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Spinal cord injury (SCI) patients have an increased susceptibility to coronary heart disease (CHD) due to dysregulated lipid deposition. We conducted a comprehensive investigation to gain insights into the specific roles of Apolipoprotein B-100 (APOB-100) in the development of CHD in patients suffering from SCI. First, we established an SCI rat model through semitransection. APOB-100 expression in plasma exosomes obtained from patients were determined. Subsequently, we found APOB-100 affected macrophage polarization when treating co-cultured neurons/macrophages lacking Sortilin with extracellular vesicles derived from SCI rats, where APOB-100 co-immunoprecipitated with Sortilin. Moreover, APOB-100 upregulation reduced neuronal cell viability and triggered apoptosis by upregulating Sortilin, leading to a decline in the Basso, Beattie, and Bresnahan (BBB) scale, exacerbation of neuron injury, increased macrophage infiltration, and elevated blood lipid-related indicators in SCI rats, which could be reversed by silencing Sortilin. In conclusion, APOB-100 from post-SCI patients' extracellular vesicles upregulates Sortilin, thereby endangering those patients to CHD.
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Conventional wastewater treatment methods cannot completely remove the ultraviolet (UV) filters or dissolved organic matter. The transformation characteristics of these substances during chlorination disinfection and the varying species-specific toxicities of their combinations remain unclear. Here, Daphnia magna and zebrafish were exposed to benzophenone-3 (BP-3) and humic acid (HA) before and after chlorination disinfection. The results from chemical indicators showed that chlorination treatment decreased UV254 values and changed the intensity of parallel factors in three-dimensional fluorescence. Based on chemical analysis, the chlorine concentration and chlorination time for the toxicity experiments were set at 5 mg/L and 6 h, respectively. Exposure to HA and BP-3 before and after chlorination decreased the heart rate (by 1.37-28.12 %) in both species. However, species-specific responses, including survival rate, swimming distance, and expression of genes related to neurodevelopment, growth, and oxidative stress, were induced by chlorination. Chlorination reduced the impact of HA exposure but worsened the effects of HA and BP-3 co-exposure on D. magna. However, in zebrafish, the toxic effects intensified in most of the exposure groups after chlorination. Correlation analysis showed that the parallel factors of three-dimensional fluorescence were correlated with toxic effects on zebrafish, whereas UV254 was more significantly correlated with toxic effects on D. magna. This study provides insights into the combined toxicity of UV filters and dissolved organic matter in different aquatic organisms during chlorination, which is useful for risk control and optimization of the chlorination process.
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Benzofenonas , Desinfección , Halogenación , Sustancias Húmicas , Contaminantes Químicos del Agua , Animales , Benzofenonas/toxicidad , Cloro/toxicidad , Cloro/química , Daphnia magna/efectos de los fármacos , Daphnia magna/fisiología , Desinfección/métodos , Frecuencia Cardíaca/efectos de los fármacos , Sustancias Húmicas/toxicidad , Rayos Ultravioleta , Contaminantes Químicos del Agua/toxicidad , Purificación del Agua/métodos , Pez Cebra/fisiologíaRESUMEN
Spinal cord injury (SCI) is a severe neurological complication following spinal fracture, which has long posed a challenge for clinicians. Microglia play a dual role in the pathophysiological process after SCI, both beneficial and detrimental. The underlying mechanisms of microglial actions following SCI require further exploration. The present study combined three different machine learning algorithms, namely weighted gene co-expression network analysis, random forest analysis and least absolute shrinkage and selection operator analysis, to screen for differentially expressed genes in the GSE96055 microglia dataset after SCI. It then used protein-protein interaction networks and gene set enrichment analysis with single genes to investigate the key genes and signaling pathways involved in microglial function following SCI. The results indicated that microglia not only participate in neuroinflammation but also serve a significant role in the clearance mechanism of apoptotic cells following SCI. Notably, bioinformatics analysis and lipopolysaccharide + UNC569 (a MerTK-specific inhibitor) stimulation of BV2 cell experiments showed that the expression levels of Anxa2, Myo1e and Spp1 in microglia were significantly upregulated following SCI, thus potentially involved in regulating the clearance mechanism of apoptotic cells. The present study suggested that Anxa2, Myo1e and Spp1 may serve as potential targets for the future treatment of SCI and provided a theoretical basis for the development of new methods and drugs for treating SCI.
