RESUMEN
Citrus grandis (L.) Osbeck is a popular fruit cultivated around the world, and its peels are sometimes used for the treatment of cough, abdominal pain, and indigestion in China. However, the peel is discarded after fruit consumption in most cases, and its chemical constituents and biological activities have not been validated before. The present study focused on evaluation of the chemical and pharmacological profile of coumarins from peels of C. grandis against inflammation. The extracts and phytochemicals from peels of C. grandis were prepared, and anti-inflammatory activities were carried out in vivo and in vitro, including inhibiting xylene-induced ear edema and carrageenan-induced paw edema in mice and the production of inflammatory cytokines (interleukin 1ß, prostaglandin 2, and tumor-necrosis factor α) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results indicated that methanolic extract, ethyl acetate fraction, and four major coumarins (compounds 7, 8, 13, and 16) inhibited swelling induced by xylene and carrageenan, separately, in vivo. Furthermore, 18 coumarins inhibited inflammatory factor secretion in macrophages primed by LPS, in which compounds 4, 6, 7, 10, 17 showed the most pronounced change, which were comparable to dexamethasone. In summary, peel of C. grandis showed an anti-inflammatory effect and coumarin compounds were responsible for regulating inflammatory mediators and cytokines, which might provide a novel nutritional strategy for inflammatory diseases.
Asunto(s)
Antiinflamatorios/administración & dosificación , Citrus/química , Cumarinas/administración & dosificación , Edema/tratamiento farmacológico , Frutas/química , Extractos Vegetales/administración & dosificación , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Cumarinas/química , Cumarinas/aislamiento & purificación , Dinoprostona/inmunología , Edema/genética , Edema/inmunología , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos ICR , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Residuos/análisisRESUMEN
BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive and frequently recurrent malignant brain tumor, and to date, the clinically effective drugs against GBM remain scarce. Natural products play an important role in drug discovery, and might be the resource of antitumor agents for GSCs. Alstonia scholaris (L.) R. Br. is rich in monoterpenoid indole alkaloids (MIAs) and used extensively for treatment of tumor in the traditional medicine system of Asia. PURPOSE: To search for new MIAs with antitumor activity against glioma stem cells from clinical patients and explore their mechanism. METHODS: Compounds were obtained from the fruits of A. scholaris by chromatographic separation, including silica gel, Sephadex LH-20 and recrystallization. Their structures were elucidated by the use of UV, IR, NMR and MS spectra. The antitumor activity of the compounds against the glioma stem cells (GSC-3#, GSC-12#, GSC-18#) were investigated by phenotypic screening and MTS assays. Cell proliferation assay by BrdU immunofluorescence staining, and apoptosis assay by cleaved-caspase-3 immunofluorescence staining and real-time PCR assay. The soft-agar clonal formation assay was performed to determine the antitumor efficacy of the compounds in vitro. RESULTS: Two new nor-monoterpenoid indole alkaloids were isolated from the fruits of A. scholaris. They exhibited selective antitumor activity against glioma stem cells (GSC-3#, GSC-12#, GSC-18#) with IC50 values of 15-25⯵g/ml. Furthermore, they inhibited GSCs proliferation, induced GSCs apoptosis by increasing the expression of TNF-α and cleavage of caspase-3, and significantly damaged colony forming capacity of GSCs. CONCLUSION: New nor-monoterpenoid indole alkaloids from the fruits of A. scholaris provide new type promising molecule for the selective killing of human glioma stem cells.
Asunto(s)
Alstonia/química , Antineoplásicos Fitogénicos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Alcaloides de Triptamina Secologanina/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Caspasa 3/metabolismo , Línea Celular , Frutas/química , Glioblastoma/tratamiento farmacológico , Glioma/tratamiento farmacológico , Humanos , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
The fruits of Avicennia marina are widely used for both medicine and food in Guangxi of China. As a part of our continuous effort to search for bioactive molecules from the plant, the fruits of A. marina were investigated, which has led to one new triterpenoid saponin (1) and 29 known compounds been isolated and their structures were established by using spectroscopic methods and comparing with literature data. The new triterpenoid saponin showed cytotoxicity against GSC-3# and GSC-18# with the IC50 values were 12.21 and 5.53 µg/mL respectively, and most of the known compounds had significant antioxidant capacity with the IC50 values ranging from 0.36 to 13.07 µg/mL.
