Table 3.

Flavonols’ beneficial effects and bioavailability in human subjects.

Cohort and Study Details	Flavonol Intake	Aim	Bioavailability Data	Outcome	Reference
25 participants (12 M; 13 F) (mean age: 64.1 ± 6.3 years) with at least one CVD risk factor (sBP 120–160 mmHg, FPG 5.6–6.5 mM, total cholesterol 5–8 mM or a waist circumference > 94 cm for men or >80 cm for women) Duration: acute consumption Randomized, controlled crossover trial	Treatment group: - 4.89 mg/kg bw/day of EMIQ® (Enzymatically Modified IsoQuercitrin), - half teaspoon of maltodextrin, - one and half tablespoons of Cottee’s Raspberry flavored cordial. Placebo group: - half teaspoon of maltodextrin, - one and half tablespoons of Cottee’s Raspberry flavored cordial, The treatments were given in 250 mL of water.	To evaluate if FMD, BP, and cognitive function improve whether an acute intake of EMIQ® was administered.	After 3 h from the consumption of EMIQ®, quercetin metabolites concentration was significantly higher in plasma respect placebo group (quercetin aglycone 144.9 ± 12.3 nM vs. 12.6 ± 12.3 nM; and isorhamnetin 245.5 ± 16.5 nM vs. 41.7 ± 16.5 nM) (p < 0.001).	EMIQ® significantly affected FMD compared with the placebo (p = 0.025).	[37]
14 healthy males (46.6 ± 5.6 years) with a slightly elevated total cholesterol level (5.3–7.2 mmol/L) Duration: 4 weeks Double-blind, placebo-controlled, crossover study	Group 1: daily consumption of 185 g of an oatmeal porridge supplemented with a flavonols extract of sea buckthorn (Hippopae rhamnoides L.) Group 2: consumption of control porridge without flavonols. 0.4 g of extract, added to the porridge, contained: 78 mg of total flavonol aglycones, of which 70% isorhamnetin, 26% quercetin, and 4% kaempferol.	To evaluate the effects on CRP, conjugated dienes and oxidized LDL, homocysteine, and paraoxonase activity (potential risk factors of CVD) of a flavonols extract of sea buckthorn.	Flavonols were mainly present as glucuronide and sulfate metabolites in plasma fluid. When was intake porridge added with flavonols extract, AUC was significantly higher for kaempferol and isorhamnetin (p < 0.05).	The flavonols ingested did not significantly affect the following: - Oxidized LDL; - CRP; - Homocysteine levels; - Plasma antioxidant potential; - Paraoxonase activity.	[38]
9 overweight/obese men (n = 4) and post-menopausal women (n = 5) (mean age = 55.9 ± 2.1 years) Duration: acute consumption Randomized, crossover study	Subjects ingested quercetin aglycone (1095 mg) with 3 types of standardized breakfast: - Fat-free (<0.5 g); - Low-fat (4.0 g); - High-fat (15.4 g).	To verify whether dietary fat improve quercetin and its metabolites bioavailability in adults with high CVD risk.	During the high-fat breakfast, compared to the fat-free trial: - Plasma quercetin: ↑ 45% Cmax; ↑ 32% AUC (0–24 h); - plasma isorhamnetin: ↑ 40% Cmax; ↑ 19% AUC (0–24 h); - Plasma O-methyl-isorhamnetin: ↑ 46% Cmax; ↑ 43% AUC (0–24 h).	Dietary fat improved quercetin bioavailability by increasing its absorption leading to a possible dietary approach for reducing CVD risk.	[39]
6 heathy subjects (4 M; 2 F) (mean age 34 ± 7 years) Duration: 1 day Randomized, double-blind, crossover study	Participants ingested either a high- or a low-quercetin soup (600 mL), made using 500 g of onions for portion. 1 L of low quercetin onion soup (LQS) contained 0.1 mg L−1 quercetin aglycone, 3.8 mg L−1 quercetin-4′-glucoside, 4.3 mg L−1 quercetin 3,4′-glucoside. 1 L of high quercetin onion soup (HQS) contained: 1.1 mg L−1 quercetin aglycone, 53.2 mg L−1 quercetin-4′-glucoside, 60.5 mg L−1 quercetin 3,4′-glucoside.	To investigate the possible inhibitory effects of quercetin ingestion from a dietary source on platelet function (collagen-stimulated platelet aggregation and collagen-stimulated tyrosine phosphorylation).	