RESUMEN
Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of Ê-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in Ê-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE-/-) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.
Asunto(s)
Aterosclerosis , Ajo , Microbioma Gastrointestinal , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Disulfuros , Humanos , Metilaminas , Ratones , Ratones Endogámicos C57BL , Óxidos , Ácidos SulfínicosRESUMEN
Compelling evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs) can contribute to postnatal neovascularization and tumor angiogenesis. EPCs have been shown to play a "catalytic" role in metastatic progression by mediating the angiogenic switch. Understanding the pharmacological functions and molecular targets of natural products is critical for drug development. Butein, a natural chalcone derivative, has been reported to exert potent anticancer activity. However, the antiangiogenic activity of butein has not been addressed. In this study, we found that butein inhibited serum- and vascular endothelial growth factor- (VEGF-) induced cell proliferation, migration, and tube formation of human EPCs in a concentration dependent manner without cytotoxic effect. Furthermore, butein markedly abrogated VEGF-induced vessels sprouting from aortic rings and suppressed microvessel formation in the Matrigel implant assay in vivo. In addition, butein concentration-dependently repressed the phosphorylation of Akt, mTOR, and the major downstream effectors, p70S6K, 4E-BP1, and eIF4E in EPCs. Taken together, our results demonstrate for the first time that butein exhibits the antiangiogenic effect both in vitro and in vivo by targeting the translational machinery. Butein is a promising angiogenesis inhibitor with the potential for treatment of cancer and other angiogenesis-related diseases.
RESUMEN
A new acetophenone derivative, melicopone, along with twenty-nine known compounds has been isolated from the root wood of Melicope semecarpifolia. The structure of this new compound was determined using spectral analyses. The compound oxynitidine isolated in this study adds the Melicope genus to the benzo[c]phenanthridine-containing members chemotaxonomically. Three isolates were cytotoxic in P-388 and HT-29 cell lines, and anti-platelet aggregation activities were shown for 10 known compounds.
Asunto(s)
Acetofenonas/química , Acetofenonas/farmacología , Antineoplásicos/química , Inhibidores de Agregación Plaquetaria/química , Rutaceae/química , Acetofenonas/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Benzaldehídos/aislamiento & purificación , Benzaldehídos/farmacología , Ácido Benzoico/aislamiento & purificación , Ácido Benzoico/farmacología , Cumarinas/aislamiento & purificación , Cumarinas/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Células HT29 , Humanos , Lignanos/aislamiento & purificación , Lignanos/farmacología , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Inhibidores de Agregación Plaquetaria/aislamiento & purificación , Inhibidores de Agregación Plaquetaria/farmacología , Quinolinas/aislamiento & purificación , Quinolinas/farmacologíaRESUMEN
It is increasingly evident that the stromal cells are involved in key metastatic processes of melanoma and some malignant solid tumors. (-)-Epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, has been shown to have anti-tumor activity, inhibiting adhesion, migration, and proliferation of tumor cells. However, little attention has been paid on its effects on stromal cells. In the present study, we determined the effects of EGCG on stromal fibroblasts. We showed that fibroblast adhesion to collagen, fibronectin, and fibrinogen were inhibited by EGCG. One of the possible mechanisms is binding of EGCG to fibronectin and fibrinogen but not to collagen. We then focused how EGCG affected fibroblast adhesion to collagen. EGCG treatment attenuated the antibody binding to fibroblast's integrin alpha2beta1, indicating EGCG may affect the expression and affinity of integrin alpha2beta1. Moreover, intracellular H2O2 level was decreased by EGCG treatment, suggesting that the tonic maintenance of intracellular H2O2 may be required for cell adhesion to collagen. In parallel, collagen-induced FAK phosphorylation, actin cytoskeleton reorganization in fibroblasts, migration and matrix metalloproteinase(s) (MMPs) activity were also affected by EGCG. Tubular networks formed by melanoma cells grown on three-dimensional Matrigel were also disrupted when fibroblasts were treated with EGCG in a non-contact coculture system. Taken together, we provided here the first evidence that EGCG is an effective inhibitor on behaviors of the stromal fibroblasts, affecting their adhesion and migration. The inhibitory activity of EGCG may contribute to its anti-tumor activity. The findings and concepts disclosed here may provide important basis for a further experiment towards understanding tumor-stroma interaction.