Wear particle induced periprosthetic osteolysis is the main cause of aseptic loosening of orthopedic implants. The aim of the present study is to determine the protective effect of quercetin (QUE) against titanium (Ti) particle induced endoplasmic reticulum stress (ERS) related apoptosis and osteolysis. In the present study, RAW264.7 cells were pretreated with different concentrations (40, 80, and 160 μmol/l) of QUE for 30 min and then treated with Ti particle (5 mg/ml) for 24 h. Cell viability and apoptosis were determined using MTT assay and Annexin V-FITC Apoptosis Detection Kit, respectively. Protein and mRNA expressions of ERS-related genes were examined by Western blot and real-time PCR, respectively. The release of inflammatory cytokines was detected by ELISA. Then, a mouse calvarial osteolysis model was established. Histological sections of calvaria were stained with Hematoxylin-Eosin (H&E) or tartrate-resistant acid phosphatase (TRAP). The results showed that Ti particle reduced cell viability and induced apoptosis in RAW264.7 macrophages. The cytotoxic effects of Ti particle were dramatically inhibited by QUE pretreatment. Interestingly, we found that QUE also significantly reduced Ti particle induced up-regulation of the expression levels of protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1), glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and caspase-3 and enhanced the down-regulation of Bcl-2. In addition, QUE decreased Ti particle-induced inflammatory cytokines release from RAW264.7 cells. Moreover, treatment with QUE markedly decreased osteoclast number. In a mouse calvarial osteolysis model, QUE inhibited Ti particle induced osteolysis in vivo by inhibiting osteoclast formation and expressions of ERS-related genes. In conclusion, QUE can protect RAW264.7 cells from Ti particle induced ERS-related apoptosis and suppress calvarial osteolysis in vivo.
Background Garlic-derived S-allylmercaptocysteine (SAMC) has widely been used in many disease therapies. However, the potential effects and mechanism of SAMC on IL-1β-stimulated chondrocytes are unclear. Methods Chondrocytes were isolated, and 5 ng/mL of IL-1β was added to mimic the in vitro osteoarthritis (OA) model. SAMC (20 and 60 μM) was used for the treatment in OA model. Cell viability was assessed by MTT method. Western blotting, Quantitative RT-PCR, and ELISA were performed to evaluate the mechanisms in SAMC treated OA model. Results Following 48 h of IL-1β exposure, SAMC exhibited protection effect on IL-1β-injured chondrocyte viability. Type II collagen was elevated with reduced degradation products, as a consequence of altered MMPs/TIMP-1 ratio after SAMC treatment in IL-1β-treated chondrocytes. The protein and mRNA level of TNF-α in cellular supernatant and cells were downregulated in a dose-dependent manner. Besides, IκBα in cytoplasmic fraction was increased, while p65 level in nuclear fraction was decreased after SAMC treatment in OA. Conclusions This study showed that SAMC may play a protective role in IL-1β induced osteoarthritis (OA) model. This effect may be through inhibiting the NF-κB signaling pathway, therefore altering the MMPs/TIMP-1 ratio change which induced type II collagen destruction and decreasing inflammatory cytokine secretion such as TNF-α.
Osteosarcoma (OS) is an uncommon tumour that mainly affects bone in children and adolescents. The current treatment options of OS are of limited significance due to their immense side effects. In the present manuscript, we have developed a novel series of 1,2,3-triazole chalcone derivatives as potential agents against OS. The compounds were synthesized and evaluated for their PI3K and mTOR inhibitory activity using luminescent kinase assay, and Lance ultra assay, resp. The entire set of compounds showed significant to moderate inhibition of both kinases in the nanomolar range. The three most active compounds: 4e (N-(4-(3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-nitrobenzamide), 4f (N-(4-(3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-chlorobenzamide) and 4g (4-bromo-N-(4-(3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)acryloyl)phenyl)benzamide), were evaluated for anticancer activity against human OS cancer cell line (MG-63), liver cancer cell line (HepG2), lung cancer cell line (A549) and cervical cancer (HeLa), using MTT assay. Among the tested series, compound 4e showed a better inhibitory profile than gedatolisib against PI3K and was approximately comparable to that of gedatolisib against mTOR. The most significant inhibitory activity was observed for compound 4e against all cell lines (MG-63, HepG2, A549 and HeLa), still somewhat lower to comparable to that of gedatolisib, but with the highest potency against MG-63 cells. Compound 4e was further tested for anti-cancer activity against other OS cells and showed to be equipo-tent to gedatolisib against U2OS and Saos-2 cells. Moreover, it was also found non-toxic to normal cells (BEAS-2B and MCF 10A). The effect of compound 4e was further determined on apoptosis of Saos-2 cells by Annexin-PI assay, where it significantly amplified the percentage of apoptotic cells. Novel 1,2,3-triazole chalcone derivatives are potential agents against OS.
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