After HQS treatment, plasma levels of quercetin did the following: - Peaked at 2.59 ± 0.42 mmol L−1 (p = 0.0001); - AUC 911.61 ± 85·17 mmol L−1 per min (p = 0.001). Plasma levels of isorhamnetin peaked after 2 h at 0.119 ± 0.02 mmol L−1 (HQS) and 0.0133 ± 0.04 mmol L−1 (LQS) (p = 0.0001). Plasma levels of tamarixetin peaked after 2.5 h at 0.172 ± 0.035) mmol L−1 (HQS) and 0.0049 ± 0.001 mmol L−1 (LQS) (p = 0.0001).	HQS treatment inhibited the following: - Collagen-stimulated platelet aggregation (time-dependent); - Collagen-stimulated tyrosine phosphorylation (p = 0.001). The inhibition of tyrosine phosphorylation was correlated with AUC of quercetin after HQS intake.	[40]
36 healthy human subjects (16 M; 20 F) (mean age: 31.4 ± 7.7 years) Duration: 4 weeks Randomized crossover study	Treatment period: high flavonol (HF) diet based on daily consumption of 150 g onion cake (89.7 mg quercetin) + 300 mL black tea (1.4 mg quercetin). Control period: low flavonol (LF) period based on exclusion of flavonol and flavone foods and tea.	To determine the effect of dietary intake of quercetin from onions and black tea on oxidative damage to leukocytes DNA bases.	Plasma quercetin was <LOD (66.2 nmol L−1) after the HF period and increased at 228.5 ± 34.7 nmol L−1 after HF period.	The concentrations of the products of oxidative damage to DNA bases did not differ significantly between the two dietary treatment periods for any of the products measured.	[41]
32 healthy subjects (mean age 30.4 ± 7.3 years) Duration: 4 weeks Randomized crossover study	Treatment period: high flavonol (HF) diet based on daily consumption of 150 g onion cake (89.7 mg quercetin) + 300 mL black tea (1.4 mg quercetin). Control period: low flavonol (LF) period based on exclusion of flavonol and flavone foods and tea.	To investigate the effects of a high-flavonoid (HF) diet on markers of oxidative stress (F2 -isoprostanes and malondialdehyde (MDA)-modified LDL) compared with a low-flavonoid (LF) diet.	After the HF treatment, plasma quercetin concentrations were significantly higher (221.6 ± 37.4 nmol L−1) than after the LF treatment (compared with less than the LOD of 66.2 nmol L−1).	There were no significant differences in plasma F2-isoprostane concentrations, and MDA–LDL between the HF and LF dietary treatments.	[42]
229 healthy subjects (mean age 31.05 ± 8.9 years) Duration: 3 months Randomized double-blind, placebo controlled study	Participants consumed 16.7 mg/day of sea buckthorn extract or placebo, added to 28 g of puree. The daily dose of sea buckthorn extract contained: - 5.8 ± 0.7 mg isorhamnetin 3-O-glucoside-7-O-rhamnoside; - 1.5 ± 0.9 mg quercetin 3-Orutinoside; - 1.6 ± 0.4 mg quercetin 3-O-glucoside; - 5.1 ± 0.8 mg isorhamnetin 3-O-rutinoside; - 2.4 ± 0.4 mg isorhamnetin 3-O-glucoside; - 0.3 ± 0.4 mg kaempferol 3-O-rutinoside.	To study the effect of flavonoid-rich sea buckthorn berry on circulating lipid markers associated with CVD risk (total, HDL and LDL cholesterol, triacylglycerols) and CRP.	The consumption of sea buckthorn extract significantly modified the plasma concentration in treated group: ↑ quercetin (3.0 ng mL−1, p = 0.03); ↑ isorhamnetin (3.9 ng mL−1, p < 0.01).	Sea buckthorn extract did not affect serum concentration of any CVD risk factors considered.	[43]
15 healthy volunteers (6 M; 9 F) (mean age 60.8 ± 9.3 years) Duration: 1 week Randomized, controlled, crossover study	Each subject received 5 doses of quercetin-3-O-glucoside: - 0 mg; - 50 mg; - 100 mg; - 200 mg; - 400 mg. Each compound (control or treatment) was provided once in the morning in a cup of coffee.	To determine whether endothelial function, BP and NO were affected in a dose-dependent mode of administration of quercetin-3-O-glucoside.	After the intake of increasing doses of quercetin-3-O-glucoside, was observed: ↑ quercetin dose-dependent plasma concentrations (R2 = 0.52, p < 0.001), ↑ isorhamnetin dose-dependent plasma concentrations (R2 = 0.12, p = 0.005). Baseline: - free quercetin 1.90 ± 1.1 mM; - isorhamnetin 0.99 ± 0.06 mM.	After any intervention, no improvements were observed in: - endothelial function, - BP; - NO production.	[47]
