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Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.
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Diferenciação Celular , Macrófagos , Células Precursoras de Oligodendrócitos , Remielinização , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Macrófagos/metabolismo , Remielinização/fisiologia , Diferenciação Celular/fisiologia , Células Precursoras de Oligodendrócitos/metabolismo , Camundongos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recuperação de Função Fisiológica/fisiologia , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Transgênicos , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Oligodendroglia/metabolismoRESUMO
BACKGROUND: A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically exhibit short stature, facial deformities, long tubular bones, and high vertebral bodies but generally lack mental abnormalities or other organ damage. Pathogenic genes associated with 3M syndrome include CUL7, OBSL1 and CCDC8. The clinical and molecular characteristics of patient with 3M syndrome are unique and serve as important diagnostic indicators. CASE SUMMARY: In this case, the patient displayed square shoulders, scoliosis, long slender tubular bones, and normal neurological development. Notably, the patient did not exhibit the typical dysmorphic facial features, relative macrocephaly, or growth retardation commonly observed in individuals with 3M syndrome. Whole exon sequencing revealed a novel heterozygous c.56681+1G>C (Splice-3) variant and a previously reported nonsense heterozygous c.3341G>A (p.Trp1114Ter) variant of OBSL1. Therefore, it is important to note that the clinical features of 3M syndrome may not always be observable, and genetic confirmation is often required. Additionally, the identification of the c.5683+1G>C variant in OBSL1 is noteworthy because it has not been previously reported in public databases. CONCLUSION: Our study identified a new variant (c.5683+1G>C) of OBSL1 that contributes to expanding the molecular profile of 3M syndrome.
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BACKGROUND: Vague spinal anatomical landmarks in patients with ankylosing spondylitis (AS) make intraoperative insertion of pedicle screws difficult under direct vision. Currently, the clinical outcome is significantly improved with robot guidance. This study aims to explore the efficacy of robot-assisted pedicle screw insertion in treating AS combined with spinal fractures. METHODS: Forty patients (341 screws) who underwent pedicle screw insertion with AS complicated with spinal fractures were included. According to different surgical methods, 16 patients (135 screws) were classified into the robot group and 24 (206 screws) into the free-hand group. Intraoperative blood loss, operative duration, and adverse events were compared between the 2 groups. Gertzbein and Robbins classification was used to classify the accuracy of screw position. Clinical outcomes were evaluated by Visual Analog Scale, Japanese Orthopedic Association, and Oswestry Disability Index. RESULTS: No statistically significant differences between baseline data of the groups. The difference in the blood loss between groups wasn't significant, nor was the operative duration. No severe adverse events related to pedicle screw insertion were reported in either group. Notably, the accuracy of screw insertion was significantly higher in the robot group (129/135) than in the free-hand group (182/206). The lateral perforation prevalence didn't differ among groups. Visual Analog Scale in the third month postoperatively was lower in the robot group than in the free-hand group, with a significant difference. CONCLUSIONS: The study demonstrates statistically superior accuracy and surgical outcome of robot-assisted pedicle screw insertion in the treatment of AS complicated with spinal fractures compared with the traditional free-hand operation.
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Parafusos Pediculares , Procedimentos Cirúrgicos Robóticos , Robótica , Fraturas da Coluna Vertebral , Fusão Vertebral , Espondilite Anquilosante , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/cirurgia , Espondilite Anquilosante/complicações , Espondilite Anquilosante/cirurgia , Vértebras Lombares/cirurgia , Estudos Retrospectivos , Fusão Vertebral/métodos , Resultado do TratamentoRESUMO
Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.