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Excitotoxicity represents the primary cause of neuronal death following spinal cord injury (SCI). While autophagy plays a critical and intricate role in SCI, the specific mechanism underlying the relationship between excitotoxicity and autophagy in SCI has been largely overlooked. In this study, we isolated primary spinal cord neurons from neonatal rats and induced excitotoxic neuronal injury by high concentrations of glutamic acid, mimicking an excitotoxic injury model. Subsequently, we performed transcriptome sequencing. Leveraging machine learning algorithms, including weighted correlation network analysis (WGCNA), random forest analysis (RF), and least absolute shrinkage and selection operator analysis (LASSO), we conducted a comprehensive investigation into key genes associated with spinal cord neuron injury. We also utilized protein-protein interaction network (PPI) analysis to identify pivotal proteins regulating key gene expression and analyzed key genes from public datasets (GSE2599, GSE20907, GSE45006, and GSE174549). Our findings revealed that six genes-Anxa2, S100a10, Ccng1, Timp1, Hspb1, and Lgals3-were significantly upregulated not only in vitro in neurons subjected to excitotoxic injury but also in rats with subacute SCI. Furthermore, Hspb1 and Lgals3 were closely linked to neuronal autophagy induced by excitotoxicity. Our findings contribute to a better understanding of excitotoxicity and autophagy, offering potential targets and a theoretical foundation for SCI diagnosis and treatment.
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Autofagia , Galectina 3 , Aprendizaje Automático , Neuronas , Animales , Ratas , Galectina 3/metabolismo , Galectina 3/genética , Ácido Glutámico/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neuronas/metabolismo , Mapas de Interacción de Proteínas , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/genéticaRESUMEN
The railway rivet is one of the most important and easily damaged parts of the connection. If rivets develop cracks during the production process, their load-bearing capacity will be reduced, thereby increasing the risk of failure. Fluorescent magnetic particle flaw detection (FMPFD) is a widely used inspection method for train fasteners. Manual inspection is not only time-consuming but also prone to miss detection, therefore intelligent detection system has important application value. However, the fluorescent crack images obtained by FMPFD present challenges for intelligent detection, such as the dense, multi-scaled and uninstantiated cracks. In addition, there is limited research on fluorescent rivet crack detection. This paper adopts instance segmentation to achieve automatic cracks detection of rivets. A decentralized target center and low overlap rate labeling method is proposed, and a Gaussian-weighted correction post-processing method is introduced to improve the recall rate in the areas of dense cracks. An efficient channel spatial attention mechanism for feature extraction is proposed in order to enhance the detection of multi-scale cracks. For uninstantiated cracks, an improvement of crack detection in uninstantiated regions based on multi task feature learning is proposed, thoroughly utilizing the semantic and spatial features of the fluorescent cracks. The experimental results show that the improved methods are better than the baseline and some cutting-edge algorithms, achieving a recall rate and mAP0.5 of 86.4% and 90.3%. In addition, a single coil non-contact train rivet composite magnetization device is built for rivets that can magnetize different shapes of rivets and has universality.
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Osteoarthritis (OA) is a low-grade, nonspecific inflammatory disease that affects the entire joint. This condition is characterized by synovitis, cartilage erosion, subchondral bone defects, and subpatellar fat pad damage. There is mounting evidence demonstrating the significance of crosstalk between synovitis and cartilage destruction in the development of OA. To comprehensively explore the phenotypic alterations of synovitis and cartilage destruction, it is important to elucidate the crosstalk mechanisms between chondrocytes and synovial cells. Furthermore, the updated iteration of single-cell sequencing technology reveals the interaction between chondrocyte and synovial cells. In the present review, the histological and pathological alterations between cartilage and synovium during OA progression are described, and the mode of interaction and molecular mechanisms between synovial cells and chondrocytes in OA, both of which affect the OA process mainly by altering the inflammatory environment and cellular state, are elucidated. Finally, the current OA therapeutic approaches are summarized and emerging therapeutic targets are reviewed in an attempt to provide potential insights into OA treatment.