6 healthy subjects (4 M; 2 F) (mean age 34 ± 7 years) Duration: 1 day Randomized placebo-controlled crossover study	Participants were randomly treated with the following: - 150 mg Q-4-G in 5% ethanol; - 300 mg Q-4-G in 5% ethanol; - 5% (v/v) ethanol control drink.	To investigate the effect of the dietary ingestion of quercetin on platelet function (platelet aggregation and platelet collagen-stimulated tyrosine phosphorylation).	Plasma concentrations peaked 30 min after ingestion. Group 150 mg: - Quercetin 4.66 ± 0.77 μM; - Isorhamnetin 0.16 ± 0.05 μM; - Tamarixetin 0.24 ± 0.07 μM; - Total flavonoid 5.07 ± 0.90 μM. Group 300 mg: - Quercetin 9.72 ± 1.38 μM; - Isorhamnetin 0.44 ± 0.07 μM; - Tamarixetin 0.54 ± 0.09 μM (after 45 min); - Total flavonoid 10.66 ± 1.55 μM. These results indicating dose-dependent bioavailability of flavonoid.	After 30 and 120 min since intake of both doses of Q-4-G were inhibited: - platelet aggregation (p = 0.001); - collagen-stimulated tyrosine phosphorylation of TPP (p = 0.001).	[48]
12 healthy men (mean age of 43.2 ± 4.3 years) Duration: acute consumption Randomized, placebo-controlled, crossover trial	Each participant received, in random order, 4 treatments: - 300 mL water (control); - 0.67 mg/mL quercetin; - 0.67 mg/mL epicatechin; - 0.67 mg/mL EGCG.	To evaluate the effects of quercetin and epicatechin on the endothelial function (measuring endothelin-1 and NO production) and oxidative stress (measuring urinary F2-isoprostanes).	Acute treatment with quercetin and epicatechin significantly increased (p < 0.001) the total circulating concentration of each flavonoid (from 0.84 ± 0.39 μmol L−1 to 3.54 ± 1.57 μmol L−1 for quercetin and from and 0.70 ± 0.34 μmol L−1 to 3.57 ± 1.21 μmol L−1 for epicatechin). In urine, concentrations of total quercetin increased from 0.61 ± 0.15 to 2.51 ± 0.65 μmol mmol−1 creatinine and total epicatechin from 0.50 ± 0.28 to 2.62 ± 0.98 μmol mmol−1 creatinine (p < 0.001). Plasma concentrations of EGCG increased from 0.06 ± 0.01 to 0.10 ± 0.01 μmol L−1 (p < 0.05). EGCG was not detected in urine.	EGCG did not affect NO production. Quercetin and epicatechin significantly reduced plasma endothelin-1 concentration (p < 0.05), but only quercetin significantly decreased the urinary endothelin-1 concentration. None of the 3 treatments significantly decreased plasma or urinary F2-isoprostane concentrations.	[49]
15 healthy subjects (9 M; 6 F) (mean age 25.8 ± 5.2 years) Duration: 3 weeks Double blind, randomized, placebo-controlled trial.	Subjects received a capsule containing the following: - Placebo; - 200 mg of quercetin; - 400 mg of quercetin.	To evaluate whether the deconjugation of quercetin-3-O-glucuronide (Q3GA) may improve vasodilator effects of quercetin.	At 2 h post ingestion, plasma levels were as follows: - 200 mg quercetin group: 0.35 μM Q3GA, 0.043 μM quercetin aglycone, 0.008 μM isorhamnetin aglycone, - 400 mg quercetin group: 0.95 μM Q3GA, 0.031 μM quercetin aglycone, 0.035 μM isorhamnetin aglycone. Glucuronides of isorhamnetin were not detected.	After ingestion (2 or 5 h) of both doses, were not changes in systolic and diastolic blood pressure. A time-dependent increase in brachial artery diameter was detected after 400 mg quercetin intake, correlated with the levels of Q3GA mediated by glucuronidase activity.	[50]

CRP, C reactive protein; CVD, cardiovascular disease; BP, blood pressure; FMD, flow-mediated dilatation; FPG, fasting plasma glucose; sBP, systolic blood pressure; HF, high-flavonoid; LF, low flavonoid; LOD, Limit of Detection; EGCG, Epigallocatechin gallate; Q-4-G, quercetin-4-O-β-glucoside; TPP, total platelet proteins.