Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25-65 years with metabolic syndrome traits. Subjects were randomised to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period. Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l (P,0·001) during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2·6 mmHg (P,0·01) in the entire study group, by 2·9 mmHg (P,0·01) in the subgroup of hypertensive subjects and by 3·7 mmHg (P,0·001) in the subgroup of younger adults aged 25 -50 years. Quercetin decreased serum HDL-cholesterol concentrations (P,0·001), while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL, but did not affect TNF-a and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematology and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.Quercetin: Blood pressure: Inflammation: Oxidised LDL: CVD Flavonoids in general and quercetin in particular have been associated with a decreased risk for CVD (1) . Furthermore, there was a trend towards a reduction in the incidence of type 2 diabetes mellitus at higher quercetin intakes (2) . In Western populations, the primary dietary sources of quercetin are tea, red wine, fruits and vegetables (3,4) . Quercetin is one of the major flavonoids, ubiquitously distributed in (edible) plants, and one of the most potent antioxidants of plant origin (1) . Numerous biological effects of quercetin, including antioxidant, anti-inflammatory, anti-thrombotic and vasodilatory actions, have been described in vitro (1) . However, quercetin intervention trials in human subjects have so far shown inconclusive and even conflicting results (5) . Quercetin supplementation increased plasma antioxidant capacity, ex vivo resistance of LDL to oxidation and resistance of lymphocyte DNA to strand breakage, but decreased urinary 8-hydroxy-2 0 -deoxyguanosine concentrations (5) . Other human studies, however, failed to confirm effects on these biomarkers (5) . A recent meta-analysis of 133 controlled flavonoid trials (6) suggested that there may be clinically relevant effects of some flavonoids or flavonoid-ri...

Quercetin is a dietary polyphenolic compound with potentially beneficial effects on health. Claims that quercetin has biological effects are based mainly on in vitro studies with quercetin aglycone. However, quercetin is rapidly metabolized, and we have little knowledge of its availability to tissues. To assess the long-term tissue distribution of quercetin, 2 groups of rats were given a 0.1 or 1% quercetin diet [approximately 50 or 500 mg/kg body weight (wt)] for 11 wk. In addition, a 3-d study was done with pigs fed a diet containing 500 mg quercetin/kg body wt. Tissue concentrations of quercetin and quercetin metabolites were analyzed with an optimized extraction method. Quercetin and quercetin metabolites were widely distributed in rat tissues, with the highest concentrations in lungs (3.98 and 15.3 nmol/g tissue for the 0.1 and 1% quercetin diet, respectively) and the lowest in brain, white fat, and spleen. In the short-term pig study, liver (5.87 nmol/g tissue) and kidney (2.51 nmol/g tissue) contained high concentrations of quercetin and quercetin metabolites, whereas brain, heart, and spleen had low concentrations. These studies have for the first time identified target tissues of quercetin, which may help to understand its mechanisms of action in vivo.

Our aim was to investigate the effects of an oral supplementation of quercetin at 3 different doses on plasma concentrations of quercetin, parameters of oxidant/antioxidant status, inflammation, and metabolism. To this end, 35 healthy volunteers were randomly assigned to take 50, 100, or 150 mg/d (group Q50-Q150) quercetin for 2 wk. Fasting blood samples were collected at the beginning and end of the supplementation period. Compared with baseline, quercetin supplementation significantly increased plasma concentrations of quercetin by 178% (Q50), 359% (Q100), and 570% (Q150; P , 0.01 for all).High interindividual variation was found for plasma quercetin concentrations (36-57%). Quercetin did not affect concentrations of serum uric acid or plasma a-and g-tocopherols, oxidized LDL, and tumor necrosis factor-a, or plasma antioxidative capacity as assessed by the ferric-reducing antioxidant potential and oxygen radical absorbance capacity assays. In addition,

Summary. Background: Quercetin, a flavonoid present in the human diet, which is found in high levels in onions, apples, tea and wine, has been shown previously to inhibit platelet aggregation and signaling in vitro. Consequently, it has been proposed that quercetin may contribute to the protective effects against cardiovascular disease of a diet rich in fruit and vegetables. Objectives: A pilot human dietary intervention study was designed to investigate the relationship between the ingestion of dietary quercetin and platelet function. Methods: Human subjects ingested either 150 mg or 300 mg quercetin-4¢-O-b-D-glucoside supplement to determine the systemic availability of quercetin. Platelets were isolated from subjects to analyse collagen-stimulated cell signaling and aggregation. Results: Plasma quercetin concentrations peaked at 4.66 lM (± 0.77) and 9.72 lM (± 1.38) 30 min after ingestion of 150-mg and 300-mg doses of quercetin-4¢-O-b-Dglucoside, respectively, demonstrating that quercetin was bioavailable, with plasma concentrations attained in the range known to affect platelet function in vitro. Platelet aggregation was inhibited 30 and 120 min after ingestion of both doses of quercetin-4¢-O-b-D-glucoside. Correspondingly, collagen-stimulated tyrosine phosphorylation of total platelet proteins was inhibited. This was accompanied by reduced tyrosine phosphorylation of the tyrosine kinase Syk and phospholipase Cc2, components of the platelet glycoprotein VI collagen receptor signaling pathway. Conclusions: This study provides new evidence of the relatively high systemic availability of quercetin in the form of quercetin-4¢-O-b-D-glucoside by supplementation, and implicates quercetin as a dietary inhibitor of platelet cell signaling and thrombus formation.

