RESUMEN
AIM OF THE STUDY: We had reported that Astragalus saponins (AST) exert promising anti-tumorigenic effects by suppressing the growth of HT-29 human colon cancer cells and tumor xenograft. In the present study, we further investigated the anti-angiogenic property of AST in human gastric adenocarcinoma cells (AGS) and attempted to elucidate the underlying mechanism. MATERIALS AND METHODS: Viability of AGS cells was measured by using the MTT reduction method. Western blotting was performed to examine the effect of AST on apoptotic- and cell growth-related protein expression. Effect of AST on cell cycle progression was also evaluated using PI staining. A Matrigel invasion assay was then employed to demonstrate the effect of AST on the invasiveness of gastric cancer cells. The expression of invasion-associated proteins (VEGF and MMPs) was also investigated. RESULTS: AST could induce apoptosis in AGS cells by activating caspase 3 with subsequent cleavage of poly(ADP-ribose) polymerase. Besides, cell cycle arrest at the G2/M phase had been observed in AST-treated cells, leading to substantial growth inhibition. The anti-proliferative effect of AST was associated with the regulation of cyclin B1, p21 and c-myc. Results indicate that the number of AGS cells invaded through the Matrigel membrane was significantly reduced upon AST treatment, with concomitant down-regulation of the pro-angiogenic protein vascular endothelial growth factor (VEGF) as well as the metastatic proteins metalloproteinase (MMP)-2 and MMP-9. CONCLUSION: AST derived from the medicinal plant Astragalus membranaceus could modulate the invasiveness and angiogenesis of AGS cells besides its pro-apoptotic and anti-proliferative activities. These findings also suggest that AST has the potential to be further developed into an effective chemotherapeutic agent in treating advanced and metastatic gastric cancers.
Asunto(s)
Adenocarcinoma/patología , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos Fitogénicos/farmacología , Planta del Astrágalo , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/prevención & control , Extractos Vegetales/farmacología , Saponinas/farmacología , Neoplasias Gástricas/patología , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/metabolismo , Inhibidores de la Angiogénesis/aislamiento & purificación , Proteínas Angiogénicas/metabolismo , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Planta del Astrágalo/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Neovascularización Patológica/metabolismo , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Saponinas/aislamiento & purificación , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/metabolismo , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Eighty-seven of 175 laboratory raised F1 generation brook charr (Salvelinus fontinalis) were resistant to experimental Cryptobia salmositica infection. Susceptibility to the pathogen was not related to age nor to route of infection. Plasma of resistant charr lysed the parasite under in vitro conditions while those of susceptible fish did not. Sperm from 4 susceptible and 4 resistant male charr, from 8 F1 families, were used to fertilize eggs from 2 hatchery raised susceptible charr. Susceptibility of progenies (F2 families) was determined 4 weeks after inoculation of the parasite. All progenies (seven F2 families) of 4 susceptible males were susceptible to experimental infection and their plasma did not lyse the parasite. It was presumed that these susceptible progenies were homozygous recessive (rr), and that the resistant allele was dominant. All progenies (two F2 families) of 1 resistant male (presumed RR) and 2 susceptible females were all resistant to infection and their plasma lysed the parasite. The ratio of resistant to susceptible charr in 6 other F2 families from the other 3 resistant males (presumed Rr) and two susceptible females was about 1:1. The results suggest a single Mendelian locus which determines innate resistance to C. salmositica infection in brook charr and that it is possible to breed Cryptobia-resistant fish.
Asunto(s)
Enfermedades de los Peces/etiología , Kinetoplastida/patogenicidad , Infecciones Protozoarias en Animales , Trucha/parasitología , Alelos , Animales , Cruzamientos Genéticos , Femenino , Enfermedades de los Peces/genética , Enfermedades de los Peces/inmunología , Genes Dominantes , Genes Recesivos , Homocigoto , Inmunidad Innata/genética , Masculino , Infecciones por Protozoos/etiología , Infecciones por Protozoos/genética , Trucha/genética , Trucha/inmunologíaRESUMEN
Renin inhibitors having 13 different isosteres connecting the P3 and P2 positions have been prepared. Synthetic routes and in vitro activity exhibited by these compounds are discussed. The two most potent compounds, 47 and 48, contained the hydroxyethylene isostere, psi [CHOHCH2], and had IC50 values of 61 and 22 nM, respectively.