Identification of hub genes and key pathways in spinal cord injury via bioinformatics analysis.

This study aimed to explore the hub genes and related key pathways in Spinal Cord Injury (SCI) based on the bioinformatics analysis. Two microarray datasets (GSE45006, GSE45550) were obtained from the GEO database and were merged and batch-corrected. The differentially expressed genes (DEGs) in SCI were explored with the Limma, and the weighted gene co-expression network analysis (WGCNA) was conducted to explore the module genes. Functional enrichment analysis and Gene set variation analysis (GSVA) were used to investigate the biological functions and key pathways of the key genes related to SCI. Then the protein-protein interaction (PPI) network was generated using the STING online tool, and the hub genes in SCI were identified. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic value of the selected hub genes. We identified 554 DEGs in SCI, and 1236 key genes in SCI were selected via WGCNA. Totally 111 key genes related to SCI were discovered. Furthermore, the functional enrichment analysis showed that these key mRNAs were primarily enriched in the extracellular matrix (ECM)-related pathways and processes associated with wound healing and cell growth. The PPI network further filtered six hub genes (Cd44, Timp1, Loxl1, Col6a1, Col3a1, Col5a1) ranked by the degree, and the diagnostic value of the six hub genes was confirmed by the ROC curves. Six hub genes including Cd44, Timp1, Loxl1, Col6a1, Col3a1, and Col5a1 were identified in SCI, with differential expression and excellent diagnostic value, which might provide insight into the targeted therapy of SCI.

Dual protective role of velutin against articular cartilage degeneration and subchondral bone loss via the p38 signaling pathway in murine osteoarthritis.

Osteoarthritis (OA) is a common degenerative joint condition associated with inflammation and characterized by progressive degradation of the articular cartilage and subchondral bone loss in the early stages. Inflammation is closely associated with these two major pathophysiological changes in OA. Velutin, a flavonoid family member, reportedly exerts anti-inflammatory effects. However, the therapeutic effects of velutin in OA have not yet been characterized. In this study, we explore the effects of velutin in an OA mouse model. Histological staining and micro-CT revealed that velutin had a protective effect against cartilage degradation and subchondral bone loss in an OA mouse model generated by surgical destabilization of the medial meniscus (DMM). Additionally, velutin rescued IL-1ß-induced inflammation in chondrocytes and inhibited RANKL-induced osteoclast formation and bone resorption in vitro. Mechanistically, the p38 signaling pathway was found to be implicated in the inhibitory effects of velutin. Our study reveals the dual protective effects of velutin against cartilage degradation and subchondral bone loss by inhibiting the p38 signaling pathway, thereby highlighting velutin as an alternative treatment for OA.

Galangin attenuates IL-1ß-induced catabolism in mouse chondrocytes and ameliorates murine osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is one of the most common chronic diseases, which is characterized by cartilage degeneration, subchondral osteosclerosis, and synovitis. Accumulating evidence has shown that galangin, a flavonoid derived from medicinal herbs, exhibits numerous pharmacological activities in various diseases. This study aimed to investigate the effects of galangin on interleukin (IL)-1ß-induced inflammation in mouse chondrocytes and explore the underlying mechanisms. METHODS: In this study, we investigated the protective effects of galangin on IL-1ß-induced inflammatory response in vitro using the CCK-8 assay, RT-qPCR, western blotting, and immunofluorescence staining. In addition, the therapeutic effects of galangin on the anterior cruciate ligament transection (ACLT) mouse model were also explored in vivo. Results: Galangin treatment suppressed the expression of IL-1ß-induced inflammatory cytokines, such as nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-6. Furthermore, galangin attenuated hypertrophic conversion and the extracellular matrix degradation via inhibiting the expression of catabolic enzymes. Mechanistically, galangin inhibited the activation of the JNK and ERK MAPK pathways and nuclear factor kappa-B (NF-κB) signaling pathway. In addition, galangin treatment ameliorated cartilage degeneration in an OA model in vivo. Conclusion: Galangin suppressed the IL-ß-induced inflammatory response in vitro and ameliorated cartilage degeneration in vivo via inhibiting the NF-κB pathway and JNK and ERK pathways, suggesting its potential as an effective candidate for the treatment of OA.

Hinokitiol inhibits RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced bone loss in vivo.

Osteoporosis is a metabolic bone-loss disease characterized by abnormally excessive osteoclast formation and bone resorption. Identification of natural medicines that can inhibit osteoclastogenesis, bone resorption, and receptor activator of nuclear factor-κB ligand (RANKL)-induced signaling is necessary for improved treatment of osteoporosis. In this study, hinokitiol, a tropolone-related compound extracted from the heart wood of several cupressaceous plants, was found to inhibit RANKL-induced osteoclast formation and bone resorption in vitro. Hinokitiol inhibited early activation of the ERK, p38, and JNK-MAPK pathways, thereby suppressing the activity and expression of downstream factors (c-Jun, c-Fos, and NFATC1). Consistent with the above in vitro findings, hinokitiol treatment protected against ovariectomy-induced bone loss in vivo. Collectively, our results imply that hinokitiol can potentially serve as an effective agent for treating osteoclast-induced osteoporosis.

Pristimerin Inhibits Osteoclast Differentiation and Bone Resorption in vitro and Prevents Ovariectomy-Induced Bone Loss in vivo.