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BACKGROUND: Spinal cord injury (SCI) remains a significant health concern, with limited available treatment options. This condition poses significant medical, economic, and social challenges. SCI is typically categorized into primary and secondary injuries. Inflammation, oxidative stress, scar formation, and the immune microenvironment impede axon regeneration and subsequent functional restoration. Numerous studies have shown that the destruction of the blood-brain barrier (BBB) and microvessels is a crucial factor in severe secondary injury. Additionally, reactive oxygen species (ROS)-induced lipid peroxidation significantly contributes to endothelial cell death. Pericytes are essential constituents of the BBB that share the basement membrane with endothelial cells and astrocytes. They play a significant role in the establishment and maintenance of BBB. RESULTS: Immunofluorescence staining at different time points revealed a consistent correlation between pericyte coverage and angiogenesis, suggesting that pericytes promote vascular repair via paracrine signaling. Pericytes undergo alterations in cellular morphology and the transcriptome when exposed to hypoxic conditions, potentially promoting angiogenesis. We simulated an early ischemia-hypoxic environment following SCI using glucose and oxygen deprivation and BBB models. Co-culturing pericytes with endothelial cells improved barrier function compared to the control group. However, this enhancement was reduced by the exosome inhibitor, GW4869. In vivo injection of exosomes improved BBB integrity and promoted motor function recovery in mice following SCI. Subsequently, we found that pericyte-derived exosomes exhibited significant miR-210-5p expression based on sequencing analysis. Therefore, we performed a series of gain- and loss-of-function experiments in vitro. CONCLUSION: Our findings suggest that miR-210-5p regulates endothelial barrier function by inhibiting JAK1/STAT3 signaling. This process is achieved by regulating lipid peroxidation levels and improving mitochondrial function, suggesting a potential mechanism for restoration of the blood-spinal cord barrier (BSCB) after SCI.
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MicroRNAs , Traumatismos da Medula Espinal , Camundongos , Animais , Pericitos/metabolismo , Células Endoteliais/metabolismo , Peroxidação de Lipídeos , Axônios , Regeneração Nervosa , Traumatismos da Medula Espinal/metabolismo , Transdução de Sinais , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Bone defects have long been a major healthcare issue because of the difficulties in regenerating bone mass volume and the high cost of treatment. G protein-coupled receptor kinase 2 interacting protein 1 (GIT1) has been proven to play an important role both in vascular development and in bone fracture healing. In this study, a type of thermoresponsive injectable hydrogel from oligoethylene glycol-based dendronized chitosan (G1-CS) was loaded with GIT1-plasmids (G1-CS/GIT1), and used to fill unicortical bone defects. RT-PCR analysis confirmed that G1-CS/GIT1 enhanced DNA transfection in MSCs both in vitro and in vivo. From the results of micro-CT, RT-PCR and histological analysis, it can be concluded that G1-CS/GIT1 accelerated the bone healing rate and increased the amount of neovascularization around the bone defects. In addition, an adeno-associated virus (AAV)-GIT1 was constructed to transfect mesenchymal stem cells. The results of capillary tube formation assay, immunofluorescence staining and western blot analysis proved that high expression of GIT1 induces mesenchymal stem cells to differentiate into endothelial cells. RT-PCR analysis and capillary tube formation assay confirmed that the Notch signaling pathway was activated in the differentiation process. Overall, we developed an efficient strategy through combination of injectable hydrogel and G1T1 for bone tissue engineering.
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Destruction of the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) is an important factor promoting the progression of the injury. This study addressed how to repair the BSCB in order to promote the repair of injured spinal cords. Iguratimod (IGU), an anti-rheumatic drug, has been approved for clinical use. A spinal cord injury mouse model and TNF-α-stimulated bEnd.3 cells were used to investigate the effect and mechanism of IGU on injured BSCB. An intracerebroventricular osmotic pump was used to administer drugs to the SCI mouse model. The results showed that the SCI mice in the treatment group had better recovery of neurological function than the control group. Examination of the tissue revealed better repair of the BSCB in injured spinal cords after medication. According to the results from the cell model, IGU promoted the expression of tight junction proteins and reduced cell permeability. Further research found that IGU repaired the barrier function by regulating glycolysis levels in the injured endothelial cells. In studying the mechanism, IGU was found to regulate HIF-1α expression through the NF-κB pathway, thereby regulating the expression of the glycolytic enzymes related to endothelial injury. In summary, IGU promoted functional recovery in vivo by repairing the BSCB. In vitro, IGU regulated the level of glycolysis in the damaged endothelium through the NF-κB pathway, thereby repairing the tight junctions between the endothelium. Therefore, IGU may become a potential drug for treating spinal cord injury.
