HIF-2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells.

Recent reports suggest that hypoxia inducible factor-2α (HIF-2α) is a key regulator of osteoarthritis cartilage destruction. However, the precise role of HIF-2α in the inflammatory response and osteoclast differentiation remains unclear. The purpose of this study was to investigate the effect of HIF-2α on inflammatory cytokines, extracellular matrix (ECM) destruction enzymes, and osteoclastic differentiation in nicotine and lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (PDLCs). HIF-2α was upregulated in chronically inflamed PDLCs of periodontitis patients, and in nicotine- and LPS-exposed PDLC in dose- and time-dependent manners. HIF-2α inhibitor and HIF-2α siRNA attenuated the nicotine- and LPS- induced production of NO and PGE2 , upregulation of iNOS, COX-2, pro-inflammatory cytokines (IL-1ß, TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-11, and IL-17), and matrix metalloproteinases (MMPs; MMP-1, -8, -13, -2 and -9), and reversed the effect on TIMPs (TIMP-1 and -2) in PDLCs. The conditioned medium produced by nicotine and LPS-treated PDLCs increased the number of TRAP-stained osteoclasts, TRAP activity and osteoclast-specific genes, which has been blocked by HIF-2α inhibition and silencing. HIF-2α inhibitor and HIF-2α siRNA inhibited the effects of nicotine and LPS on the activation of Akt, JAK2 and STAT3, ERK and JNK MAPK, nuclear factor-κB, c-Jun, and c-Fos. Taken together, this study is the first to demonstrate that HIF-2α inhibition exhibits anti-inflammatory activity through the inhibition of inflammatory cytokines and impairment of ECM destruction, as well as blocking of osteoclastic differentiation in a nicotine- and periodontopathogen-stimulated PDLCs model. Thus, HIF-2α inhibition may be a novel molecular target for therapeutic approaches in periodontitis.

Savolitinib: A Promising Targeting Agent for Cancer.

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

Scalable Fabrication of Flexible Microstencils by Using Sequentially Induced Dewetting Phenomenon.

We present the physics of sequential dewetting phenomenon and continuous fabrication of a polymeric microstencil using dewetting phenomenon with roll-to-roll imprinting equipment. To realize dewetting-assisted residual-free imprinting, mold material, polymer resin, and substrate were selected via interfacial surface energy analysis. In addition, optimal parameters of the continuous process were also studied by experimentally comparing the resultant shape of the microstencil depending on the process speed, aspect ratio of the mold, and applied pressure. As a result, the polymeric microstencil was produced continuously in very high yields, and its maximum resolution reached 20 µm in diameter. For an easy, continuous demolding during the roll-to-roll process, the material chosen for the substrate film was paraffin-coated film, which has the surface energy low enough for dewetting while having a higher adhesion value than polydimethylsiloxane mold. This versatile, high-throughput microstencil fabrication process can be used in many applications requiring flexibility, scalability, and specific material, and high productivity.

Involvement of Nrf2-mediated upregulation of heme oxygenase-1 in mollugin-induced growth inhibition and apoptosis in human oral cancer cells.

Although previous studies have shown that mollugin, a bioactive phytochemical isolated from Rubia cordifolia L. (Rubiaceae), exhibits antitumor effects, its biological activity in oral cancer has not been reported. We thus investigated the effects and putative mechanism of apoptosis induced by mollugin in human oral squamous cell carcinoma cells (OSCCs). Results show that mollugin induces cell death in a dose-dependent manner in primary and metastatic OSCCs. Mollugin-induced cell death involved apoptosis, characterized by the appearance of nuclear shrinkage, flow cytometric analysis of sub-G1 phase arrest, and annexin V-FITC and propidium iodide staining. Western blot analysis and RT-PCR revealed that mollugin suppressed activation of NF- κ B and NF- κ B-dependent gene products involved in antiapoptosis (Bcl-2 and Bcl-xl), invasion (MMP-9 and ICAM-1), and angiogenesis (FGF-2 and VEGF). Furthermore, mollugin induced the activation of p38, ERK, and JNK and the expression of heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2). Mollugin-induced growth inhibition and apoptosis of HO-1 were reversed by an HO-1 inhibitor and Nrf2 siRNA. Collectively, this is the first report to demonstrate the effectiveness of mollugin as a candidate for a chemotherapeutic agent in OSCCs via the upregulation of the HO-1 and Nrf2 pathways and the downregulation of NF- κ B.

Embryonic toxicity changes of organic nanomaterials in the presence of natural organic matter.

When elucidating the potential fate and bioavailability of nanomaterials (NMs) in an aquatic system, it is important to consider the interactions between NMs and natural organic matter (NOM). The present study compared the toxicities of carbon-based NMs, with disparate physicochemical properties, on Japanese medaka (Oryzias latipes) embryos after the addition of NOM. The measured embryonic toxicity parameters were mortality, malformation and hatching delay. Various physicochemical properties of water suspended fullerenes (nC(60)) and multi-walled carbon nanotubes (MWNTs) were modulated by organic exchange (Tol/nC(60)), stirring over time (Aqu/nC(60)) and acid treatment (f-MWNTs) followed by characterization. Tol/nC(60) produced relatively more hydrophobic surfaces and exhibited smaller closed spherical agglomerates than Aqu/nC(60). Acid-treated f-MWNTs displayed functionalized hydrophilic surfaces compared to raw MWNTs (r-MWNTs). The resultant embryonic toxicities, in the absence of NOM, were ranked in the order: f-MWNTs>Tol/nC(60)>Aqu/nC(60). As the NOM concentrations were increased, no changes in embryonic toxicities were observed on exposure of Aqu/nC(60) and r-MWNTs; whereas, the toxicities were reduced on exposure to Tol/nC(60) and f-MWNTs, due to a disappearance of hydrophobic primary spherical aggregates and partial coating, respectively. These data suggest that in the presence of NOM, the morphological differences of NMs, as well as their physicochemical properties, play a significant role in their reactions and subsequent medaka embryonic nanotoxicity.

Effect of preparation methods on toxicity of fullerene water suspensions to Japanese medaka embryos.

The physicochemical properties of fullerene water suspensions (nC(60)) and their subsequent toxicity were influenced by different preparation methods. The nC(60) suspensions were produced by three methods: toluene exchange (Tol/nC(60)), DMSO dissolving (DMSO/nC(60)), and stirring overtime (Aqu/nC(60)). The particle size, zeta potential, and nC(60) structure were strongly dependent on both the type of aggregates formed and the test medium addition. Specifically, Tol/nC(60) exhibited small and spherical closed aggregates, whereas DMSO/nC(60) and Aqu/nC(60) presented mesoscale aggregates of smaller spherical aggregates. These differences in the physicochemical properties of nC(60) determined the embryonic toxicity and oxidative stress of Japanese medaka (Oryzias latipes). The mortality and glutathione (GSH) induction of embryos were ranked in the order of Tol/nC(60)>DMSO/nC(60)>Aqu/nC(60), and the morphological malformations were in the order of DMSO/nC(60)>Tol/nC(60)>Aqu/nC(60). The mortality of Tol/nC(60) was attributed to its closely packed fullerene structure, which remained as largely underivatized C(60). The malformations of DMSO/nC(60) might have originated from the co-effect of organic solvent remaining in the fullerene colloid. To summarize, these findings clearly illustrated the need to consider the effect of preparation method on the physicochemical properties when assessing nC(60) toxicity.