INTRODUCTION: Osteoporosis is a metabolic bone disease characterized by reduced bone quantity and microstructure, typically owing to increased osteoclastogenesis and/or enhanced osteoclastic bone resorption, resulting in uncontrolled bone loss, which primarily affects postmenopausal women. In consideration of the severe side effects of current drugs for osteoporosis, new safe and effective medications are necessary. Pristimerin (Pri), a quinone methide triterpene extracted from Celastraceae and Hippocrateaceae members, exhibits potent antineoplastic and anti-inflammatory effects. However, its effect on osteoclasts remains unknown. MATERIALS AND METHODS: We evaluated the anti-osteoclastogenic and anti-resorptive effect of Pri on bone marrow-derived osteoclasts and its underlying mechanism in vitro. In addition, the protective effect of Pri on ovariectomy model was also explored in vivo. RESULTS: In vitro, Pri inhibited osteoclast differentiation and mature osteoclastic bone resorption in a time- and dose-dependent manner. Further, Pri suppressed the expression of osteoclast-related genes and the activation of key proteins. Pri also inhibited the early activation of ERK, JNK MAPK, and AKT signaling pathways in bone marrow-derived macrophages (BMMs), ultimately inhibiting the induction and activation of the crucial osteoclast transcriptional factor nuclear factor of activated T-cell cytoplasmic 1 (NFATc1). In vivo, consistent with our in vitro data, Pri clearly prevented ovariectomy-induced bone loss. CONCLUSION: Our data showed that Pri inhibits the differentiation and activation of osteoclasts in vitro and in vivo, and could be a promising candidate for treating osteoporosis.

Sarsasapogenin Suppresses RANKL-Induced Osteoclastogenesis in vitro and Prevents Lipopolysaccharide-Induced Bone Loss in vivo.

INTRODUCTION: Osteoclasts are giant polynuclear cells; their main function is bone resorption. An increased number of osteoclasts and enhanced bone resorption exert significant effects on osteoclast-related bone-lytic diseases, including osteoporosis. Given the limitations of current therapies for osteolytic diseases, it is urgently required to develop safer and more effective alternatives. Sarsasapogenin, a major sapogenin from Anemarrhena asphodeloides Bunge, possesses potent antitumor effects and inhibits NF-κB and MAPK signaling. However, the manner in which it affects osteoclasts is unclear. METHODS: We investigated the effects of anti-osteoclastogenic and anti-resorptive of sarsasapogenin on bone marrow-derived osteoclasts. RESULTS: Sarsasapogenin inhibited multiple RANKL-induced signaling cascades, thereby inhibiting the induction of key osteoclast transcription factor NFATc1. The in vivo and in vitro results were consistent: sarsasapogenin treatment protected against bone loss in a mouse osteolysis model induced by lipopolysaccharide. CONCLUSION: Our research confirms that sarsasapogenin can be used as a new treatment for osteoclast-related osteolytic diseases.

Byakangelicin inhibits IL-1ß-induced mouse chondrocyte inflammation in vitro and ameliorates murine osteoarthritis in vivo.

Osteoarthritis (OA) is a chronic musculoskeletal degeneration disease, resulting in severe consequences such as chronic pain and functional disability. Owing to the complex pathology, there are currently available preventative clinical therapies for OA. Several studies have reported the potential anti-inflammatory effects of byakangelicin (BYA), a component of the Angelica dahurica root extract; however, the effects of BYA in OA remain unknown. In this study, we investigated the protective effects of BYA in interleukin (IL)-1ß-induced mouse chondrocytes in vitro and on surgical destabilization in a medial meniscus (DMM) mouse OA model in vivo. In vitro, BYA treatment inhibited IL-1ß-mediated inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-alpha, and IL-6 expression. Moreover, BYA promoted the expression of type two collagen and aggrecan but inhibited the expression of thrombospondin motifs 5 and matrix metalloproteinases, leading to degradation of the extracellular matrix. In addition, BYA mechanistically suppressed nuclear factor-kappa B signaling in the IL-1ß-induced chondrocytes. The protective effects of BYA in OA development were also observed in vivo using the DMM model. In conclusion, our results highlight BYA as a candidate for OA treatment and prevention.

Morusin Ameliorates IL-1ß-Induced Chondrocyte Inflammation and Osteoarthritis via NF-κB Signal Pathway.

PURPOSE: Osteoarthritis (OA) is one of the most common degenerative joint diseases in the world, characterized primarily by the progressive degradation of articular cartilage. Accumulating evidence has shown that Morusin, a flavonoid derived from the root bark of Morus alba (mulberry) plants, exerts unique protective properties in several diseases. However, its effects on OA, specifically, have not yet been characterized. METHODS: In this study, we evaluated the anti-inflammatory effect of Morusin on mouse chondrocytes and its underlying mechanism in vitro. In addition, the protective effect of Morusin on destabilization of the medial meniscus (DMM) model was also explored in vivo. RESULTS: In vitro, IL-1ß-induced activation of inflammatory factors (TNF-α, IL-6, INOS and COX2) was dramatically suppressed by Morusin. Further, Morusin treatment inhibited the expression of ADAMTS5 and metalloproteinase (MMPs), both of which regulate extracellular matrix degradation. Morusin also decreased IL-1ß-induced p65 phosphorylation and IκBα degradation. In vivo, degradation of the articular cartilage following surgical DMM, which mimicked OA pathology, was abrogated following treatment with Morusin, thus demonstrating a protective effect in the DMM model. CONCLUSION: Herein, we demonstrate that Morusin reduces the OA inflammatory response in vitro and protects against articular cartilage degradation in vivo potentially via regulation of the NF-κB pathway. Hence, Morusin may prove to be an effective candidate for novel OA therapeutic strategies.