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Spinal cord injury (SCI) often results in irreversible loss of sensory and motor functions, and most SCIs are incurable with current medical practice. One of the hardest challenges in treating SCI is the development of a dysfunctional pathological microenvironment, which mainly comprises excessive inflammation, deposition of inhibitory molecules, neurotrophic factor deprivation, glial scar formation, and imbalance of vascular function. To overcome this challenge, implantation of functional biomaterials at the injury site has been regarded as a potential treatment for modulating the dysfunctional microenvironment to support axon regeneration, remyelination at injury site, and functional recovery after SCI. This review summarizes characteristics of dysfunctional pathological microenvironment and recent advances in biomaterials as well as the technologies used to modulate inflammatory microenvironment, regulate inhibitory microenvironment, and reshape revascularization microenvironment. Moreover, technological limitations, challenges, and future prospects of functional biomaterials to promote efficient repair of SCI are also discussed. This review will aid further understanding and development of functional biomaterials to regulate pathological SCI microenvironment.
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SUMMARY: Utilizing the Mendelian randomization technique, this research clarifies the putative causal relationship between body mass index (BMI) andbone mineral density (BMD), and the mediating role of low-density lipoprotein (LDL). The implications of these findings present promising opportunities for enhancing our understanding of complex bone-related characteristics and disorders, offering potential directions for treatment and intervention. OBJECTIVE: The objective of this study is to examine the correlation between BMI and BMD, while exploring the intermediary role of LDL in mediating the causal impact of BMI on BMD outcomes via Mendelian randomization. METHODS: In this study, we employed genome-wide association study (GWAS) data on BMI, LDL, and BMD to conduct a comparative analysis using both univariate and multivariate Mendelian randomization. RESULTS: Our study employed a two-sample Mendelian randomization design. Considering BMI as the exposure and BMD as the outcome, our results suggest that BMI may function as a potential protective factor for BMD (ß = 0.05, 95% CI 1.01 to 1.09, P = 0.01). However, when treating LDL as the exposure and BMD as the outcome, our findings indicate LDL as a risk factor for BMD (ß = -0.04, 95% CI 0.92 to 0.99, P = 0.04). In our multivariate Mendelian randomization (MVMR) model, the combined influence of BMI and LDL was used as the exposure for BMD outcomes. The analysis pointed towards a substantial protective effect of LDL on BMD (ß = 0.08, 95% CI 0.85 to 0.97, P = 0.006). In the analysis of mediation effects, LDL was found to mediate the relationship between BMI and BMD, and the effect was calculated at (ß = 0.05, 95% CI 1.052 to 1.048, P = 0.04). CONCLUSION: Our findings suggest that BMI may be considered a protective factor for BMD, while LDL may act as a risk factor. Moreover, LDL appears to play a mediatory role in the causal influence of BMI on BMD.
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Índice de Massa Corporal , Densidade Óssea , Estudo de Associação Genômica Ampla , Lipoproteínas LDL , Análise da Randomização Mendeliana , Humanos , Densidade Óssea/genética , Lipoproteínas LDL/sangue , Polimorfismo de Nucleotídeo Único , FemininoRESUMO
From the perspective of lncRNA MALAT1 regulating cholesterol metabolism in chondrocytes, this paper explores the effect and mechanism of Tougu Xiaotong Capsules(TGXTC) in delaying the degeneration of osteoarthritis. After one week of adaptive feeding, 48(8-week-old) C57BL/6 mice were randomly divided into a blank group(12 mice) and a model group(36 mice) by random number table method. The mice in the model group were anesthetized by inhalation of 5% isoflurane, and the OA model was induced by Hulth method. The experiment randomly divided the mice into a model group(12 mice), a drug-positive group(taururso-deoxycholic acid)(12 mice), and a TGXTC group(12 mice). The drug-positive group was given 500 mg·kg~(-1) taurodeoxycholic acid by intragastric administration. TGXTC group was given TGXTC 368 mg·kg~(-1) by gavage. The blank group and model group were given the same amount of normal saline for four weeks. After the intervention, the mice in each group were killed under anesthesia, and the knee cartilage tissue was separated and collected. The morphologic changes of knee cartilage were observed. The level of lncRNA MALAT1 in the cartilage tissue was detected by real-time PCR. The protein expressions of ABCA1, ApoA1, LXRß, CHOP, and