Doping is an essential process to engineer the conductivity and work-function of graphene for higher performance optoelectronic devices, which includes substitutional atomic doping by reactive gases, electrical/electrochemical doping by gate bias, and chemical doping by acids or reducing/oxidizing agents. Among these, the chemical doping has been widely used due to its simple process and high doping strength. However, it also has an instability problem in that the molecular dopants tend to gradually evaporate from the surface of graphene, leading to substantial decrease in doping effect with time. In particular, the instability problem is more serious for n-doped graphene because of undesirable reaction between dopants and oxygen or water in air. Here we report a simple method to tune the electrical properties of CVD graphene through n-doping by vaporized molecules at 70 °C, where the dopants in vapor phase are mildly adsorbed on graphene surface without direct contact with solution. To investigate the dependence on functional groups and molecular weights, we selected a series of ethylene amines as a model system, including ethylene diamine (EDA), diethylene triamine (DETA), and triethylene tetramine (TETA) with increasing number of amine groups showing different vapor pressures. We confirmed that the vapor-phase doping provides not only very high carrier concentration but also good long-term stability in air, which is particularly important for practical applications.

Growth differentiation factor 15 (GDF15) is an emerging biomarker of cardiovascular risk and disease. Microarray analyses revealed that GDF15 levels were increased during cellular senescence induced by ionizing radiation (IR) in human aortic endothelial cells (HAECs). However, the role of GDF15 in HAEC cellular senescence remains unclear. This study demonstrated that downregulation of GDF15 in HAECs partially prevented cellular senescence triggered by IR, which was confirmed by recovery of cell proliferation and reverse senescence-associated β-galactosidase (SA-β-gal) staining. Conversely, upregulation of GDF15-induced cellular senescence in HAECs, confirmed by G0/G1 cell cycle arrest, decreased during cell proliferation and increased SA-β-gal staining. GDF15-induced cellular senescence was observed in p16-knockdown cells but not in p53-knockdown cells. GDF15 expression in endothelial cells also generated reactive oxygen species (ROS), which led to activation of extracellular signal-regulated kinases (ERKs) and induction of senescence by oxidative stress. These results suggested that GDF15 might play an important role in cellular senescence through a ROS-mediated p16 pathway and contribute to the pathogenesis of atherosclerosis via pro-senescent activity.

Nerve growth factor (NGF) is a well characterized neurotrophic agonist in the nervous system that triggers angiogenesis. In this study, we investigated the signaling mechanisms involved in NGF-induced angiogenesis. NGF stimulated endothelial cell invasion and cord formation on Matrigel in vitro but had marginal effect on proliferation and migration of these cells. NGF stimulated matrix metalloproteinase (MMP)-2 mRNA expression and protein secretion in human umbilical vein endothelial cells. Using synthetic and endogenous inhibitors of MMP-2 and MMP-2 small interfering RNA suppressed NGF-induced invasion and cord formation. We demonstrated that NGF-induced MMP-2 secretion, invasion, and cord formation are regulated via activation of the NGF receptor, TrkA, phosphatidylinositol 3-kinase (PI3K), and Akt using various pharmacological inhibitors. Specifically, NGF enhanced TrkA phosphorylation, PI3K activity, and Akt phosphorylation. Introduction of NGF-neutralizing antibodies, dominant-negative Akt, or wild-type PTEN effectively inhibited NGF-induced MMP-2 secretion and cord formation. Deletion and site-directed mutagenesis analysis of the MMP-2 promoter demonstrated that the AP-2-binding site is critical for NGF-induced MMP-2 promoter activity. NGF increased the DNA binding activity of AP-2, which was suppressed by inhibitors of TrkA and PI3K. Furthermore, transfection of AP-2 small interfering RNA effectively blocked NGFinduced MMP-2 secretion and cord formation. Finally, NGF promoted neovessel formation in Matrigel plugs in vivo, which was significantly inhibited by K252a and LY294002, but it failed to promote angiogenesis using MMP-2 knock-out mice. Our data collectively suggest that NGF stimulates endothelial cell invasion and cord formation by augmenting MMP-2 via the PI3K/Akt signaling pathway and AP-2 transcription factor, which may be responsible for triggering angiogenesis.

Epithelial-mesenchymal transition (EMT) is essential for increased invasion and metastasis during cancer progression. Among the candidate EMT-regulating microRNAs that we previously identified, miR-181b-3p was found to induce EMT in MCF7 breast cancer cells, as indicated by an EMT-characteristic morphological change, increased invasiveness, and altered expression of an EMT marker. Transfection with a miR-181b-3p inhibitor reduced the expression of mesenchymal markers and the migration and invasion of highly invasive breast cancer cells. miR-181b-3p induced the upregulation of Snail, a master EMT inducer and transcriptional repressor of E-cadherin, through protein stabilization. YWHAG was identified as a direct target of miR-181b-3p, downregulation of which induced Snail stabilization and EMT phenotypes. Ectopic expression of YWHAG abrogated the effect of miR-181b-3p, including Snail stabilization and the promotion of invasion. In situ hybridization and immunohistochemical analyses indicated that YWHAG expression was inversely correlated with the expression of miR-181b-3p and Snail in human breast cancer tissues. Furthermore, transfection with miR-181b-3p increased the frequency of metastatic nodule formation in the lungs of mice in experimental metastasis assays using MDA-MB-231 cells. Taken together, our data suggest that miR-181b-3p functions as a metastasis activator by promoting Snail-induced EMT, and may therefore be a therapeutic target in metastatic cancers.

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