Table 5.

Stilbenes’, isoflavones’, and flavanones’ beneficial effects and bioavailability in human subjects.

Cohort and Study Details	Phenols Intake	Aim	Bioavailability Data	Outcome	Reference
Stilbenes
60 subjects (9 M; 51 F) (mean age: 20.52 years) Duration: 28 days Randomized, double-blind, placebo-controlled, parallel-groups study	500 mg/day of pure trans-resveratrol (also containing 10 mg of piperine/capsule) or a placebo.	To evaluate the effect of resveratrol on cognitive performance (measured as serial subtractions, rapid visual information processing, 3 Back test), mood, sleep quality and cerebral blood flow (CBF).	Resveratrol 3-O-sulfate was the predominant metabolite in all volunteers, contributing 73–77% of total metabolites, followed by resveratrol 4′ glucuronide and 3′ glucuronide. Total resveratrol metabolites increased in plasma from 3 to 13 μM 110 min after administration.	Although stilbene metabolite levels increase in plasma, supplementing with 500 mg of resveratrol for 28 days did not improve cognitive function.	[68]
22 healthy subjects (4 M; 20 F) (mean age: 20.17 years) Duration: 7 days Randomized, double-blind, placebo-controlled, crossover study	Subjects received the following treatments: - inert placebo; - 250 mg trans-resveratrol; - 500 mg trans-resveratrol;	To evaluate the effects of oral resveratrol on cognitive performance and CBF. In a separate group (n = 9) was investigated plasma levels of resveratrol and its conjugates after the intake of the same treatments.	Resveratrol sulfate and glucuronide were the main metabolites and reached a peak plasma concentration at 90 min after both 250 and 500 mg supplementation. As regards unmetabolized resveratrol, 90 min after both supplementations, reached low concentrations, peaking at 5.65 and 14.4 ng mL−1, respectively.	CBF increased in a dose-dependent fashion of resveratrol intake during task performance. No changes in cognitive function were registered.	[69]
Isoflavones
10 overweight or obese men (mean age: 56.2 ± 6.18 years) Duration: acute consumption Randomized, double-blind, placebo-controlled, crossover study	Subjects consumed a high-fat, high-fructose breakfast with 4 dietary supplementations: - Placebo: fish oil placebo and isoflavone placebo; - FO: fish oil and isoflavone placebo; - ISO: fish oil placebo and isoflavones; - FO + ISO: fish oil and isoflavones. The soy isoflavone supplements provided 150 mg glycoside isoflavones (eq. to 96 mg aglycone form) in proportions of 1.05/1.0/0.29 for genistein/daidzein/glycitein. Fish oil supplement (1 g of refined fish oil concentrate) providing 0.4 g EPA and 0.2 g DHA.	To evaluate the effect of acute supplementation with fish oil (n-3), PUFA, soy isoflavones, and their combination on postprandial serum triglycerides (TG) and oxidative biomarkers in a proatherogenic high-fat, high-fructose meal.	At 4 h, postprandially serum concentration was as follows: - Genistein ISO: 1.027 ± 0.122 μmol L−1, FO + ISO: 1.185 ± 0.079 μmol L−1; - Daidzein ISO: 0.838 ± 0.096 μmol L−1, FO + ISO: 1.017 ± 0.046 μmol L−1.	The high-fat, high-fructose meal significantly increased serum total FA and TG without affecting oxidative stress biomarkers. Serum TG and oxidative stress biomarkers did not differ between treatments. The FO and ISO were bioavailable but did not reduce the postprandial rise in serum TG. Neither the study meal nor the FO or ISO induced significant changes in oxidative stress.	[71]
78 postmenopausal osteopenic women (mean age: 61.85 ± 1.03 years) Duration: 12 months Double-blind, parallel design, placebo-controlled trial	Participants received supplementation: 1.2 g/day calcium, 0.55 g/day magnesium, 0.025 g/day calcitriol, and a red clover extract (0.06 g/day isoflavone aglycones and probiotics) or a placebo.	To determine the beneficial effects of a bioavailable isoflavone and probiotic treatment in postmenopausal osteopenia.	After 12 month, isoflavone concentration in the treated group was 3.933 μg mL−1 (median), significantly higher from baseline (p = 0.0094) (compared with the control group, where median values were 2.323 μg mL−1).	Treatments with red clover extract: ↓ BMD loss, ↓ plasma concentrations of collagen type 1 crosslinked C-telopeptide (p < 0.05).	[72]
237 women (mean age: 53 ± 3 years) Duration: 12 months Randomized, double-blind, placebo-controlled, parallel, multicenter trial (including the Netherlands, Italy and France)	Subjects, during their habitual diet and lifestyle, consumed 110 mg/day isoflavone aglycones or control.	To evaluate whether bone metabolism and mineral density, and hormonal conditions were affected by chronic consumption of isoflavone-enriched foods.	↑ isoflavones plasma levels in treated group. Both genistein and daidzein were higher in the Netherlands (1522 ± 1136.2 nmol L−1 and 338.2 ± 261.3 nmol L−1, respectively) than in France (533.4 ± 607.4 nmol L−1 and 92.9 ± 145.8 nmol L−1, respectively) and Italy (541.5 ± 557.6 nmol L−1 and 133.4 ± 188.3 nmol L−1, respectively).	Bone mineral density or biomarkers of bone were not affected by isoflavone-enriched products chronic intake. Hormone concentrations did not differ between the two groups.	[73]
Flavanones
16 men at moderate CVD risk (mean age: 60.6 ± 1.4 years) Duration: acute consumption Randomized, placebo-controlled crossover trial	Participants received 767 mL orange juice or a hesperidin supplement (both providing 320 mg hesperidin and 439 mg vitamin C) or control.	To evaluate the effects of orange juice or a hesperidin supplement on plasma concentrations of flavanone metabolites and their effects on cardiovascular risk biomarkers (blood pressure, endothelial function, central arterial stiffness, cardiac autonomic function, platelet activation, and NADPH oxidase gene expression).	After 5 h from the orange juice intake, significantly increased plasma concentrations of 8 flavanones (1.75 ± 0.35 mmol L−1, p < 0.0001), and 15 other phenolic metabolites (13.27 ± 2.22 mmol L−1, p < 0.0001) were significantly increased. In particular, 47% hesperidin-glucuronide, 15% naringenin-7-O-glucuronide, 14% a second hesperidin-glucuronide, 54% hippuric acid, 15% dihydroferulic acid, 8% dihydroferulic acid–glucuronide, 7% 4-hydroxyphenylacetic acid, and 5% vanillic acid increase were detected.	Effects on CVD risk factor were not observed.	[74]

BMD, bone mineral density; CBF, cerebral blood flow; PUFA, polyunsaturated fatty acids; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; NADPH, nicotinamide adenine dinucleotide phosphate.