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Células Endoteliais , Traumatismos da Medula Espinal , Ratos , Camundongos , Animais , Células Endoteliais/metabolismo , NF-kappa B/metabolismo , Junções Íntimas/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Barreira Hematoencefálica/metabolismoRESUMO
Background: The pathophysiology of bone defects (BDs) is complex, and the treatment for bone defects, in particular massive bone defects, remains a major clinical challenge. Our study was conducted to explore the molecular events related to the progression of bone defects a common clinical condition. Methods: First, microarray data of GSE20980 were obtained from the Gene Expression Omnibus (GEO) database, where 33 samples in total were used to analyze the molecular biological processes related to bone defects. Next, the original data were normalized and differentially expressed genes (DEGs) were identified. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, a protein-protein interaction (PPI) network was constructed and the trends of the different genes were confirmed. Results: Compared with the samples of non-critical size defects (NCSD), the samples of critical size defects (CSD) had 2057, 827, and 1,024 DEGs at 7, 14, and 21 days post injury, respectively. At day 7, the DEGs were significantly enriched in metabolic pathways, at day 14 the DEGs were predominantly enriched in G-protein coupled signaling pathways and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and at day 21 the DEGs were mainly enriched in circadian entrainment and synaptic-related functions. The PPI network showed similar results. Quantitative real-time PCR (qRT-PCR) and western blot (WB) were performed to validate the partial results of sequencing. Conclusion: This study provides some clues about the molecular mechanism behind bone defects, which should contribute to scientific research and clinical treatment of this condition.
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OBJECTIVE: This study aims to examine the biomechanical effects of different reconstruction methods, including single-bundle, double-bundle anatomical reconstruction, and double-bundle truly anatomical reconstruction of the coracoclavicular ligament on the acromioclavicular joint using finite element analysis, to provide a theoretical basis for the clinical application of truly anatomical coracoclavicular ligament reconstruction. METHODS: One volunteer, aged 27 years old, with a height of 178 cm and a weight of 75 kg, was selected for CT scanning of the shoulder joint. Three-dimensional finite element models of single-bundle reconstruction, double-bundle anatomical reconstruction, and double-bundle truly anatomical reconstruction of coracoclavicular ligament were established by using Mimics17.0, Geomagic studio 2012, UG NX 10.0, HyperMesh 14.0 and ABAQUS 6.14 software. The maximum displacement of the middle point of the distal clavicle in the main loading direction and the maximum equivalent stress of the reconstruction device under different loading conditions were recorded and compared. RESULTS: The maximum forward displacement and the maximum backward displacement of the middle point of the distal clavicle in the double-bundle truly anatomic reconstruction were the lowest, which were 7.76 mm and 7.27 mm respectively. When an upward load was applied, the maximum displacement of the distal clavicle midpoint in the double-beam anatomic reconstruction was the lowest, which was 5.12 mm. Applying three different loads forward, backward, and upward, the maximum equivalent stress of the reconstruction devices in the double-beam reconstruction was lower than that in the single-beam reconstruction. The maximum equivalent stress of the trapezoid ligament reconstruction device in the double-bundle truly anatomical reconstruction was lower than that in the double-bundle anatomical reconstruction, which was 73.29 MPa, but the maximum equivalent stress of the conoid ligament reconstruction device was higher than that of the double-bundle anatomical reconstruction. CONCLUSION: The truly anatomical reconstruction of coracoclavicular ligament can improve the horizontal stability of acromioclavicular joint and reduce the stress of the trapezoid ligament reconstruction device. It can be a good method for the treatment of acromioclavicular joint dislocation.
