RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Korean Red ginseng extract (RG) is one of the most widely used traditional health functional food in Asia, which invigorates immunity and vital energy. RG have been suggested to inhibit proliferation, invasion, and inflammation in several cancer cell lines. Correspondingly, clinical studies have raised the possibility that RG could augment therapeutic efficacy in cancer patients. However, little is known about the anti-cancer effects of RG in glioblastoma (GBM), the most common and aggressive brain tumor for which effective therapeutic regimens need to be developed. AIM OF THIS STUDY: Here, we assessed the in vivo and in vitro anti-cancer properties of RG in a patient-derived xenograft mouse model and GBM stem cell (GSC) line. MATERIALS AND METHODS: We evaluated the anti-cancer effects of RG in patient-derived GBM xenograft mice with and without combined concurrent chemo- and radiation therapy (CCRT). Furthermore, we verified the in vitro effects of RG on the proliferation, cell death, and stem cell-like self-renewal capacity of cancer cells. Finally, we investigated the signaling pathway affected by RG, via which its anti-cancer effects were mediated. RESULTS: When combined with CCRT, RG impeded GBM progression by reducing cancer cell proliferation and ionized calcium-binding adapter molecule 1 (IBA1)-positive immune cell recruitment. The anti-cancer effects of RG were mediated by Rg3 and Rh2 ginsenosides. Rg3 promoted cell death while Rh2 did not. Furthermore, both Rg3 and Rh2 reduced cell viability and self-renewal capacity of GSCs by inhibiting Wnt/ß-catenin signaling. CONCLUSION: Therefore, our observations imply that RG could be applied to the GBM patients in parallel with CCRT to enhance therapeutic efficacy.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Panax/química , Extratos Vegetais/farmacologia , Adulto , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Encéfalo/citologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Medicina Tradicional Coreana , Camundongos , Células-Tronco Neoplásicas , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma multiforme (GBM) is one of the most aggressive and lethal human brain tumors, and the median survival of patients with GBM is only 14 months. Glioblastoma stem cells (GSCs) are regarded as a main cause of GBM recurrence, because of their self-renewal and drug resistance properties. Therefore, targeting GSCs is an important therapeutic strategy for GBM. In this study, we show the effects of BRM270, a compound from natural plant extracts, on GSCs in vitro and GBM recurrence in vivo. BRM270 induced apoptotic cell death and inhibited cell growth and "stemness" both in vitro and in vivo. Combining BRM270 treatment with concurrent chemoradiotherapy (CCRT) dramatically increased mice survival and tumor growth inhibition. Taken together, our results suggested that BRM270 synergizes with CCRT as a therapeutic agent to target GSCs.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/citologia , Extratos Vegetais/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/radioterapia , Proliferação de Células/efeitos da radiação , Quimiorradioterapia , Terapia Combinada , Glioblastoma/fisiopatologia , Glioblastoma/radioterapia , Humanos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiaçãoRESUMO
Application of microbial stress to soybean during germination induces the accumulation of phytoalexins, which have many health benefits. In this study, the effects of stress induced by Aspergillus oryzae on the phytochemical composition of germinating soybeans were investigated, and their radical scavenging activity was compared with those of ungerminated (US) and germinated (GS) soybeans. Additionally, the antioxidant activity of coumestrol, a soybean phytoalexin, against hydrogen peroxide-induced reactive oxygen species (ROS) was investigated in HepG2 cells. A. oryzae exposure significantly decreased the total isoflavone content and induced coumestrol and glyceollin I. A. oryzae-challenged germinated soybeans exhibited the highest radical scavenging activity (IC(50) = 0.55 mg/mL) as compared to US and GS. Coumestrol exhibited significantly higher radical scavenging activity than daidzein and genistein. Furthermore, coumestrol significantly prevented hydrogen peroxide-induced ROS production and lipid peroxidation and inhibited decreases in cell viability, intracellular glutathione (GSH) levels, and superoxide dismutase (SOD) activity. These results indicate that using food-grade A. oryzae to elicit the biosynthesis of phytoalexins alters the secondary metabolite profiles of the soybeans and offers enhanced bioactivity of soybean as a functional food ingredient.