caspase-3 in mouse articular cartilage were detected by Western blot. Lentivirus-coated plasmid was used to transfect mouse chondrocytes with sh-MALAT1. The gene levels of lncRNA MALAT1 in mouse chondrocytes transfected with sh-MALAT1 were detected by real-time PCR. Western blot was used to detect the effect of TGXTC on the protein content of ABCA1, ApoA1, LXRß, CHOP, and caspase-3 in thapsigargin(TG)-induced mouse chondrocytes after lncRNA MALAT1 knockdown. Flow cytometry was used to detect the effect of TGXTC on apoptosis of TG-induced mouse chondrocytes after lncRNA MALAT1 knockdown. The results of HE and saffranine O staining showed that compared with the model group, the structure of the cartilage layer was basically intact; the damage degree of joint structure was significantly improved, and the cartilage matrix was significantly enhanced by saffranine O staining in the TGXTC group and drug-positive group. Compared with the model group, the lncRNA MALAT1 level was significantly decreased in the TGXTC group and drug-positive group. Compared with the model group, the protein content of ABCA1, ApoA1, and LXRß was significantly increased, while that of CHOP and caspase-3 in the TGXTC group and drug-positive group significantly decreased. Compared with the TG group, the lncRNA MALAT1 level in the TG+sh-MALAT1 group was decreased. The lncRNA MALAT1 level in the TG+sh-MA-LAT1+TGXTC group was increased compared with the TG+TGXTC group. Western blot results showed that compared with the model group, protein expressions of ABCA1, ApoA1, LXRß, CHOP, and caspase-3 in the TGXTC group were significantly decreased, after lncRNA MALAT1 knockdown, the regulation and apoptosis of ABCA1, ApoA1, LXRß, CHOP, and caspase-3 in TG-induced mouse chondrocytes were weakened by TGXTC. TGXTC can improve the disorder of cholesterol metabolism in OA chondrocytes and delay OA degeneration, which is closely related to the regulation of lncRNA MALAT1.
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Colesterol , Condrócitos , Medicamentos de Ervas Chinesas , Camundongos Endogâmicos C57BL , Osteoartrite , RNA Longo não Codificante , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Camundongos , Osteoartrite/metabolismo , Osteoartrite/genética , Osteoartrite/tratamento farmacológico , Colesterol/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Humanos , CápsulasRESUMO
Osteoarthritis (OA) is a common joint disease characterized by chronic pain, and the perception of pain is closely associated with brain function and neuropeptide regulation. Rehmannia is common plant herb with anti-inflammatory and analgesic properties that is used to treat OA. However, it is unclear whether Rehmannia alleviates OA-related pain via regulation of neuropeptides and brain function. We examined the pain relief regulatory pathway in OA after treatment with Rehmannia by verifying the therapeutic effect of Rehmannia alcohol extract in vivo and vitro and exploring of the potential mechanism underlying the analgesic effect of Rahmanian using functional magnetic resonance imaging and measuring neuropeptide secretion. Our results showed that Rehmannia alcohol extract and the related active ingredient, Rehmannioside D, can delay cartilage degradation and alleviate inflammation in OA rats. The Rehmannia alcohol extract can also relieve OA pain, reduce the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP), and reverse the pathological changes in the cerebral cortex and hippocampus. Our research results demonstrate that Rehmannia alleviates OA pain by protecting cartilage, preventing the stimulation of inflammatory factors on neuropeptide secretion, and influencing the relevant functional areas of the brain.
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Endoplasmic reticulum stress (ERS) has been identified to be an important factor leading to chondrocyte apoptosis in osteoarthritis (OA). Previous studies have confirmed that Achyranthes bidentata polysaccharides (ABPS) can inhibit chondrocyte apoptosis; however, the mechanism of action of ABPS on chondrocyte ERS remains unclear. Thus in this study, we aim to investigate whether ABPS could inhibit OA-associated chondrocyte apoptosis by regulating ERS, especially by observing the relationship between the lncRNA NEAT1 and miR-377-3p, to explore further the protective mechanism of ABPS in OA. In vitro and in vivo experiments showed that ABPS inhibited chondrocyte ERS by regulating the expression of lncRNA NEAT1 and miR-377-3p. Moreover, both lncRNA NEAT1 silencing and miR-377-3p inhibition could attenuate the therapeutic effect of ABPS on ERS. Dual-luciferase results indicated that miR-377-3p targets the lncRNA NEAT1 gene in mouse chondrocytes. Therefore, we concluded that ABPS could inhibit thapsigargin (TG)-induced chondrocyte ERS through the lncRNA NEAT1/miR-377-3p axis.
