ABSTRACT
BACKGROUND: Rhizoma drynariae, a classic prescription in traditional Chinese medicine, has long been used for the treatment of osteonecrosis of the femoral head (ONFH), but its potential targets and molecular mechanisms remain to be further explored. OBJECTIVE: This study aims to explore the mechanism of Rhizoma drynariae in ONFH treatment via network pharmacology and in vitro experiments. METHODS: Targets of Rhizoma drynariae and ONFH were predicted using relevant databases, and intersection analysis was conducted to screen for shared targets. A PPI network of the shared targets was built using STRING to identify the key targets. Functional enrichment analyses of Gene Ontology and KEGG pathway data were carried out using R software. The compound-target-pathway network was constructed for Rhizoma Drynariae in the treatment with ONFH using Cytoscape 3.9.0. Cell proliferation was assessed using CCK8 and apoptosis was detected using (Propidium Iodide) PI staining and western blotting. RESULTS: This study depicts the interrelationship of the bioactive compounds of Rhizoma drynariae with ONFH-associated signaling pathways and target receptors and is a potential reagent for ONFH treatment. CONCLUSION: Based on a network pharmacology analysis and in vitro experiment, we predicted and validated the active compounds and potential targets of Rhizoma drynariae, provide valuable evidence of Rhizoma Drynariae in future ONFH treatment.
Subject(s)
Osteonecrosis , Polypodiaceae , Femur Head , Network Pharmacology , Apoptosis , Molecular Docking SimulationABSTRACT
BACKGROUND: Osteoarthritis is a type of age-related, chronic, and degenerative joint disease. Ezetimibe, a cholesterol absorption inhibitor, is widely used for the treatment of various diseases. However, the role of ezetimibe in osteoarthritis remains unclear. OBJECTIVES: This study aimed to explore the anti-inflammation effect of ezetimibe on mouse chondrocytes. METHODS: In the present study, ELISA, qPCR and western blot analysis were performed to evaluate the anti-inflammatory effects of ezetimibe. In addition, enzymes that are highly associated with the anabolism and catabolism of the extracellular matrix of the articular cartilage were also evaluated. RESULTS: Treatment with ezetimibe attenuated the IL-1ß-induced degradation of the extracellular matrix, including aggrecan and collagen II. Ezetimibe also attenuated the IL-1ß-induced expression levels of MMP3, MMP13 and ADAMTS5, thus exerting protective effects against IL-1ß- induced extracellular matrix degradation. The complex mechanism of the anti-inflammatory reaction contributed to the activation of the Nrf2/HO-1 pathway and the suppression of the NF-κB pathway. CONCLUSION: On the whole, the present study demonstrates that ezetimibe may be a promising agent for further osteoarthritis therapy.
Subject(s)
Chondrocytes , Osteoarthritis , Animals , Mice , Aggrecans/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Cells, Cultured , Cholesterol , Ezetimibe/pharmacology , Ezetimibe/therapeutic use , Inflammation/drug therapy , Interleukin-1beta/metabolism , Matrix Metalloproteinase 13 , Matrix Metalloproteinase 3/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Osteoarthritis/drug therapyABSTRACT
Development of cisplatin (DDP)-resistance is a major challenge that largely limits the efficacy of chemotherapy for osteosarcoma. LncRNA Taurine up-regulated gene 1 (TUG1) is a recently identified oncogenic lncRNA that has been involved in chemo-resistance of various cancers. In this study, over-expression of TUG1 was found in two osteosarcoma cell lines resistant to DDP (Saos-2/DDP, MG-63/DDP). Knockdown of TUG1 inhibited the DDP-resistance and promoted the cytotoxicity and apoptosis induced by DDP in Saos-2/DDP and MG-63/DDP cells. TUG1 knockdown also markedly inhibited the expression level of MET and p-Akt. In conclusion, knockdown of TUG1 suppressed cell growth and increased apoptotic rate under DDP treatment possibly via regulating MET/Akt signalling pathway.
Subject(s)
Bone Neoplasms/drug therapy , Cisplatin/pharmacology , Osteosarcoma/drug therapy , RNA, Long Noncoding/genetics , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Osteosarcoma/genetics , Osteosarcoma/pathology , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-met/metabolism , Signal Transduction/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Development of doxorubicin-resistance is the main difficulty for osteosarcoma treatment. LncRNA Taurine upregulated gene 1 (TUG1) has been identified as oncogenic lncRNA in different types of carcinomas and was involved in chemoresistance. We aim to evaluate the anti-proliferative effects and the underlying molecular mechanism of Polydatin in doxorubicin-resistant osteosarcoma. METHODS: Doxorubicin-resistant osteosarcoma cell lines were established. MTT, colony formation, apoptosis assay, qRT-PCR and Western blotting analysis, immunohistochemistry and animal study were carried out. RESULTS: It has been showed Polydatin (50-250⯵M) inhibited the cell proliferation in a dose- and time-dependent manner at 24â¯h, 48â¯h, and 72â¯h. Polydatin promoted the cell apoptosis significantly with the highest apoptosis rate >50%. Polydatin down-regulated TUG1 expression and TUG1/Akt signaling suppression was involved in Polydatin treated doxorubicin-resistant osteosarcoma cells. The in vivo study further confirmed the anti-cancer effect of Polydatin and related mechanisms. CONCLUSIONS: Polydatin may be a novel therapeutic agent for doxorubicin-resistant osteosarcoma treatment and TUG1 would be a potential molecular target.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Bone Neoplasms/drug therapy , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Drug Resistance, Neoplasm , Glucosides/pharmacology , Osteosarcoma/drug therapy , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/metabolism , Stilbenes/pharmacology , Animals , Bone Neoplasms/enzymology , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic , Humans , Male , Mice, Inbred BALB C , Mice, Nude , Osteosarcoma/enzymology , Osteosarcoma/genetics , Osteosarcoma/pathology , RNA, Long Noncoding/genetics , Signal Transduction , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: The response of conventional chemotherapy for osteosarcoma treatment is usually poor, and chemotherapy-related severe side effects and drug resistance remain a problem. Abundant evidence has shown that Astragaloside IV, extracted from Astragalus membranaceus Bunge, strongly inhibits the growth of many carcinomas. We aimed to investigate the chemosensitive effects of Astragaloside IV in osteosarcoma in vitro and in vivo. METHODS: Human osteosarcoma cell lines MG-63 and 143B, and BALB/c nu/nu mice xenograft were used. MTT, Clonogenic assay, Annexin V/PI assay and Western bloting analysis were carried out. RESULTS: Our present study found that Astragaloside IV was a critical chemosensitizing agent for osteosarcoma treatment. Astragaloside IV suppressed cell proliferation and enhanced chemosensitivity in osteosarcoma cell lines and xenograft. Caspase-dependent Fas/FasL signaling was involved in cisplatin-induced apoptosis which was enhanced by Astragaloside IV. CONCLUSION: It indicated that Astragaloside IV might be a promising therapeutic agent for osteosarcoma treatment.
