Vimang is the brand name of formulations containing an extract of Mangifera indica L., ethnopharmacologically used in Cuba for the treatment of some immunopathological disorders, including bronchial asthma, atopic dermatitis and other allergic diseases. However, the effects of Vimang on allergic response have not been reported until now. In this study, the effects of Vimang and mangiferin, a C-glucosylxanthone isolated from the extract, on different parameters of allergic response are reported. Vimang and mangiferin showed a significant dose-dependent inhibition of IgE production in mice and anaphylaxis reaction in rats, histamine-induced vascular permeability and the histamine release induced by compound 48/80 from rat mast cells, and of lymphocyte proliferative response as evidence of the reduction of the amount of B and T lymphocytes able to contribute to allergic response. In these experiments, ketotifen, promethazine and disodium cromoglicate were used as reference drugs. Furthermore, we demonstrated that Vimang had an effect on an in-vivo model of inflammatory allergy mediated by mast cells. These results constitute the first report of the anti-allergic properties of Vimang on allergic models, as well as suggesting that this natural extract could be successfully used in the treatment of allergic disorders. Mangiferin, the major compound of Vimang, contributes to the anti-allergic effects of the extract.

Advanced metastatic melanoma, one of the most aggressive skin malignancies, is currently without reliable therapy. The process of angiogenesis is crucial for progression and metastasis of the majority of solid tumors including melanomas. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone which exerts many pharmacological activities against cancer-inflammation. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we demonstrate that mangiferin interferes with inflammation, lipid and calcium signaling which selectively inhibits multiple NFkB target genes including interleukin-6, tumor necrosis factor, interferon gamma, vascular endothelial growth factor receptor 2, plasminogen activator urokinase, matrix metalloprotease 19, C-C Motif Chemokine Ligand 2 and placental growth factor. This abrogates angiogenic and invasive processes and capillary tube formation of metastatic melanoma cells as well as human placental blood vessel explants in-vitro and blocks angiogenesis characteristic of the chicken egg chorioallantoic membrane assay and in melanoma syngeneic studies in vivo. The results obtained in this research illustrate promising anti-angiogenic effects of the natural glucosylxanthone mangiferin for further (pre)clinical studies in melanoma cancer patients.

In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic immunocompetent allograft mouse model of murine CT26 colon carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits tumor growth, metastasis and angiogenesis by multi-targeting of mitochondrial oxidoreductase and fatty acid β-oxidation metabolism, PPAR, SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on fatty acid β-oxidation metabolism and carnitine palmitoyltransferase 1 (CPT1) protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.

Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 μg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.

The protective effect of the supplementation with an aqueous-ethanolic extract obtained from Ulva lactuca (Delile) green seaweed on benzo[a] pyrene-induced damage in mice was evaluated. Animals were treated with oral doses of U. lactuca extract (100 and 400 mg/kg) for 9 weeks. They were exposed to 50 mg/kg of oral doses of benzo(a)pyrene starting from the second week and up to the fifth week. Groups treated with benzo(a)pyrene only (second to fifth weeks), sunflower oil (vehicle, 9 weeks), or U. lactuca extract (100 and 400 mg/kg, 9 weeks) were also included in the study. The treatment with 400 mg/kg of the extract ameliorated the oxidative damage, decreased IL-1β and TNF-α levels, and favorably regulated the antioxidant defenses compared with benzo(a)pyrene-exposed group. The benzo(a)pyrene-induced DNA damage was also reduced, as it was evidenced by the lower micronucleus formation in U. lactuca extract-supplemented animals. The extract protected the hepatic tissue, and it reduced the liver activity/expression of CYP1A1. These results altogether suggested a chemoprotective effect of U. lactuca extract against benzo(a)pyreneinduced-toxicity in mice, probably associated with an inhibitory effect of carcinogen bioactivation.