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Articulação Acromioclavicular , Luxações Articulares , Procedimentos de Cirurgia Plástica , Articulação do Ombro , Humanos , Adulto , Articulação Acromioclavicular/cirurgia , Análise de Elementos Finitos , Ligamentos Articulares/cirurgia , Articulação do Ombro/cirurgia , Luxações Articulares/cirurgiaRESUMO
Spinal cord injury (SCI) treatment requires a nanosystem for drug delivery that can effectively penetrate the blood-spinal cord barrier (BSCB). Herein, we designed poly(2-methacryloyloxyethyl phosphorylgallylcholine) (PMPC)/l-arginine (PMPC/A)-based nanomotors that can release nitric oxide (NO). The nanomotors were loaded with the inducible NO synthase inhibitor 1400W and nerve growth factor (NGF). PMPC with a zwitterionic structure not only provided good biocompatibility for the nanomotors but also facilitated their passage through the BSCB owing to the assistance of a large number of choline transporters on the BSCB. Additionally, the l-arginine loaded on the nanomotors was able to react with reactive oxygen species in the microenvironment of the injured nerve to produce NO, thereby conferring the ability of autonomic movement to the nanomotors, which facilitated the uptake of drugs by cells in damaged areas and penetration in pathological tissues. Moreover, in vivo animal experiments indicated that the PMPC/A/1400W/NGF nanomotors could effectively pass through the BSCB and restore the motion function of a rat SCI model by regulating its internal environment as well as the release of therapeutic drugs. Thus, the drug delivery system based on nanomotor technology offers a promising strategy for treating central nervous system diseases.
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Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Ratos , Nanopartículas/administração & dosagem , Fator de Crescimento Neural/uso terapêutico , Óxido Nítrico Sintase/antagonistas & inibidores , Sistemas de Liberação de MedicamentosRESUMO
BACKGROUND: Post-traumatic related limb osteomyelitis (PTRLO) is a complex bone infection. Currently, there are no available microbial data on a national scale that can guide appropriate antibiotic selection, and explore the dynamic changes in dominant pathogens over time. This study aimed to conduct a comprehensive epidemiological analysis of PTRLO in China. METHODS: The study was approved by the Institutional Research Board (IRB), and 3526 PTRLO patients were identified from 212 394 traumatic limb fracture patients at 21 hospitals between 1 January 2008 and 31 December 2017. A retrospective analysis was conducted to investigate the epidemiology of PTRLO, including changes in infection rate (IR), pathogens, infection risk factors and antibiotic resistance and sensitivity. RESULTS: The IR of PTRLO increased gradually from 0.93 to 2.16% (Z=14.392, P <0.001). Monomicrobial infection (82.6%) was significantly higher than polymicrobial infection (17.4%) ( P <0.001). The IR of Gram-positive (GP) and Gram-negative (GN) pathogens showed a significant increase from the lowest 0.41% to the highest 1.15% (GP) or 1.62% (GN), respectively. However, the longitudinal trend of GP vs. GN's composition did not show any significance (Z=±1.1918, P >0.05). The most prevalent GP strains were Methicillin-sensitive Staphylococcus aureus (MSSA) (17.03%), Methicillin-resistant Staphylococcus aureus (MRSA) (10.46%), E. faecalis (5.19%) and S. epidermidis (4.87%). In contrast, the dominant strains GN strains were Pseudomonas Aeruginosa (10.92%), E. cloacae (10.34%), E. coli (9.47%), Acinetobacter Baumannii (7.92%) and Klebsiella Pneumoniae (3.33%). In general, the high-risk factors for polymicrobial infection include opened-fracture (odds ratio, 2.223), hypoproteinemia (odds ratio, 2.328), and multiple fractures (odds ratio, 1.465). It is important to note that the antibiotics resistance and sensitivity analysis of the pathogens may be influenced by complications or comorbidities. CONCLUSIONS: This study provides the latest data of PTRLO in China and offers trustworthy guidelines for clinical practice. (China Clinical Trials.gov number, ChiCTR1800017597).