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Extracts of Ginkgo biloba leaves are consumed as dietary supplements to counteract chronic, age-related neurological disorders. We have applied high-density oligonucleotide microarrays to define the transcriptional effects in the cortex and hippocampus of mice whose diets were supplemented with the herbal extract. Gene expression analysis focused on the mRNAs that showed a more than 3-fold change in their expression. In the cortex, mRNAs for neuronal tyrosine͞threonine phosphatase 1, and microtubuleassociated were significantly enhanced. Hyperphosphorylated is the major constituent of the neurofibrillary tangles in the brains of Alzheimer's disease patients. The expression of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-2, calcium and chloride channels, prolactin, and growth hormone (GH), all of which are associated with brain function, were also up-regulated. In the hippocampus, only transthyretin mRNA was upregulated. Transthyretin plays a role in hormone transport in the brain and possibly a neuroprotective role by amyloid-␤ sequestration. This study reveals that diets supplemented with Ginkgo biloba extract have notable neuromodulatory effects in vivo and illustrates the utility of genome-wide expression monitoring to investigate the biological actions of complex extracts.

Recent investigations suggest that the bioavailability of quercetin depends on the glycoside moiety of the quercetin glycosides present in the diet. In this study, we compared the oral bioavailability of quercetin from quercetin aglycone and two different quercetin glycosides in pigs. Pigs were equipped with permanent catheters in the jugular and portal veins. After consumption of a test meal containing the respective compounds, blood samples were drawn repeatedly over a period of 24 h and analyzed by HPLC. In a first set of experiments, pigs received a single oral dose of 148 micromol/kg body (equivalent to 50 mg/kg) provided as quercetin aglycone, quercetin-3-O-glucoside (Q3G) or quercetin-3-O-glucorhamnoside (rutin) as part of their diet. The main metabolite in plasma was always conjugated quercetin, whereas free quercetin was not detected in either the jugular or the portal blood. For Q3G and rutin, the relative total bioavailability of quercetin (i.e., conjugated quercetin and conjugated methylethers of quercetin) was 148% (P = 0.07) and 23% (P < 0.05), respectively, compared with quercetin aglycone. In another experiment with a dose of 29.6 micro mol/kg (equivalent to 10 mg/kg), the relative total bioavailability of Q3G was 167% compared with the aglycone (P < 0.05). Bioavailability of Q3G was significantly higher when the test meal was ground beef rather than the standard ration. Our results indicate that the bioavailability of quercetin from quercetin glycosides is determined by a complex interdependence between the chemical form of the flavonols and dietary factors.

In the present study we investigated a possible involvement of the intestinal sodium-dependent glucose transporter (SGLT)1 in the absorption of quercetin-3-glucoside (Q3G). Pieces of rat jejunum or proximal colon were mounted in Ussing-type chambers and incubated under short-circuited conditions. Test flavonols were added to the mucosal or serosal bathing solution (initial concentration, 100 micromol/L) and disappearance from the donor compartment was monitored for 2 h. With jejunal tissue, only 13.6 +/- 3.5% of the initial dose of Q3G was found in the mucosal compartment 2 h after mucosal addition. Simultaneous addition of D-glucose (10 mmol/L) significantly reduced the disappearance of Q3G (remaining concentration, 33.4 +/- 6.9%) as did a Na(+)-free buffer solution containing phloridzin (final mucosal concentration of Q3G, 54.2 +/- 7.7%). In these experiments, disappearance of Q3G was paralleled by the appearance of quercetin in the mucosal solutions. In contrast, D-fructose (10 mmol/L) did not influence the disappearance of Q3G (Na(+)-free conditions). With proximal colon, 78.2 +/- 11.5% of the initial concentration of Q3G was still present in the mucosal solution after 2 h. When added to the serosal side, the concentration of Q3G decreased only slightly (jejunum, 96.1 +/- 2.1%; proximal colon, 90.7 +/- 1.2%). The concentration of rutin did not change after mucosal or serosal addition. Neither transport of intact glycosides nor of free quercetin from the donor into the acceptor compartment was observed under our experimental conditions. Taken together, the results clearly indicate a role of SGLT1 in mucosal uptake of the Q3G.