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STUDY DESIGN: Observational study. OBJECTIVE: To assess the reproducibility and reliability of the system. BACKGROUND: The Huashan radiologic classification system for cervical spinal cord injury without fracture and dislocation (CSCIWFD) was recently proposed and found useful for clinical practice. PATIENTS AND METHODS: Patients diagnosed with CSCIWFD between 2015 and 2021 were recruited. Six spine surgeons from different institutions, three experienced and other inexperienced respectively, were trained as observers of the system, and these surgeons classified the recruited patients using the system. Then, 8 weeks later, they repeated the classification on the same patients in a different order. The interobserver and intraobserver agreement between the results was analyzed using percentage agreement, weighted kappa, and Cohen kappa (κ) statistics. RESULTS: A total of 60 patients were included in the analysis. Type I was the most frequent type (29 cases, 48.3%), followed by type II (13 cases, 21.7%), type III (12 cases, 20%), and type IV (6 cases, 10%). For all the observers, experienced observers, and inexperienced observers, the overall agreement percentages were 77.6% (κ = 0.78), 84.4% (κ = 0.84), and 72.8% (κ = 0.74), respectively, indicating substantial to nearly perfect interobserver reproducibility. A higher level of agreement was found for differentiating type I from other types, with the percentage agreement ranging from 87.8% to 94.4% (κ= 0.74-0.88). For distinguishing compression on the spinal cord (types I and II vs types III and IV) among the different groups of observers, the percentage agreement was 97.8% (κ = 0.94), indicating nearly perfect reproducibility. As for intraobserver agreement, the percentage agreement ranged from 86.7% to 96.7% (κ = 0.78-0.95), indicating at least substantial reliability. CONCLUSIONS: The Huashan radiologic classification system for CSCIWFD was easy to learn and apply in a clinical environment, showing excellent reproducibility and reliability. Therefore, it would be promising to apply and promote this system for the precise evaluation and personalized treatment strategy.
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Objective: To assess the effectiveness of using mobile health platforms for continuous care in preventing and treating osteoporosis. Methods: 114 patients with osteoporosis admitted to Nantong First People's Hospital from March 2021 to June 2022 were recruited and assigned equally via random number table method to receive either routine care (namely education on osteoporosis disease, dietary guidance, exercise guidance, activity guidance, medication supervision, fall prevention, psychological care, and secondary health education at the time of discharge) (routine group) or mobile health platform-based continuity of care (continuity group), with 57 patients in each group. Outcome measures included treatment compliance, disease knowledge of osteoporosis (diet, exercise, risk factors), quality of life level, and care satisfaction. Results: All eligible patients were followed up for one year after discharge from the hospital. Patients with continuity of care showed higher treatment compliance and disease knowledge of diet, exercise, and risk factors than those with routine care (P = .004). Continuity of care was associated with significantly higher MOS 36-item short-form health survey (SF-36) scores (The SF-36 is a self-administered questionnaire containing 36 items that survey overall health status) and nursing satisfaction in patients versus routine care (P = .004). Conclusion: Mobile health platform-based continuity of care effectively enhances post-discharge compliance and knowledge of osteoporosis in patients with osteoporosis, thereby improving post-discharge quality of life and satisfaction with care. Multi-center studies involving diverse healthcare settings and patient populations would provide more robust evidence. Moreover, these findings highlight the potential benefits of incorporating mobile health platforms into the care continuum for osteoporosis patients. Also, by utilizing mobile health platforms, healthcare providers can extend their reach beyond hospital settings and provide continuous care and support to patients, potentially reducing the burden on healthcare systems and improving overall population health outcomes.