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Achyranthes , MicroRNAs , Osteoartrite , RNA Longo não Codificante , Animais , Apoptose , Condrócitos/metabolismo , Estresse do Retículo Endoplasmático , Camundongos , MicroRNAs/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/metabolismo , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , RNA Longo não Codificante/metabolismoRESUMO
Achyranthes bidentata polysaccharides (ABPS) is an active ingredient of the flowering plant Achyranthes bidentata that has been previously reported to be effective for the treatment of osteoarthritis (OA). However, the underlying molecular mechanism remain to be fully clarified. Emerging studies have shown that the long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) is involved in the pathogenesis of OA. Therefore, the present study aimed to investigate the potential mechanism of ABPS by focusing on its effects on the regulation of chondrocyte extracellular matrix (ECM) homeostasis, with particular emphasis on lncRNA GAS5. In the present study, the modified Hulth method was used to construct OA rats, which were gavaged with 400 mg/kg ABPS for 8 weeks. Histopathological changes in cartilage and subchondral bone were evaluated by hematoxylin-eosin staining and Safranin O-fast green staining. In in vitro experiments, IL-1ß-treated chondrocytes were infected with Lenti-lncRNA GAS5. Fluorescence in situ hybridization assay was performed to measure the expression of the lncRNA GAS5 in chondrocytes. Moreover, the relative expression level of lncRNA GAS5 in cartilage tissue and chondrocytes was detected using reverse transcription-quantitative PCR. Western blot analysis was used to detect protein expression levels of MMP-9, MMP-13, TIMP-1, TIMP-3 and type II collagen in cartilage tissue and chondrocytes. The results indicated that ABPS delayed the degradation of the ECM by chondrocytes in addition to reducing lncRNA GAS5 expression both in vivo and in vitro. Furthermore, silencing of lncRNA GAS5 expression in IL-1ß-treated chondrocytes downregulated the protein expression of MMP-9 and MMP-13 whilst upregulating the expression of tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-3 and type II collagen. To conclude, the present study provides evidence that ABPS can inhibit the expression of lncRNA GAS5 in chondrocytes to regulate the homeostasis of ECM, which in turn may delay the occurrence of cartilage degeneration during OA.
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This study aimed to identify whether the NF-κB signaling pathway plays a key role in the treatment of osteoarthritis (OA) with Bushen Zhuangjin Decoction (BZD) based on a typical network pharmacology approach (NPA). Four sequential experiments were performed: 1) conventional high-performance liquid chromatography (HPLC), 2) preliminary observation of the therapeutic effects of BZD, 3) NPA using three OA-related gene expression profiles, and 4) verification of the key pathway identified by NPA. Only one HPLC-verified compound (paeoniflorin) was identified from the candidate compounds discovered by NPA. The genes verified in the preliminary observation were also identified by NPA. NPA identified a key role for the NF-κB signaling pathway in the treatment of OA with BZD, which was confirmed by conventional western blot analysis. This study identified and verified NF-κB signaling pathway as the most important inflammatory signaling pathway involved in the mechanisms of BZD for treating OA by comparing the NPA results with conventional methods. Our findings also indicate that NPA is a powerful tool for exploring the molecular targets of complex herbal formulations, such as BZD.
