the induced OA model rats, and miR-99a agomir injection relieved the cartilage damage. At the molecular level, miR-99a overexpression downregulated the levels of MMP13, ß-catenin, Bax, and caspase-3 protein expression and upregulated the levels of COL2A1 and Bcl-2 protein expression in the in vitro OA-like chondrocyte model and also in the experimental OA model rats. CONCLUSIONS: Our data showed that miR-99a alleviated apoptosis and extracellular matrix degradation by targeting FZD8, and thereby suppressed the development and progression of experimentally induced spine osteoarthritis.

Genetically Engineered Hematopoietic Stem Cells Deliver TGF-ß Inhibitor to Enhance Bone Metastases Immunotherapy.

Owing to the immune microenvironment of bones and low selectivity of the drug, patients with bone metastases often respond poorly to immunotherapy. In this study, programmed cell death protein 1 (PD1)-expressing hematopoietic stem cells (HSCs) are genetically engineered for bone-targeted delivery of the transforming growth factor beta (TGF-ß) small-molecule inhibitor SB-505124 (SB@HSCs-PD-1). Intriguingly, compared to anti-PD-L1 monoclonal antibodies, as "living drugs", HSCs-PD-1 not only show great targeting ability to the bone marrow, but are also able to reduplicate themselves within the bone marrow niche and continuously express PD-1 molecules. The SB released from HSCs-PD-1 competitively bound to TGF-ß receptors on CD4+ T cells and facilitate CD4+ T cell differentiation to helper T (TH )1 and TH 2 cells, thereby reprogramming the local immunosuppressive milieu of the bone marrow. Additionally, HSCs-PD-1 can block programmed death-ligand 1 on tumor and myeloid cells, resulting in reinvigorated anti-tumor immunity of T cells. In conclusion, in the present study, an alternative cell engineering strategy is delineated for immune checkpoint blockade therapy, to target bone metastasis using HSCs as a platform, which shows great promise in the treatment of bone metastases.

Prussian blue analogue assisted formation of iron doped CoNiSe2 nanosheet arrays for efficient oxygen evolution reaction.

Electrochemical water splitting is a promising approach to produce hydrogen gas, but sluggish four-electron transfer of the oxygen evolution reaction (OER) severely limits the overall energy conversion efficiency of water splitting. Herein, as an excellent OER electrocatalyst, a technique of synthesizing Fe doped CoNiSe2 nanosheet (Fe-CoNiSe2) whole series using CoFe prussian blue analog produced by Co-ZIF-L reaction as a template is proposed here. The introduction of iron ions promotes the redistribution of the cobalt-nickel charge density, which enhances the OER kinetics. In view of the abovementioned points, Fe-CoNiSe2/NF has excellent activity, electrocatalytic properties and excellent stability in alkaline media, which only demands a lower overpotential of 244 mV and 271 mV to deliver a current density of 10 mA cm-2 and 50 mA cm-2, respectively. The material also exhibits excellent stability for at least 24 h during the OER process. This work may provide some new insights into the assembly of advanced and highly-active materials for a variety of other energy conversion applications.

Four-octyl itaconate improves osteoarthritis by enhancing autophagy in chondrocytes via PI3K/AKT/mTOR signalling pathway inhibition.

Osteoarthritis (OA) is a highly prevalent and chronic disorder that is associated with a substantial social and economic burden. Itaconate, as an important regulator of cellular inflammation, is a metabolite synthesised by an enzyme encoded by immune-responsive gene 1. However, there are few studys regarding the effects of itaconate on OA. Here, we show the effect of the cell-permeable itaconate derivative 4-octyl itaconate (OI) on OA. OI attenuates the chondrocyte apoptosis induced by interleukin 1ß (IL-1ß) in vitro, indicating that OI protect chondrocytes against apoptosis. Moreover, OI ameliorates the chondrocyte autophagy inhibition induced by IL-1ß via the inhibition of PI3K/AKT/mTOR signalling pathway. Finally, OI enhances autophagy and reduces cartilage degradation in a rat model of OA established by destabilization of medial meniscus (DMM). In summary, our findings reveal that OI is involved in regulating the progression of OA. The above results shed light on the treatment of OA.