The effects of an extract from the marine plant Thalassia testudinum on rat liver cytochrome P450s were investigated. Male Wistar rats were administered for 10 days with 20, 200 or 400 mg/kg oral doses of the extract. The activities of CYP1A1/A2, CYP2B1/B2, CYP2E1 and CYP3A were evaluated. CYP1A1 activity and protein content increased after 200 mg/kg of the extract but mRNA levels remain unchanged. The activity of other CYP isoforms did not change. The S9 fraction derived from the livers of the rats treated with the extract was used to evaluate the effects of this product on the mutagenic activation of benzo [a]pyrene. The number of Salmonella mutant colonies induced by benzo [a]pyrene in the presence of S9 obtained from animals treated with 200 and 400 mg/kg of the extract were respectively 1.8 and 2.3-fold higher than controls, while it was reduced at the 20 mg/kg dose. This strongly support the idea that the extract modulated the liver enzymes which transform benzo[a]pyrene into mutagenic metabolites. Another set of male rats were treated for 10 days with the same doses. Sixteen hours later, rats received oral doses of theophylline (10 mg/kg), blood samples were extracted from each animal at 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h after administration and plasma theophylline concentration was measured. Pretreatment with the extract increased theophylline clearance. Our results suggested that the extract modify CYP1A in vivo activity and metabolism-based pharmacokinetic interactions between the extract and CYP1A substrates may occur in vivo.I. Rodeiro-Guerra et al. 548Palabras clave: citocromo P450, interacciones de fármacos, teofilina, benzo[a]pireno RESUMEN Se investigaron los efectos del extracto de la planta marina Thalassia testudinum sobre isoenzimas del citocromo-P450 del hígado de ratas. A ratas machos Wistar se les administró oralmente el extracto durante 10 días en dosis de 20, 200 o 400 mg/kg. Se estimó la actividad de CYP1A1/A2, CYP2B1/B2, CYP2E1 y CYP3A. La actividad de CYP1A1 y el contenido de proteína aumentaron con 200 mg/kg del extracto, pero los niveles de ARNm no se modificaron. La actividad de las otras isoformas tampoco cambió. La fracción postmitocondrial (S9) obtenida de los hígados de los animales se usó en la prueba de Ames para evaluar los efectos del extracto sobre la modulación de enzimas activadoras del benzo[a]pireno. El número de colonias mutantes aumentó 1.8 y 2.3 veces con las dosis de 200 y 400 mg/kg, pero disminuyó con 20 mg/kg, lo cual sugiere una capacidad moduladora del extracto sobre la actividad de las enzimas que transforman el benzo[a]pireno en el hígado de ratas. Otro grupo de ratas macho tratadas durante 10 días con las dosis antes descritas, recibieron teofilina oral (10 mg/kg) 16 h después de concluir el tratamiento. De cada animal se extrajeron muestras de sangre a 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 y 24 h después de administrar la teofilina y se midió la concentración de ésta en plasma. El pretratamiento con el extracto aumentó la eliminación de la te...

Clusia minor L. is traditionally used to treat many disorders that including pain and inflammation such as sores and warts. Four extracts from the leaves of plant were prepared: hexane (CMH-A), ethyl acetate (CMH-B), methanol (CMH-C) and ethanol (CMH-E) and the pharmacological (antioxidant and anti-inflammatory properties) and toxicity effects were examined. Previously, the main constituents from CMH-A extract was revealed. Here, we present the GC/MS analysis of CMH-B and CMH-C. Thirty three compounds were identified in the CMH-B extract and twenty seven compounds in the CMH-C. The presence of D-α-tocopherol and lupeol was relevant in both extracts. The only sterols identified were sitosterol and stigmasterol. All of them showed effective radical scavenger properties in the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay, being CMH-E extract the most promissory (IC50 = 10.25 µg/mL). CMH-A, C and E extracts, administered topically (0.5–4 mg per ear), significant reduced ear edema induced by croton oil at 4 mg per ear, meanwhile CMH-B that was be able to significant reduce the inflammation at the dose of 2 mg per ear. We evaluated also the cytotoxic activity of the extracts against kidney cells (BHK), colon cancer (CT26), endothelial cancer cells (EA.hy926) and breast cancer (4T1). CMH-B extract showed the most cytotoxicity effect, with IC50 values in the range of 32.01-203.5 µg/mL. In addition, no oral acute toxicity after mice exposure to Clusia minor L. extracts was observed. The results suggest Clusia minor L. may be a good potential source of new bioactive agents for developing medicinal agents.

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