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Radix Angelicae biseratae is a widely used Chinese traditional herbal medicine for osteoarthritis (OA). Its therapeutic efficacy has been confirmed in clinical practice. However, its mechanisms of action in treating OA have remained elusive. The purpose of the present study was to identify active components with good oral bioavailability and drug-like properties from Radix Angelicae biseratae through systematic pharmacology and in vitro experiments to determine targets of Radix Angelicae biseratae in the treatment of OA. The functional components of Radix Angelicae biseratae were screened from the Traditional Chinese Medicine Systems Pharmacology database based on oral bioavailability and drug-like properties. Subsequently, the databases STITCH, Open Targets Platform and DrugBank were searched and microarray analysis was performed to screen the active components of Radix Angelicae biseratae to treat OA and predict its potential target proteins. The interaction network and protein interaction network were then generated and examined, molecular docking between active components and targets was performed and the enrichment of potential target proteins was analyzed. Finally, reverse transcription-quantitative (RT-q)PCR and western blot analyses were used to verify the therapeutic effect of Radix Angelicae biseratae extract on the expression of OA-associated target proteins. The results provided eight active components in Radix Angelicae biseratae, which were firmly linked to 20 targets of OA. In combination with molecular docking and the analysis of the interaction network between components and targets, it was suggested that sitosterol was a major active component of Radix Angelicae biseratae in the treatment of OA. Protein interaction network analysis suggested that prostaglandin-endoperoxide synthase 2 (PTGS2), nitric oxide synthase 3 and cytochrome P450 2B6 may be critical targets for Radix Angelicae biseratae in the treatment of OA. In addition, RT-qPCR and western blot analyses suggested that Radix Angelicae biseratae extract inhibited the mRNA and protein expression of PTGS2 in degenerative articular cartilage cells in vitro, whilst other targets remain to be verified. Functional enrichment analysis indicated that Radix Angelicae biseratae confers pharmacological efficacy towards OA through exerting anti-inflammatory effects and immune regulation.
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Osteoarthritis (OA) is a chronic arthropathy that occurs in the middleaged and elderly population. The present study aimed to identify gene signature differences between synovial cells from OA synovial membrane with and without inflammation, and to explain the potential mechanisms involved. The differentially expressed genes (DEGs) between 12 synovial membrane with inflammation and 12 synovial membrane without inflammation from the dataset GSE46750 were identified using the Gene Expression Omnibus 2R. The DEGs were subjected to enrichment analysis, proteinprotein interaction (PPI) analysis and module analysis. The analysis results were compared with textmining results. A total of 174 DEGs were identified. Gene Ontology enrichment results demonstrated that functional molecules encoded by the DEGs primarily had extracellular location, molecular functions predominantly involving 'chemokine activity' and 'cytokine activity', and were associated with biological processes, including 'inflammatory response' and 'immune response'. The Kyoto Encyclopedia of Genes and Genomes results demonstrated that DEGS may function through pathways associated with 'rheumatoid arthritis', 'chemokine signaling pathway', 'complement and coagulation cascades', 'TNF signaling pathway', 'intestinal immune networks for IgA production', 'cytokinecytokine receptor interaction', 'allograft rejection', 'Tolllike receptor signaling pathway' and 'antigen processing and presentation'. The top 10 hub genes [interleukin (IL)6, IL8, matrix metallopeptidase (MMP)9, colony stimulating factor 1 receptor, FOS protooncogene, AP1 transcription factor subunit, insulinlike growth factor 1, TYRO protein tyrosine kinase binding protein, MMP3, cluster of differentiation (CD)14 and CD163] and four gene modules were identified from the PPI network using Cytoscape. In addition, textmining was used to identify the commonly used drugs and their targets for the treatment of OA. It was initially verified whether the results of the present study were useful for the study of OA treatment targets and pathways. The present study provided insight for the molecular mechanisms of OA synovitis. The hub genes and associated pathways derived from analysis may be targets for OA treatment. IL8 and MMP9, which were validated by textmining, may be used as molecular targets for the OA treatment, while other hub genes require further validation.
