Neuropilin-1 (NRP-1) has been found to be expressed by endothelial cells and tumor cells as an isoform-specific receptor for vascular permeability factor/vascular endothelial growth factor (VEGF). Previous studies were mainly focused on the extracellular domain of NRP-1 that can bind to VEGF 165 and, thus, enables NRP-1 to act as a co-receptor for VEGF 165 , which enhances its binding to VEGFR-2 and its bioactivity. However, the exact functional roles and related signaling mechanisms of NRP-1 in angiogenesis are not well understood. In this study we constructed a chimeric receptor, EGNP-1, by fusing the extracellular domain of epidermal growth factor receptor to the transmembrane and intracellular domains of NRP-1 and transduced it into HUVECs with a retroviral expression vector. We observed that NRP-1/EGNP-1 mediates ligand-stimulated migration of human umbilical vein endothelial cells (HUVECs) but not proliferation. Our results show that NRP-1 alone can mediate HUVEC migration through its intracellular domain, and its C-terminal three amino acids (SEA-COOH) are essential for the process. We demonstrate that phosphatidylinositol 3-kinase inhibitor Ly294002 and the p85 dominant negative mutant can block NRP-1-mediated HUVEC migration. NRP-1-mediated migration can be significantly reduced by overexpression of the dominant negative mutant of RhoA (RhoA-19N). In addition, G q family proteins and G␤␥ subunits are also required for NRP-1-mediated HUVEC migration. These results show for the first time that NRP-1 can independently promote cell signaling in endothelial cells and also demonstrate the importance of last three amino acids of NRP-1 for its function.Angiogenesis, the formation of vascular networks by endothelial cells (ECs) 1 sprouting from the vascular bed, occurs in many physiological or pathological processes (1). Vascular permeability factor/vascular endothelial growth factor (VPF/ VEGF) plays a major role in the regulation of angiogenesis; it is regarded as a key contributor to the growth of cancer and vascular disease (2). VPF/VEGF activities are mediated by high affinity receptor tyrosine kinases that are associated primarily with ECs (2). Two important VPF/VEGF binding receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), have been identified, both of which are functionally active during angiogenesis. Recent studies have found a third VPF/ VEGF receptor, neuropilin-1 (NRP-1), that is expressed by ECs and tumor cells (3, 4).NRP-1 is a 130 -135-kDa cell surface glycoprotein. It was originally characterized as a semaphorin III receptor that is important for guiding neural development (5, 6). There is also evidence that NRP-1 mediates angiogenesis. NRP-1-null mice were found to be embryonic lethal and exhibit cardiovascular defects (7). Furthermore, overexpression of NRP-1 in mice resulted in excessive capillary and blood vessel formation and hemorrhaging in embryos (8). NRP-1 also contributes to tumor angiogenesis. Induction of NRP-1 expression in tumor cells in vivo resulted in larger an...

Our previous study (Z. X. Peng et al., Carbohydr. Polym. 81:275-283, 2010) demonstrated that water-soluble quaternary ammonium salts, which are produced by the reaction of chitosan with glycidyl trimethylammonium chloride, provide chitosan derivatives with enhanced antibacterial ability. Because biofilm formation is believed to comprise the key step in the development of orthopedic implant-related infections, we further evaluated the efficacy of hydroxypropyltrimethyl ammonium chloride chitosan (HACC) with different degrees of substitution (DS; referred to as HACC 6%, 18%, and 44%) in preventing biofilm formation on a titanium surface. We used a tissue culture plate method to quantify the biomass of Staphylococcus epidermidis and Staphylococcus aureus biofilms and found that HACC, especially HACC 18% and 44%, significantly inhibited biofilm formation compared to the untreated control, even at concentrations far below their MICs (P < 0.05). Scanning electron microscopy showed that inhibition of biofilm formation on titanium increased dramatically with increased DS and HACC concentrations. Confocal laser scanning microscopy indicated that growth of a preexisting biofilm on titanium was inhibited by concentrations of HACC 18% and 44% below their minimum biofilm eradication concentrations. We also demonstrated that HACC inhibited the expression of icaA, which mediates the production of extracellular polysaccharides, both in new biofilms and in preexisting biofilms on titanium. Our results indicate that HACC may serve as a new antibacterial agent to inhibit biofilm formation and prevent orthopedic implant-related infections.

An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti-renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer.

BackgroundExposure to titanium dioxide nanoparticles (TiO2 NPs) that are widely used in food, medicine, sunscreen products and cosmetics is reported to cause ovarian damage and lower fertility in animals. However, the potential effects of TiO2 NPs application on premature ovarian failure (POF) have rarely been evaluated to date.MethodsIn this study, female mice were continuously exposed to TiO2 NPs at doses of 2.5, 5 or 10 mg/kg via gavage instillation for 30 days, and investigated the serum hormones and autoimmunity markers associated with POF.ResultsExposure to TiO2 NPs resulted in POF, reductions in the levels of estradiol, progesterone and inhibin B and increases in luteinizing hormone, follicle-stimulating hormone, follicle-stimulating hormone/luteinizing hormone ratio, anti-Müllerian hormone, thyroid-stimulating hormone, free triiodothyronine, free tetraiodothyronine, anti-nuclear antibody and anti-thyroid peroxidase antibody levels in serum.ConclusionExposure to TiO2 NPs induced POF triggered by alterations in hormones and autoimmunity markers. Our findings highlight the necessity for significant caution in handling and usage of TiO2 NPs by female consumers.