Dietary supplementation with strawberry induces marked changes in the composition and functional potential of the gut microbiome in diabetic mice.

Gut microbiota contributes to the biological activities of berry anthocyanins by transforming them into bioactive metabolites, and anthocyanins support the growth of specific bacteria, indicating a two-way relationship between anthocyanins and microbiota. In the present study, we tested the hypothesis that strawberry supplementation alters gut microbial ecology in diabetic db/db mice. Control (db/+) and diabetic (db/db) mice (7 weeks old) consumed standard diet or diet supplemented with 2.35% freeze-dried strawberry (db/db + SB) for 10 weeks. Colon contents were used to isolate bacterial DNA. V4 variable region of 16S rRNA gene was amplified. Data analyses were performed using standardized pipelines (QIIME 1.9 and R packages). Differences in predictive metagenomics function were identified by PICRUSt. Principal coordinate analyses confirmed that the microbial composition was significantly influenced by both host genotype and strawberry consumption. Further, α-diversity indices and ß-diversity were different at the phylum and genus levels, and genus and operational taxonomical units levels, respectively (P<.05). At the phylum level, strawberry supplementation decreased the abundance of Verrucomicrobia in db/db + SB vs. db/db mice (P<.05). At the genus level, db/db mice exhibited a decrease in the abundance of Bifidobacterium, and strawberry supplementation increased Bifidobacterium in db/db + SB vs. db/db mice (P<.05). PICRUSt revealed significant differences in 45 predicted metabolic functions among the 3 groups. Our study provides evidence for marked changes in the composition and functional potential of the gut microbiome with strawberry supplementation in diabetic mice. Importantly, strawberry supplementation increased the abundance of beneficial bacteria Bifidobacterium which play a pivotal role in the metabolism of anthocyanins.

γ-Carboxyethyl hydroxychroman, a metabolite of γ-tocopherol, preserves nitric oxide bioavailability in endothelial cells challenged with high glucose.

Endothelial dysfunction occurs when there are imbalances between factors that regulate the synthesis and degradation of nitric oxide (NO•), and has been reported in patients with hyperglycemia and insulin resistance. We reported that supplementation with γ-tocopherol (γ-T) in humans limits impairments in endothelial function otherwise induced by postprandial hyperglycemia. Given the rapid metabolism of γ-T into γ-carboxyethyl hydroxychroman (γ-CEHC), we hypothesized that the vasoprotective activities of γ-T could be attributed to its metabolite γ-CEHC. To test this, human aortic endothelial cells (HAECs) treated with 0 (vehicle control) or 3 µM γ-CEHC for 24 h prior to incubation with normal (5 mM) or high (25 mM) glucose for 48 h. High-glucose increased levels of uncoupled endothelial nitric oxide synthase (eNOS) as evidenced by reduced ( p < 0.05) eNOS dimer:monomer. High glucose also prevented insulin-stimulated increases in p-AktSer473: total Akt, p-eNOSSer1177: total eNOS, and NO• production. These adverse changes were accompanied by increased ( p < 0.05) reactive oxygen species and mRNA expression of inflammatory mediators (VCAM-1, E-selectin, IL-8). However, each deleterious response evoked by high glucose was prevented when HAECs were incubated with γ-CEHC prior to the high glucose challenge. Taken together, our data support the hypothesis that vascular protection provided by γ-T in vivo may be elicited through the bioactivity of its metabolite, γ-CEHC. Furthermore, it is possible that the antioxidant and anti-inflammatory activities of γ-CEHC may mediate this protective activity.

Acute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: nitric oxide.