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Benzophenone-3 (BP-3) is a commonly used ultraviolet absorber that has the potential to accumulate in organisms, leading to toxicity. Benzophenone-8 (BP-8) is one of the major metabolites of BP-3. In this study, zebrafish were exposed to different concentrations of BP-3 and BP-8 (1 µg/L, 30 µg/L, and 300 µg/L) to investigate their accumulation and toxic effects in various tissues, including zebrafish brain, gut, and liver. The analysis focused on neurotoxicity, oxidative damage, inflammation, and gene expressions. The results showed that both BP-3 and BP-8 accumulated in the tissues, with the highest concentration observed in the gut, followed by the liver and brain. BP-8 exhibited a stronger ability to accumulate. In the brain, exposure to 1 µg/L of BP-3 and BP-8 promoted cortisol production, while higher exposures (30 µg/L and 300 µg/L) inhibited acetylcholinesterase activity and suppressed cortisol production. In the gut, both BP-3 and BP-8 exposures disrupted oxidative stress, inflammatory immunity, and apoptosis functions. In the liver, BP-3 and BP-8 affected hepatic metabolism, oxidative stress, apoptosis, and inflammatory immunity. Comparing gene expression in the brain, gut, and liver, it was found that BP-3 and BP-8 had a lower effect on gene expression in the brain, while the effect on the gut and liver was significantly higher. BP-8 generally had a higher effect than BP-3, which aligns with the observed accumulation pattern. These findings provide valuable insights for the risk assessment of BP-3 and BP-8 in the aquatic environment.
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Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/metabolismo , Acetilcolinesterasa/metabolismo , Hidrocortisona , Contaminantes Químicos del Agua/toxicidad , Benzofenonas/toxicidadRESUMEN
This study aims to explore the impacts of ApoB-100/SORT1-mediated immune microenvironment during acute spinal cord injury (SCI), and to investigate the potential mechanism. CB57BL/6 mice underwent moderate thoracic contusion injury to establish the SCI animal model, and received ApoB-100 lentivirus injection to interfere ApoB-100 level. Functional recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) score and footprint analysis. Transmission electron microscopy was applied to observe the ultrastructure of the injured spinal cord tissue. Hematoxylin-eosin (HE) staining and Perls staining were conducted to assess histological changes and iron deposition. Biochemical factor and cytokines were detected using their commercial kits. M1/M2 macrophage markers were detected by immunofluorescence assay in vivo and by flow cytometry in vitro. HT22 neurons were simulated by lipopolysaccharide (LPS), followed by incubation with polarized macrophage medium to simulate the immune microenvironment of injured spinal cord in vitro. The local immune microenvironment is changed in SCI mice, accompanied with the occurrence of oxidative stress and the elevation of both M1 and M2 macrophages. Knockdown of ApoB-100 ameliorates oxidative stress and lipid disorder, and inhibits inflammation and ferroptosis in SCI mice. Importantly, knockdown of ApoB-100 can partly restrict M1 macrophages but does not change M2 macrophage proportion in SCI mice. Further, M1 macrophages are observed to attenuate the inflammatory response, oxidative stress, and ferroptosis levels of LPS-induced HT22 cells, which is further strengthened by SORT1 knockdown. Blockage of ApoB-100/SORT1-mediated immune microenvironment plays a protective role against SCI via inhibiting oxidative stress, inflammation, lipid disorders, and ferroptosis, providing novel insights of the targeted therapy of SCI.
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Apolipoproteína B-100 , Ferroptosis , Inflamación , Macrófagos , Ratones Endogámicos C57BL , Estrés Oxidativo , Traumatismos de la Médula Espinal , Animales , Femenino , Ratones , Apolipoproteína B-100/metabolismo , Ferroptosis/fisiología , Inflamación/patología , Inflamación/metabolismo , Macrófagos/metabolismo , Recuperación de la Función , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/inmunologíaRESUMEN
A metabolic bone disease characterized by decreased bone formation and increased bone resorption is osteoporosis. It can cause pain and fracture of patients. The elderly are prone to osteoporosis and are more vulnerable to osteoporosis. In this study, radiomics are extracted from computed tomography (CT) images to screen osteoporosis in the elderly. Collect the plain scan CT images of lumbar spine, cut the region of interest of the image and extract radiomics features, use Lasso regression to screen variables and adjust complexity, use python language to model random forests, support vector machines, K nearest neighbor, and finally use receiver operating characteristic curve to evaluate the performance of the model, including precision, recall, accuracy and area under the curve (AUC). For the model, 14 radiolomics features were selected. The diagnosis performance of random forest model and support vector machine is good, all around 0.9. The AUC of K nearest neighbor model in training set and test set is 0.828 and 0.796, respectively. We selected the plain scan CT images of the elderly lumbar spine to build radiomics features model, which has good diagnostic performance and can be used as a tool to assist the diagnosis of osteoporosis in the elderly.