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Biologia Computacional , Osteoartrite/genética , Osteoartrite/metabolismo , Transdução de Sinais , Membrana Sinovial/metabolismo , Transcriptoma , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Osteoartrite/patologia , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Membrana Sinovial/patologiaRESUMO
In China, electroacupuncture (EA) is a therapeutic method that is extensively applied in the clinical treatment of osteoarthritis (OA); however, the underlying molecular mechanism remains unclear. Chondrocyte apoptosis may be observed in cartilage tissue in OA, and is often considered a key target for the treatment of this condition. Therefore, the present study aimed to determine the effects of EA on sodium nitroprusside (SNP)induced chondrocyte apoptosis. Chondrocytes were obtained from the knee joints of Sprague Dawley rats by type II collagenase digestion. Following microscopic observation and authentication with type II collagen immunohistochemistry, articular cartilage cells were used in subsequent experiments. Using inverted phase contrast microscopy, DAPI staining and flow cytometry, it was revealed that chondrocytes treated with SNP became apoptotic, whereas EA inhibited SNPinduced chondrocyte apoptosis. Subsequently, JC1 single staining, reverse transcriptionquantitative polymerase chain reaction analysis, western blotting, colorimetric assays and immunofluorescence staining were performed for further investigation. The results demonstrated that, when compared with normal chondrocytes, the mitochondrial membrane potential of SNPtreated chondrocytes was markedly lowered, Bcell lymphoma 2 (Bcl2) expression was reduced, and the expression levels of Bcl2associated X protein (Bax), cytochrome c, caspase9 and caspase3 were increased. Compared with in SNPtreated chondrocytes, the decrease in the mitochondrial membrane potential of chondrocytes treated with SNP and EA was smaller, Bcl2 expression was increased, and the expression levels of Bax, cytochrome c, caspase9 and caspase3 were decreased following EA intervention. In conclusion, the present study demonstrated that EA modulated the mitochondrial pathway to suppress SNPmediated chondrocyte apoptosis. Therefore, EA may be of value in the treatment of OA.
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Apoptose/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Eletroacupuntura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nitroprussiato/farmacologia , Animais , Biomarcadores , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Colágeno Tipo II/metabolismo , Masculino , Osteoartrite/etiologia , Osteoartrite/metabolismo , Polimorfismo de Nucleotídeo Único , RatosRESUMO
Cibotium barometz polysaccharides (CBPS) are one of the most important bioactive components extracted from the Cibotium barometz plant, which belongs to the Dicksoniaceae family. It has been widely used for the treatment of orthopedic diseases in traditional Chinese medicine. However, the molecular mechanisms behind the therapeutic effects of CBPS remain to be clarified. In the present study, the concentration of CBPS was detected by phenol-vitriol colorimetry. Furthermore, the effects stimulated by CBPS on the viability and G1/S cell cycle transition in primary chondrocytes from Sprague-Dawley rats were investigated. A cell viability assay demonstrated that chondrocyte proliferation may be enhanced by CBPS in a dose and timedependent manner. The mechanism underlying the promotion of chondrocyte cell cycle was suggested to involve the stimulation of G1 to S phase transition. To further confirm the results, reverse transcriptionquantitative polymerase chain reaction and western blot analyses were used to detect the expression of mRNA and protein levels of cyclin D1, cyclindependent kinase 4 and retinoblastoma protein. The results suggested that CBPS may stimulate chondrocyte proliferation via promoting G1/S cell cycle transition. Since osteoarthritis is characterized by deficient proliferation in chondrocytes, the present study indicates that CBPS may potentially serve as a novel method for the treatment of osteoarthritis.
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Condrócitos/efeitos dos fármacos , Polissacarídeos/farmacologia , Traqueófitas/química , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/citologia , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Fase G1/efeitos dos fármacos , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína do Retinoblastoma/metabolismo , Fase S/efeitos dos fármacos , Regulação para CimaRESUMO
Diesun Miaofang (DSMF) is a traditional herbal formula, which has been reported to activate blood, remove stasis, promote qi circulation and relieve pain. DSMF holds a great promise for the treatment of traumatic injury in an integrative and holistic manner. However, its underlying mechanisms remain to be elucidated. In the present study, a systems pharmacology model, which integrated cluster ligands, human intestinal absorption and aqueous solution prediction, chemical space mapping, molecular docking and network pharmacology techniques were used. The compounds from DSMF were diverse in the clusters and chemical space. The majority of the compounds exhibited drug-like properties. A total of 59 compounds were identified to interact with 16 potential targets. In the herb-compound-target network, the majority of compounds acted on only one target; however, a small number of compounds acted on a large number of targets, up to a maximum of 12. The comparison of key topological properties in compound-target networks associated with the above efficacy intuitively demonstrated that potential active compounds possessed diverse functions. These results successfully explained the polypharmacological mechanism underlying the efficiency of DSMF for the treatment of traumatic injury as well as provided insight into potential novel therapeutic strategies for traumatic injury from herbal medicine.