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Coinfecção , Fraturas Expostas , Staphylococcus aureus Resistente à Meticilina , Osteomielite , Humanos , Estudos Retrospectivos , Escherichia coli , Coinfecção/tratamento farmacológico , Testes de Sensibilidade Microbiana , Antibacterianos/uso terapêutico , China/epidemiologia , Osteomielite/epidemiologia , Osteomielite/etiologia , Osteomielite/tratamento farmacológicoRESUMO
Fibrotic scars appear after spinal cord injury (SCI) and are mainly composed of fibroblasts and excess extracellular matrix (ECM), including different types of collagen. The temporal and spatial distribution and role of excess collagens and ECM after SCI are not yet fully understood. Here, we identified that the procollagen type I C-terminal propeptide (PICP), a marker of collagen type I deposition, and bone morphogenetic protein 1 (BMP1), a secreted procollagen c-proteinase (PCP) for type I collagen maturation, were significantly elevatedin cerebrospinal fluid of patients with SCI compared with healthy controls, and were associated with spinal cord compression and neurological symptoms. We revealed the deposition of type I collagen in the area damaged by SCI in mice and confirmed that BMP1 was the only expressed PCP and induced collagen deposition. Furthermore, transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) can activate the expression of BMP1. However, inhibition of BMP1 at the acute phase eliminated fibrotic scars in the damaged area and inhibited activation and enrichment of astrocytes, which made the damage difficult to repair and increased hematoma. Unexpectedly, knockdown of Bmp1 by adeno-associated virus or the inhibition of BMP1 biological function by specific inhibitors and monoclonal antibodies at different time points after injury led to distinct therapeutic effects. Only delayed inhibition of BMP1 improved axonal regeneration and myelin repair at the subacute stage post-injury, and led to the recovery of motor function, suggesting that scarring had a dual effect. Early inhibition of the scarring was not conducive to limiting inflammation, while excessive scar formation inhibited the growth of axons. After SCI, the collagen deposition indicators increased in both human cerebrospinal fluid and mouse spinal cord. Therefore, suppression of BMP1 during the subacute phase improves nerve function after SCI and is a potential target for scar reduction.
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Colágeno Tipo I , Traumatismos da Medula Espinal , Humanos , Camundongos , Animais , Proteína Morfogenética Óssea 1/genética , Proteína Morfogenética Óssea 1/metabolismo , Colágeno Tipo I/metabolismo , Cicatriz/patologia , Colágeno/genética , Colágeno/metabolismo , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , FibroseRESUMO
Spinal cord ischemia-reperfusion (IR) injury (SCIRI) is a significant secondary injury that causes damage to spinal cord neurons, leading to the impairment of spinal cord sensory and motor functions. Excessive reactive oxygen species (ROS) production is considered one critical mechanism of neuron damage in SCIRI. Nonetheless, the molecular mechanisms underlying the resistance of neurons to ROS remain elusive. Our study revealed that the deletion of Git1 in mice led to poor recovery of spinal cord motor function after SCIRI. Furthermore, we discovered that Git1 has a beneficial effect on neuron resistance to ROS production. Mechanistically, Git1 interacted with PGK1, regulated PGK1 phosphorylation at S203, and affected the intermediate products of glycolysis in neurons. The influence of Git1 on glycolysis regulates the dimerization of Keap1, which leads to changes in Nrf2 ubiquitination and plays a role in resisting ROS. Collectively, we show that Git1 regulates the Keap1/Nrf2 axis to resist ROS in a PGK1-dependent manner and thus is a potential therapeutic target for SCIRI.
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Traumatismo por Reperfusão , Isquemia do Cordão Espinal , Animais , Camundongos , Proteínas de Ciclo Celular , Proteínas Ativadoras de GTPase , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Isquemia do Cordão Espinal/complicações , Isquemia do Cordão Espinal/prevenção & controleRESUMO
Disruption of the blood-spinal cord barrier (BSCB) leads to inflammatory cell infiltration and neural cell death, thus, contributing to poor functional recovery after spinal cord injury (SCI). Previous studies have suggested that Sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, is abundantly expressed in endothelial cells and promotes endothelial homeostasis. However, the role of SIRT1 in BSCB function after SCI remains poorly defined. Here, we report that SIRT1 is highly expressed in spinal cord endothelial cells, and its expression significantly decreases after SCI. Using endothelial cell-specific SIRT1 knockout mice, we observed that endothelial cell-specific knockout of SIRT1 aggravated BSCB disruption, thus, resulting in widespread inflammation, neural cell death and poor functional recovery after SCI. In contrast, activation of SIRT1 by the agonist SRT1720 had beneficial effects. In vitro, knockdown of SIRT1 exacerbated IL-1ß-induced endothelial barrier disruption in bEnd.3 cells, whereas overexpression of SIRT1 was protective. Using RNA-seq and IP/MS analysis, we identified p66Shc, a redox protein, as the potential target of SIRT1. Further studies demonstrated that SIRT1 interacts with and deacetylates p66Shc, thereby attenuating oxidative stress and protecting endothelial barrier function. Overall, our results indicate that SIRT1 decreases endothelial ROS production and attenuates BSCB disruption by deacetylating p66Shc after SCI, and suggest that SIRT1 activation has potential as a therapeutic approach to promote functional recovery against BSCB disruption following SCI.