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Vértebras Lumbares , Osteoporosis , Máquina de Vectores de Soporte , Tomografía Computarizada por Rayos X , Humanos , Anciano , Osteoporosis/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Femenino , Masculino , Anciano de 80 o más Años , Persona de Mediana Edad , RadiómicaRESUMEN
BACKGROUND: Spinal cord injury (SCI) occurs as a devastating neuropathic disease. The role of serine-threonine kinase 10 (STK10) in the development of SCI remains unclear. OBJECTIVE: This study aimed to investigate the action of m6A methylation on STK10 in the apoptosis of spinal cord neurons in the pathogenesis of SCI and the possible underlying mechanisms. METHODS: Rat model of SCI was established and subsequently evaluated for motor function, pathological conditions, and apoptosis of spinal cord neurons. And the effects of overexpression of STK10 on neuronal cells in animal models of spinal cord injury and glyoxylate deprivation (OGD) cell models were evaluated. m6A2Target database and SRAMP database were used to predict the m6A methylation sites of STK10. The methylation kits were used to detect overall m6A methylation. Finally, the interaction between STK10 and vir like m6A methyltransferase associated (VIRMA) was explored in animal and cellular models. RESULTS: STK10 is markedly decreased in spinal cord injury models and overexpression of STK10 inhibits neuronal apoptosis. VIRMA can induce m6A methylation of STK10. VIRMA is over-expressed in spinal cord injury models and negatively regulates the expression of STK10. m6A methylation and apoptosis of neuronal cells are reduced by the knockdown of VIRMA and STK10 shRNA have shown the opposite effects. CONCLUSIONS: VIRMA promotes neuronal apoptosis in spinal cord injury by regulating STK10 m6A methylation.
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Adenina/análogos & derivados , Metiltransferasas , Traumatismos de la Médula Espinal , Ratas , Animales , Ratas Sprague-Dawley , Metiltransferasas/metabolismo , Metiltransferasas/farmacología , Traumatismos de la Médula Espinal/patología , Apoptosis/fisiología , Médula Espinal/metabolismo , Modelos Animales , Neuronas/metabolismo , MetilaciónRESUMEN
Facet joint osteoarthritis (FJOA), a condition commonly observed in individuals of middle to old age, has been relatively under-researched compared to other subtypes of osteoarthritis (OA). This study investigated the role of transcription factor FoxO1 in FJOA using a Col2a1-creERT knock-in mouse model. It was found that FoxO1 deletion led to severe osteoarthritic changes, indicating that FoxO1 played a critical role in cartilage homeostasis. Transcriptome sequencing was performed on degenerated cartilage from FoxO1-deleted mice. This process identified differentially expressed genes (DEGs), offering insights into the molecular mechanisms underlying FJOA. Bioinformatics analysis, including Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) and protein-protein interaction (PPI) network analysis, identified Itgb3, Itga1, Itga6, Itga7, Itga8, Itga10, Col1a1, and Il6, as potential key contributors to FJOA after FoxO1 deletion. Importantly, overexpression of Itgb3 and inhibition of Il6 counteracted FoxO1 knockdown-induced impairments in chondrocyte migration and extracellular matrix synthesis, respectively. This study discovered FoxO1 as a key regulator of the pathogenesis of FJOA, helped unravel the complex molecular mechanisms underlying FJOA, and contributed to the development of promising therapeutic avenues toward FJOA.
