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Titanium (Ti) is a widely used biomaterial for dental implants because of its outstanding biocompatibility for hard tissues. Osseointegration, the interaction between implanted biomaterials and living cells in bone, is essential for successful implantation. Rosmarinic acid (RA) is a plant-derived phytochemical with low toxicity and side effects and has various effects that can be applied as a therapeutic substance. The MC3T3-E1 osteoblastic cells on the Ti surface in medium with or without 14 μg/ml RA were used to test RA effects on osteoblast differentiation, cell viability and mineralization during differentiation. RA treatment increased osteoblast differentiation, cell viability and mineralization in MC3T3-E1 osteoblastic cells on Ti surface during differentiation, upregulating Runx-2 and OPG, but downregulating RANKL. This study suggest that RA should be applied as an effective functional and therapeutic substance to enhance osseointegration of osteoblast cells by increasing differentiation, mineralization, and bone formation through the RANKL/RANK/OPG pathway during the differentiation in MC3T3-E1 osteoblastic cells on the Ti surface.

Abstract Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular domain (JICD1) forms a protein complex with DDX17/SMAD3/TGIF2. However, the molecular mechanisms underlying JICD1-mediated tumor aggressiveness remains unclear. Here, we demonstrate that JICD1 enhances the invasive phenotypes of glioblastoma cells by transcriptionally activating epithelial-to-mesenchymal transition (EMT)-related genes, especially TWIST1. The inhibition of TWIST1 reduced JICD1-driven tumor aggressiveness. Although SMAD3 is an important component of transforming growth factor (TGF)-β signaling, the JICD1/SMAD3 transcriptional complex was shown to govern brain tumor invasion independent of TGF-β signaling. Moreover, JICD1-TWIST1-MMP2 and MMP9 axes were significantly correlated with clinical outcome of glioblastoma patients. Collectively, we identified the JICD1/SMAD3-TWIST1 axis as a novel inducer of invasive phenotypes in cancer cells.

Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer and this is due to cancer cells being apoptosis-resistant and having increased cell proliferation, migration, invasion, and angiogenesis properties. Previous studies have indicated both STAT and Notch pathways being important for initiation and progression in GBM. In this work, we first studied the effects of STAT inhibitors on Notch signalling using small molecule STAT inhibitors. It was observed that STAT inhibitors surprisingly activated Notch signalling by inducing NICD and Notch target genes in GBM cells. Thus, we aimed to combine STAT inhibitor treatment with a Notch pathway inhibitor and study effects on GBM tumourigenesis. STAT5 inhibitor (Pimozide) and STAT3 inhibitor (S3I-201) were individually used in combination with γ-secretase inhibitor (DAPT), an inhibitor of Notch signalling, in a panel of GBM cells for cell proliferation and epithelial plasticity changes. Compared with single-agent treatments, combinatorial treatments with the STAT and Notch inhibitors significantly increased apoptosis in the treated cells, impairing cell proliferation, migration, and invasion. These findings suggest that concurrent blocking of STAT and Notch signalling pathways could provide added therapeutic benefit for the treatment of glioblastoma.