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Sirtuína 1 , Traumatismos da Medula Espinal , Animais , Camundongos , Barreira Hematoencefálica , Células Endoteliais/metabolismo , Camundongos Knockout , Sirtuína 1/genética , Sirtuína 1/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismoRESUMO
Keloid is a disease that seriously affects the aesthetic appearance of the body. In contrast to normal skin or hypertrophic scars, keloid tissue extends beyond the initial site of injury. Patients may complain of pain, itching, or burning. Although multiple treatments exist, none is uniformly successful. Genetic advances have made it possible to explore differences in gene expression between keloids and normal skin. Identifying the biomarker for keloid is beneficial to the mechanism exploration and treatment development of keloid. In this study, we identified seven genes with significant differences in keloids through weighted gene co-expression network analysis(WGCNA) and differential expression analysis. Then, by the Lasso regression, we constructed a keloid diagnostic model using five of these genes. Further studies found that keloids could be divided into high-risk and low-risk groups by this model, with differences in immunity, m6A methylation, and pyroptosis. Finally, we verified the accuracy of the diagnostic model in clinical RNA-sequencing data.
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Cicatriz Hipertrófica , Queloide , Humanos , Queloide/genética , Queloide/patologia , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/patologia , Perfilação da Expressão Gênica , Biomarcadores , PruridoRESUMO
Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.
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Neuroinflammation is an important cause of poor prognosis in patients with spinal cord injury. pyroptosis is a new type of inflammatory cell death. Treg cells has been shown to play an anti-inflammatory role in a variety of inflammatory diseases, including inflammatory bowel disease, amyotrophic lateral sclerosis, and arthritis. However, little is known about Treg cells' potential role in pyroptosis following spinal cord injury. The aim of this research was to look into the effect of Treg cells to motor function recovery, pyroptosis and the mechanism behind it after SCI. Here, we found that pyroptosis mainly occurred in microglia on the seventh day after spinal cord injury. Konckout Treg cells resulted in widely pyroptosis and poor motor recovery after SCI. In conversely, over-infiltration of Treg cell in mice by tail vein injection had beneficial effects following SCI.Treg cell-derived exosomes promote functional recovery by inhibiting microglia pyroptosis in vivo. Bioinformatic analysis revealed that miRNA-709 was significantly enriched in Treg cells and Treg cell-secreted exosomes. NKAP has been identified as a miRNA-709 target gene. Moreover, experiments confirmed that Treg cells targeted the NKAP via exosomal miR-709 to reduce microglia pyroptosis and promote motor function recovery after SCI. More importantly, The miR-709 overexpressed exosomes we constructed significantly reduced the inflammatory response and improved motor recovery after spinal cord injury. In brief, our findings indicate a possible mechanism for communication between Treg cells and microglia, which opens up a new perspective for alleviating neuroinflammation after SCI.
