curcumin and taxifolin

Estrogen receptor α (ERα) is a ligand-activated transcriptional activator that is also involved vascular inflammation and atherosclerosis. Whether different ligands may affect this activity has not been explored. We screened a panel of phytoestrogens for their role in ERα binding and transcriptional transcription, and correlated the findings to anti-inflammatory activities in vascular endothelial cells stably expressing either a wild-type or mutant form of ERα deficient in its membrane association. Taxifolin and silymarin were "high binders" for ERα ligand binding; quercetin and curcumin were "high activators" for ERα transactivation. Using these phytoestrogens as functional probes, we found, in endothelial cells expressing wild-type ERα, the ERα high activator, but not the ERα high binder, promoted ERα nuclear translocation, estrogen response element (ERE) reporter activity, and the downstream gene expression. In endothelial cells expressing membrane association-deficient mutant ERα, the ERα nuclear translocation was significantly enhanced by taxifolin and silymarin, which still failed to activate ERα. Inflammation response was examined using the systemic or vascular inflammation inducers lipopolysaccharide or oxidized low-density lipoprotein. In both cases, only the ERα high activator inhibited nuclear translocation of nuclear factor κB, JNK, and p38, and the production of inflammatory cytokines IL-1β and TNFα. We confirm a threshold nuclear accumulation of ERα is necessary for its transactivation. The anti-inflammatory activity of phytoestrogens is highly dependent on ERα transactivation, less so on the ligand binding, and independent of its membrane association. A pre-examination of phytoestrogens for their mode of ERα interaction could facilitate their development as better targeted receptor modifiers.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Atherosclerosis; Cell Line; Curcumin; Endothelial Cells; Estrogen Receptor alpha; Humans; Inflammation; Interleukin-1beta; Ligands; Lipopolysaccharides; Lipoproteins, LDL; MAP Kinase Kinase 4; Molecular Docking Simulation; Mutation; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phytoestrogens; Protein Transport; Quercetin; Response Elements; Signal Transduction; Silymarin; Tumor Necrosis Factor-alpha

Phytonutrients reportedly extend the life span of Caenorhabditis elegans, Drosophila, and mice. We tested extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), as well as curcumin, morin, and quercetin for their effects on the life span of mice. While many of these phytonutrients reportedly extend the life span of model organisms, we found no significant effect on the life span of male F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic end points in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were iso-caloric with respect to one another. A 40% calorically restricted and other groups not reported here did experience life span extension. Body weights were un-changed relative to controls for all but two supplemented groups, indicating most supplements did not change energy absorption or utilization. Tea extracts with morin decreased weight, whereas quercetin, taxifolin, and Pycnogenol together increased weight. These changes may be due to altered locomotion or fatty acid biosynthesis. Published reports of murine life span extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that isolated phytonutrient anti-oxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health span and life span.

Topics: Animals; Blueberry Plants; Body Weight; Cinnamomum zeylanicum; Crosses, Genetic; Curcumin; Feeding Behavior; Female; Flavonoids; Flavonols; Hybridization, Genetic; Longevity; Lythraceae; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Quercetin; Sesamum; Tea