Polydatin inhibits proliferation and promotes apoptosis of doxorubicin-resistant osteosarcoma through LncRNA TUG1 mediated suppression of Akt signaling.

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 µM) inhibited the cell proliferation in a dose- and time-dependent manner at 24 h, 48 h, and 72 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.

MXene reinforced microporous bacterial cellulose/sodium alginate dual crosslinked cryogel for bone tissue engineering.

The entangled assembly of bacterial cellulose (BC) nanofibers does not provide a three-dimensional (3D) macroporous structure for cellular infiltration thus hindering its use as a scaffold for bone tissue engineering. In addition, it is difficult to achieve uniform dispersion of bioactive agents in entangled BC nanofibers. To address this, the BC nanofibers were integrated with MXene, a two-dimensional nanomaterial known for its electrical signaling and mechanical strength, along with sodium alginate to form cryogel. The cryogel was fabricated using a cross-linking to enhance its mechanical properties, pores for cellular infilteration. MXene incorporation not only increased water absorption (852%-1446%) and retention (692%-973%) ability but also significantly improved the compressive stress (0.85 MPa-1.43 MPa) and modulus (0.22 MPa-1.17 MPa) confirming successful MXene reinforcement in cryogel. Biological evaluation revealed that the optimum concentration of MXene increased the cell proliferation and the osteogenic role of fabricated scaffolds was also confirmed through osteogenic gene expressions. The macropores in reconstructed MXene-BC-based cryogel provided ample space for cellular proliferation. The osteogenic role of the scaffold was examined through various gene expressions. The Quantitative polymerase chain reaction revealed that MXene-loaded scaffolds especially in low concentration, had an obvious osteogenic effect hence concluding that BC can not only be reconstructed into the desired form but osteogenic property can be induced. These findings can open a new way of reconstructing BC into a more optimal structure to overcome its structural limitations and retain its natural bioactivities.

Prediction of Rhizoma Drynariae Targets in the Treatment of Osteonecrosis of the Femoral Head based on Network Pharmacology and Experimental Verification.

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.

Ezetimibe Prevents IL-1ß-induced Inflammatory Reaction in Mouse Chondrocytes via Modulating NF-κB and Nrf2/HO-1 Signaling Crosstalk.

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.

Anticancer potential of TUG1 knockdown in cisplatin-resistant osteosarcoma through inhibition of MET/Akt signalling.

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.

Chemosensitive effects of Astragaloside IV in osteosarcoma cells via induction of apoptosis and regulation of caspase-dependent Fas/FasL signaling.

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.