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Osteoartritis , Articulación Cigapofisaria , Animales , Ratones , Condrocitos/metabolismo , Regulación de la Expresión Génica , Interleucina-6/metabolismo , Osteoartritis/patología , Articulación Cigapofisaria/metabolismo , Articulación Cigapofisaria/patologíaRESUMEN
Purpose: The efficacy of adjunctive ambrisentan treatment in patients with systemic sclerosis (SSc) suffering from digital ulcers (DUs) was investigated.Material and methods: Patients (4 males, 7 females) diagnosed with SSc at our hospital between 2017 and 2022 were enrolled. Ten of them had diffuse SSc, while one had limited SSc. These patients received daily 5 mg doses of ambrisentan in addition to their regular SSc treatment for 16 weeks. Parameters including the total number and size of existing and new DUs, Visual Analog Score (VAS), frequency of Raynaud's phenomenon (RP) attacks, and any adverse effects were assessed.Results: At baseline, the median number and size of DUs was 3.0 (interquartile range (IQR): 2.0-4.0 cm) and 0.4 cm (IQR: 0.3-0.5 cm), respectively. Following the intervention, seven patients with a median of 2.0 DUs and a size of 0.35 cm (IQR: 0.15-0.45 cm) at baseline achieved complete healing. Significant improvements were also observed in other patients. VAS scores decreased from a baseline median of 5.0-0.0 (IQR: 0.0-1.0), and both the frequency and duration of RP attacks notably reduced.Conclusion: Adjunctive ambrisentan therapy proved effective in promoting DU healing and preventing new DUs in SSc patients.
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Esclerodermia Sistémica , Úlcera Cutánea , Masculino , Femenino , Humanos , Dedos , Úlcera Cutánea/tratamiento farmacológico , Úlcera Cutánea/etiología , Esclerodermia Sistémica/complicacionesRESUMEN
BACKGROUND: Spinal cord injury (SCI) is a devastating disease that can lead to tissue loss and neurological dysfunction. TNIP2 is a negative regulator of NF-κB signaling due to its capacity to bind A20 and suppress inflammatory cytokines-induced NF-κB activation. However, the anti-inflammatory role of TNIP2 in SCI remains unclear. Our study's intention was to evaluate the effect of TNIP2 on the inflammatory response of microglia after spinal cord injury in rats. METHODS: HE staining and Nissl staining were performed on day 3 following SCI to analyze the histological changes. To further investigate the functional changes of TNIP2 after SCI, we performed immunofluorescence staining experiments. The effect of LPS on TNIP2 expression in BV2 cells was examined by western blot. The levels of TNF-α, IL-1ß, and IL-6 in spinal cord tissues of rats with SCI and in BV2 cells with LPS were measured by using qPCR. RESULTS: TNIP2 expression was closely associated with the pathophysiology of SCI in rats, and TNIP2 was involved in regulating functional changes in microglia. TNIP2 expression was increased during SCI in rats and that overexpression of TNIP2 inhibited M1 polarization and pro-inflammatory cytokine production in microglia, which might ultimately protect against inflammatory responses through the MAPK and NF-κB signaling pathways. CONCLUSIONS: The present study provides evidence for a role of TNIP2 in the regulation of inflammation in SCI and suggests that induction of TNIP2 expression alleviated the inflammatory response of microglia.
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Proteínas Adaptadoras Transductoras de Señales , FN-kappa B , Traumatismos de la Médula Espinal , Animales , Ratas , Inflamación/metabolismo , Lipopolisacáridos , Microglía/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
Introduction: Spinal cord injury (SCI) is a severe central nervous system injury that leads to significant sensory and motor impairment. Copper, an essential trace element in the human body, plays a vital role in various biological functions and is strictly regulated by copper chaperones and transporters. Cuproptosis, a novel type of metal ion-induced cell death, is distinct from iron deprivation. Copper deprivation is closely associated with mitochondrial metabolism and mediated by protein fatty acid acylation. Methods: In this study, we investigated the effects of cuproptosis-related genes (CRGs) on disease progression and the immune microenvironment in acute spinal cord injury (ASCI) patients. We obtained the gene expression profiles of peripheral blood leukocytes from ASCI patients using the Gene Expression Omnibus (GEO) database. We performed differential gene analysis, constructed protein-protein interaction networks, conducted weighted gene co-expression network analysis (WGCNA), and built a risk model. Results: Our analysis revealed that dihydrolipoamide dehydrogenase (DLD), a regulator of copper toxicity, was significantly associated with ASCI, and DLD expression was significantly upregulated after ASCI. Furthermore, gene ontology (GO) enrichment analysis and gene set variation analysis (GSVA) showed abnormal activation of metabolism-related processes. Immune infiltration analysis indicated a significant decrease in T cell numbers in ASCI patients, while M2 macrophage numbers were significantly increased and positively correlated with DLD expression. Discussion: In summary, our study demonstrated that DLD affects the ASCI immune microenvironment by promoting copper toxicity, leading to increased peripheral M2 macrophage polarization and systemic immunosuppression. Thus, DLD has potential as a promising biomarker for ASCI, providing a foundation for future clinical interventions.
