METTL14-upregulated miR-6858 triggers cell apoptosis in keratinocytes of oral lichen planus through decreasing GSDMC.

Oral lichen planus (OLP), a chronic inflammatory disorder, is characterized by the massive cell apoptosis in the keratinocytes of oral mucosa. However, the mechanism responsible for triggering oral keratinocyte apoptosis is not fully explained. Here, we identify that Gasdermin C (GSDMC) downregulation contributes to apoptosis in human oral keratinocytes. Mechanistically, we describe that activated nuclear factor kappa B (NF-κB) pathway induces overexpression of methyltransferase-like 14 (METTL14), which increases N6-adenosine methylation (m6A) levels in the epithelial layer of OLP. m6A modification is capable of regulating primary miR-6858 processing and alternative splicing, leading to miR-6858 increases. miR-6858 can bind and promote GSDMC mRNA degradation. Forced expression of GSDMC is able to rescue cell apoptosis in human oral keratinocyte models resembling OLP. Collectively, our data unveil that m6A modification regulates miR-6858 production to decrease GSDMC expression and to trigger keratinocyte apoptosis in the context of OLP.

Combination of niclosamide and quinacrine inactivates Akt/HK2/Cyclin D1 axis mediated by glucose deprivation towards the inhibition of melanoma cell proliferation.

Malignant melanoma is one of the most aggressive and lethal skin cancer. At present, the treatment methods for melanoma have shortcomings. Glucose is the primary energy source of cancer cells. However, it is unclear whether glucose deprivation can be used to treat melanoma. Herein, we first found glucose played an essential role in melanoma proliferation. We then further found a drug combination of niclosamide and quinacrine could inhibit melanoma proliferation and glucose intake. Thirdly, we revealed the mechanism of anti-melanoma effect of the drug combination, which suppressed the Akt pathway. In addition, the first-rate limiting enzyme HK2 of glucose metabolism was inhibited. This work also disclosed that the decrease of HK2 inhibited cyclin D1 by reducing the activity of transcription factor E2F3, which further suppressed the proliferation of melanoma cells. The drug combination treatment also resulted in significant tumor regression in the absence of obvious morphologic changes in primary organ in vivo. In summary, our study demonstrated that the drug combination treatment created glucose deprivation to inactive the Akt/HK2/cyclin D1 axis, thereby inhibited the proliferation of melanoma cells, providing a potential anti-melanoma strategy.

Improving antibacterial performance of dental resin adhesive via co-incorporating fluoride and quaternary ammonium.

OBJECTIVE: Aiming to achieve improved antibacterial performance for dental application, sodium fluoride (NaF) nanoparticles and photopolymerizable N,N-dodecylvinylimidazole (DCV) were co-introduced into the dental resin adhesive at different ratios. METHODS: The respective effect of NaF and DCV on adhesive curing kinetic, antibacterial activities against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Bacterial Flora of Human saliva (HSBF) were comprehensively evaluated. Then, the synergistic effects of NaF nanoparticles and DCV on adhesive performance were studied in terms of fluoride ion (F-) release, antibacterial activity, hydrophilicity, surface potential, cytotoxicity, and bonding strength. RESULTS: DCV monomer could polymerize with other adhesive monomers without influencing C = C double conversion rate, while the addition amount of DCV would affect the hydrophilicity and bonding strength of the cured adhesives. The cationic quaternary ammonium group could reduce the burst release of negative F- for the adhesive at a NaF/DCV ratio (1:1, 2%), hence achieving both non-contact and contact antibacterial activity in an extended term without causing cytotoxicity. CONCLUSION: Mixing NaF nanoparticles and DCV into the dental resin adhesive can slow down the initial burst release of F- and prolong the release-type antibacterial effect. The ionic interaction between F- and quaternary ammonium groups, as well as, the effect of DCV on adhesive hydrophilicity, simultaneously influence the release behavior of F-. Co-incorporation of quanternary ammonium and fluoride improves adhesive's antibacterial performance for dental application. CLINICAL SIGNIFICANCE: Incorporating both NaF nanoparticles and DCV into dental resin adhesive could provide an efficient strategy for dental restoration as well as the prevention of secondary caries.

Low doses of niclosamide and quinacrine combination yields synergistic effect in melanoma via activating autophagy-mediated p53-dependent apoptosis.

Malignant melanoma is a highly aggressive, malignant, and drug-resistant tumor. It lacks an efficient treatment approach. In this study, we developed a novel anti-melanoma strategy by using anti-tapeworm drug niclosamide and anti-malarial drug quinacrine, and investigated the molecular mechanism by in vitro and in vivo assays. Meanwhile, other types of tumor cells, immortalized epithelial cells and bone marrow mesenchymal stem cells were used to evaluate the universal role of anti-cancer and safety of the strategy. The results showed, briefly, an exposure to niclosamide and quinacrine led to an increased apoptosis-related protein p53, cleaved caspase-3 and cleaved PARP and autophagy-related protein LC3B expression, and a decreased expression of autophagy-related protein p62, finally leading to cell apoptosis and autophage. After inhibiting autophagy by Baf-A1, flow cytometry and western blot showed that the expression of apoptosis-related proteins was down-regulated and the number of apoptotic cells decreased. Subsequently, in the siRNA-mediated p53 knockdown cells, the expression of apoptosis-related proteins and the number of apoptotic cells were also reduced, while the expression of autophagy-related proteins including LC3B, p62 did not change significantly. To sum up, we developed a new, safe strategy for melanoma treatment by using low doses of niclosamide and quinacrine to treat melanoma; and found a novel mechanism by which the combination application of low doses of niclosamide and quinacrine exerts an efficient anti-melanoma effect through activation of autophagy-mediated p53-dependent apoptosis. The novel strategy was verified to exert a universal anti-cancer role in other types of cancer.