Assuntos
Antioxidantes/metabolismo , Aspergillus oryzae/fisiologia , Germinação , Glycine max/metabolismo , Glycine max/microbiologia , Isoflavonas/metabolismo , Extratos Vegetais/metabolismo , Antioxidantes/análise , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células/citologia , Células/efeitos dos fármacos , Células/metabolismo , Células Hep G2 , Humanos , Isoflavonas/análise , Isoflavonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Glycine max/química , Glycine max/crescimento & desenvolvimentoRESUMO
Ginsenoside Re is the major ginsenoside in ginseng berry(GB) extract and its pharmacokinetics were studied following the intravenous and oral administration of pure Re or ginseng berry extract in mouse with doses of 10 and 50 mg/kg using ultra performance liquid chromatography mass spectrometric (UPLC/MS) method which can simultaneously determine ginsenoside Re, Rg1 and Rh1 in mouse serum. The serum samples were pretreated by protein precipitation and chromatographic separation was performed on AQUITY UPLC BEH C(18) column using gradient elution with the mobile phase of 5 mM ammonium formate and acetonitrile. Analytes and digoxin (I.S.) were analyzed and identified using an electrospray negative ionization mass spectrometry in the selected ion monitoring mode with the linear concentration range of 5.0-5000 ng/mL and lower limits of detection (LLOD) under 2.5 ng/mL. Ginsenoside Re was rapidly cleared from the body with a short half-life (0.2+/-0.03 h for male and 0.5+/-0.08 h for female mice after i.v.) and oral absorption was generally poor (F% 0.19-0.28). Notably, GB extract showed a superior oral absorption of ginsenoside Re (F% 0.33-0.75) at equivalent ginsenoside Re dose to pure ginsenoside Re, indicating that GB extract might be a good form for ginsenoside Re intake.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ginsenosídeos/farmacocinética , Panax/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Frutas , Ginsenosídeos/administração & dosagem , Ginsenosídeos/isolamento & purificação , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Fatores SexuaisRESUMO
In the course of screening antifibrotic activity of natural products employing HSC-T6, a rat hepatic stellate cell line, as an in vitro assay system, the methanolic extract of aerial parts of Euscaphis japonica (Tunb.) Kantiz (Staphyleaceae) showed significant inhibitory activity on HSC proliferation. Activity-guided fractionation led to the isolation of four triterpenoids, friedeline (1), glut-5-en-ol (2), pomolic acid (3), and methylrotundate (4). Among the triterpenoids isolated, pomolic acid (3) significantly inhibited the proliferation of HSCs at concentrations 10 and 100 microM.
Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Magnoliopsida/química , Componentes Aéreos da Planta/química , Triterpenos/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibrose/patologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Caules de Planta/química , Ratos , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/metabolismoRESUMO
Bioactivity-guided fractionation of the methanolic extract of the aerial parts of EUSCAPHIS JAPONICA (Tunb.) Kantiz (Staphyleaceae), afforded a new compound, P-coumaroyl- D-malic acid 1-methyl ester (1), together with twelve known compounds, 3,7-dihydro-5-octanolide (2), blumenol A (3), megastigmane (4), gallic acid (5), stenophyllin H1 (6), methyl 5,7-dihydroxyoctanoate (7), TRANS-phytol (8), alpha-tocopherol (9), kaempferol (10), kaempferol 3-O-beta-D-glucopyranoside (11), quercetin (12) and quercetin 3-O-beta-D-glucopyranoside (13). Among them, compounds 1 - 5 and 8 - 13 significantly inhibited lipopolysacchride-induced nitric oxide production in murine BV2 microglial cells. Especially, compounds 5, 8, 10 and 12 exerted potent inhibitory activity comparable to that of NAME, used as positive control.