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As a key component of the innate immune system, over-activation of microglia that occurs in nervous system diseases is usually accompanied by retraction of their branched processes. Reversal of microglial process retraction is a potential strategy to prevent neuroinflammation. In our previous studies, we reported some molecules that can promote the elongation of microglial processes under in vitro and in vivo conditions, such as butyrate, ß-hydroxybutyrate, sulforaphane, diallyl disulfide, compound C, and KRIBB11. Here, we found that lactate, a molecule that mimics endogenous lactic acid and has been shown to suppress neuroinflammation, reversibly triggered significant elongations of processes in microglia under cultured and in vivo conditions. Pretreatment with lactate also prevented lipopolysaccharide (LPS)-induced shortening of microglial processes under cultured and in vivo conditions, pro-inflammatory responses in primary cultured microglia and prefrontal cortex, and depression-like behaviors in mice. Mechanistic studies revealed that incubation with lactate increased phospho-Akt levels in primary cultured microglia and inhibition of Akt blocked the pro-elongation effect of lactate on the microglial process under cultured and in vivo conditions, suggesting that the regulatory effect of lactate on the microglial process is dependent on activation of Akt. Inhibition of Akt also abolished the preventive effect of lactate on LPS-induced inflammatory responses in primary cultured microglia and prefrontal cortex and on LPS-induced depression-like behaviors in mice. Overall, these results demonstrate that lactate can induce Akt-mediated elongation of the microglial process, which appropriately contributes to the inhibition of microglia-mediated neuroinflammation.
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Microglía , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Inflamación , Ácido Láctico , Enfermedades Neuroinflamatorias , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BLRESUMEN
Increasingly intricate in their multilevel multiscale microarchitecture, metamaterials with unique physical properties are challenging the inherent constraints of natural materials. Their applicability in the nanomedicine field still suffers because nanomedicine requires a maximum size of tens to hundreds of nanometers; however, this size scale has not been achieved in metamaterials. Therefore, "nano-metamaterials," a novel class of metamaterials, are introduced, which are rationally designed materials with multilevel microarchitectures and both characteristic sizes and whole sizes at the nanoscale, investing in themselves remarkably unique and significantly enhanced material properties as compared with conventional nanomaterials. Microarchitectural regulation through conventional thermodynamic strategy is limited since the thermodynamic process relies on the frequency-dependent effective temperature, Teff (ω), which limits the architectural regulation freedom degree. Here, a novel dual-kinetic control strategy is designed to fabricate nano-metamaterials by freezing a high-free energy state in a Teff (ω)-constant system, where two independent dynamic processes, non-solvent induced block copolymer (BCP) self-assembly and osmotically driven self-emulsification, are regulated simultaneously. Fe3+ -"onion-like core@porous corona" (Fe3+ -OCPCs) nanoparticles (the products) have not only architectural complexity, porous corona and an onion-like core but also compositional complexity, Fe3+ chelating BCP assemblies. Furthermore, by using Fe3+ -OCPCs as a model material, a microstructure-biological performance relationship is manifested in nano-metamaterials.
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Osteoarthritis (OA) is a disease involving the whole joint that seriously reduces the living standards of individuals. Traditional treatments include physical therapy, administration of anti-inflammatory and analgesic drugs and injection of glucocorticoids or hyaluronic acid into the joints. However, these methods have limited efficacy and it is difficult to reverse the progression of OA, therefore it is urgent to find new effective treatment methods. Immune microenvironment is significant in the occurrence and development of OA. Recent studies have shown that macrophages are important targets for the treatment of OA. Macrophages are polarized into M1 pro-inflammatory phenotype and M2 anti-inflammatory phenotype under stimulation of different factors, which release and regulate inflammatory response and cartilage growth. Accumulating studies have tried to alleviate OA by regulating macrophage homeostasis. The present study summarized the related studies, discuss the mechanism of various therapeutic reagents on OA, expound the molecular mechanism of drug effect on OA and attempted to provide clues for the treatment of OA.