RESUMEN
Anosmin-1 is a secreted glycoprotein encoded by the ANOS1 gene, and its loss of function causes Kallmann syndrome (KS), which is characterized by anosmia and hypogonadism due to olfactory bulb (OB) dysfunction. However, the physiological function of anosmin-1 remains to be elucidated. In KS, disordered angiogenesis is observed in OB, resulting in its hypoplasia. In this study, we examined the involvement of anosmin-1 in angiogenic processes. Anosmin-1 was detected on the vessel-like structure in OB of chick embryos, and promoted the outgrowth of vascular sprouts as shown by assays of OB tissue culture. Cell migration, proliferation, and tube formation of endothelial cells were induced by treatment with anosmin-1 as well as vascular endothelial growth factor-A (VEGF-A), and further enhanced by treatment with both of them. We newly identified that anosmin-1 activated VEGF receptor-2 (VEGFR2) by binding directly to it, and its downstream signaling molecules, phospholipase Cγ1 (PLCγ1) and protein kinase C (PKC). These results suggest that anosmin-1 plays a key role in the angiogenesis of developing OB through the VEGFR2-PLCγ1-PKC axis by enhancing the VEGF function.
Asunto(s)
Endotelio Vascular/citología , Proteínas de la Matriz Extracelular/metabolismo , Neovascularización Fisiológica , Proteínas del Tejido Nervioso/metabolismo , Bulbo Olfatorio/irrigación sanguínea , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Células Cultivadas , Embrión de Pollo , Proteínas de la Matriz Extracelular/genética , Humanos , Morfogénesis , Proteínas del Tejido Nervioso/genética , Bulbo Olfatorio/citología , Bulbo Olfatorio/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
During the screening of antimalarial substances, MeOH extract from the twigs of Ficus septica was shown to have potent antimalarial activity. Bioassay-guided fractionation of a methanol extract of the twigs of F. septica led to the isolation of a new seco-phenanthroindolizine alkaloid and three known phenanthroindolizine alkaloids. Their structures were elucidated on the basis of NMR analysis. All isolated compounds were tested against Plasmodium falciparum. Compounds 2-4 displayed antimalarial activity against the 3D7 strain of P. falciparum with IC50 values 0.028-0.42 µM, whereas a new compound 1 exhibited a moderate antimalarial activity.