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Exossomos , MicroRNAs , Traumatismos da Medula Espinal , Animais , Camundongos , Exossomos/metabolismo , Microglia/metabolismo , MicroRNAs/metabolismo , Doenças Neuroinflamatórias , Piroptose , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
Deep venous thrombosis (DVT) is a common medical complication in patients with lumbar fractures. The current study aimed to investigate the predictive value of neutrophil extracellular traps (NETs) in postoperative DVT formation in patients with lumbar fractures and to develop a nomogram relating clinical admission information for prediction. Patients who underwent open reduction and pedicle screw internal fixation in the treatment of single-segment lumbar fracture in the Department of Spine Surgery, the First Affiliated Hospital of Nanjing Medical University, from December 2020 to June 2022 were enrolled in this study. Baseline data and laboratory results were collected from enrollees, and the primary study endpoint event was the occurrence of DVT in patients after surgery. Multivariable logistic regression analysis was used to identify risk factors associated with higher odds of DVT after surgery. A nomogram was constructed using the results of the multivariable model. The calibration plot and receiver operating characteristics (ROC) curve were used to show the satisfactory predictive capacity of the model. Of these 393 patients who did not have DVT preoperatively, 79 patients developed it postoperatively, and 314 did not, respectively. Multivariate analysis showed that higher body mass index (BMI) (BMI between 24 and 28: RR = 1.661, 95% CI = 0.891-3.094; BMI ≤28: RR = 5.625, 95% CI = 2.590-12.217; reference: BMI <24), neutrophils (RR = 1.157, 95% CI 1.042-1.285), D-dimer (RR = 1.098, 95% CI 1.000-1.206), and citrullinated histone H3 (CitH3) (RR = 1.043, 95% CI 1.026-1.060) were independent risk factors for postoperative DVT. Using the multivariable analysis, we then constructed a nomogram to predict DVT, which was found to have an area under the curve of 0.757 (95% CI = 0.693-0.820). Calibration plots also showed the satisfied discrimination and calibration of the nomogram. In conclusion, patients with lumbar fractures with postoperative DVT had higher levels of NETs in the circulation preoperatively compared to those without postoperative DVT. Furthermore, based on BMI, D-dimer, neutrophils, and CitH3, we developed a predictive model to predict postoperative DVT incidence in these patients.
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Robot-assisted orthopedic surgery has great application prospects, and the accuracy of the robot is the key to its overall performance. The aim of this study was to develop a new orthopedic surgical robot to assist in spinal surgeries and to compare its feasibility and accuracy with the existing orthopedic robot. A new type of high-precision orthopedic surgical robot (Tuoshou) was developed. A multicenter, randomized controlled trial was carried out to compare the Tuoshou with the TiRobot (TINAVI Medical Technologies Co., Ltd., Beijing) to evaluate the accuracy and safety of their navigation and positioning. A total of 112 patients were randomized, and 108 patients completed the study. The position deviation of the Kirschner wire placement in the Tuoshou group was smaller than that in the TiRobot group (p = 0.014). The Tuoshou group was better than the TiRobot group in terms of the pedicle screw insertion accuracy (p = 0.016) and entry point deviation (p < 0.001). No differences were observed in endpoint deviation (p = 0.170), axial deviation (p = 0.170), sagittal deviation (p = 0.324), and spatial deviation (p = 0.299). There was no difference in security indicators. The new orthopedic surgical robot was highly accurate and optimized for clinical practice, making it suitable for clinical application.
RESUMO
OBJECTIVE: Distinguishing spinal tuberculosis and pyogenic spinal infection is extremely important. The neutrophil-lymphocyte ratio (NLR), a simple indicator, has been shown to be a novel inflammatory marker. The objective of our study was to determine whether the NLR could be a potential indicator for discriminating spinal tuberculosis (STB) from pyogenic spinal infection (PSI). METHODS: We compared the clinical and laboratory characteristics of 146 patients diagnosed with STB and 60 participants with PSI from the First Affiliated Hospital of Nanjing Medical University. The NLR's diagnostic ability for differential diagnosis was assessed and compared to other hematological indicators, including the platelet-lymphocyte ratio (PLR). RESULTS: The NLR in STB patients was considerably lower than that in PSI patients [3.85 (2.70-5.71) vs. 10.82 (6.79-17.62), P < 0.001]. An NLR of 6.742 was proposed as an optimal cutoff value for distinguishing patients with STB from those with PSI (sensitivity 78.33%, specificity 83.56%). However, the NLR's area under the curve [0.87, 95% confidence interval (CI) 0.81-0.92] was considerably higher than that of the PLR (0.73, 95% CI 0.65-0.80; P < 0.0001). CONCLUSION: NLR levels could be a valuable laboratory diagnostic for distinguishing patients with STB from those who have PSI.