Quercetin (Q) reduces blood pressure (BP) in hypertensive individuals, but the mechanism is unknown. We hypothesized that acute Q aglycone administration reduces BP in hypertensive men by decreasing angiotensin-converting enzyme (ACE) activity and/or by lowering the ratio of circulating endothelin-1 (ET-1) to nitric oxide and that these alterations will improve endothelial function. Using a double-blind, placebo-controlled, crossover design Q or placebo (P) was administered to normotensive men (n = 5; 24 ± 3 years; 24 ± 4 kg/m(2)) and stage 1 hypertensive men (n = 12; 41 ± 12 years; 29 ± 5 kg/m(2)). As anticipated, ingesting 1095 mg Q did not affect BP in normotensive men but resulted in maximal plasma Q (2.3 ± 1.8 µmol/L) at approximately 10 hours, with Q returning to baseline concentrations (0.4 ± 0.08 µmol/L) by approximately 17 hours. Results from this study provided rationale for determining end-points of interest in stage 1 hypertensive men 10 hours after ingesting Q or P. In stage 1 hypertensive individuals, plasma Q increased(0.6 ± 0.4 vs. 0.05 ± 0.02 µmol/L), and mean BP decreased (103 ± 7 vs 108 ± 7 mm Hg; both P < .05) 10 hours after Q vs P, respectively. Plasma ACE activity (16 ± 10 vs 18 ± 10 U/L), ET-1 (1.6 ± 0.9 vs 1.6 ± 0.8 pg/ml), nitrites (57.0 ± 3.0 vs 56.7 ± 2.6 µmol/L), and brachial artery flow-mediated dilation (6.2 ± 2.9 vs. 6.3 ± 3.2%) were unaffected by Q. A single dose of Q aglycone reduces BP in hypertensive men through a mechanism that is independent of changes in ACE activity, ET-1, or nitric oxide bioavailability and without affecting vascular reactivity.

A quercetin supplemented diet does not prevent cardiovascular complications in spontaneously hypertensive rats.

Diets high in quercetin may decrease the risk of developing cardiovascular disease. We tested whether quercetin delays or reduces the severity of hypertension, vascular dysfunction, or cardiac hypertrophy in the spontaneously hypertensive rat (SHR). Normotensive, 5-wk-old SHR consumed standard (n = 18) or quercetin-supplemented diet (1.5 g quercetin/kg diet, n = 22, SHR-Q) for 5 or 11 wk. Wistar Kyoto rats (WKY, n = 19), fed a standard diet, served as controls. At 16 wk, plasma quercetin, measured by HPLC, was 2.09 +/- 0.33 micromol/L in SHR-Q and below assay detection limits in SHR and WKY rats. At 10 and 16 wk of age, arterial blood pressure and heart weight:body weight were not different between SHR and SHR-Q. At 16 wk, cardiac function (echocardiography), vascular morphology (hematoxylin and eosin staining of aortae), and resistance and conductance vessel reactivity (wire myography) was unchanged in SHR vs. SHR-Q. Thus, a quercetin-supplemented diet does not delay the onset or lessen the severity of cardiovascular complications that develop in SHR. These findings contrast with previous reports of cardiovascular protection when quercetin was delivered via oral gavage. To determine whether the efficacy of quercetin depends on its method of delivery, 15-wk-old SHR were given quercetin (10 mg/kg) once daily via oral gavage for 4 consecutive days. Arterial blood pressure (mm Hg) was lower in gavaged SHR (148 +/- 5) than in SHR-Q (162 +/- 2, P < 0.02) and SHR (168 +/- 3, P < 0.001). These data suggest that mode of delivery is a critical determinant in whether quercetin provides cardiovascular benefits.

Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction.

Quercetin (Q), a flavonoid found in berries and onions, can reduce blood pressure in hypertensive animals and inhibit signal transduction pathways in vitro that regulate cardiac hypertrophy. We hypothesized that quercetin could prevent cardiovascular complications in rats with abdominal aortic constriction (AAC). Rats consumed standard or Q-supplemented chow (1.5 g Q/kg chow) for 7 days before AAC or sham surgery (SHAM, n = 15; AAC, n = 15; SHAMQ, n = 15; AACQ, n = 14). Fourteen days after surgery, plasma and liver Q concentrations were elevated (P < 0.05) and hepatic lipid oxidation was reduced (P < 0.05) in Q-treated versus untreated rats. Carotid arterial blood pressure and cardiac hypertrophy were attenuated (P < 0.05), and cardiac protein kinase C betaII translocation was normalized (P < 0.05) in AACQ versus AAC. Expression of cardiac beta-myosin heavy-chain mRNA was also reduced in AACQ versus AAC (P < 0.05). However, extracellular regulated kinase 1/2 phosphorylation was similar in AAC versus AACQ. The level of aortic endothelial dysfunction (wire myography) was also similar between AAC and AACQ, in spite of reduced aortic thickening in AACQ. Importantly, Q-treated rats did not show any deleterious changes in myocardial function (echocardiography). Our data supports an antihypertensive and antihypertrophic effect of Q in vivo in the absence of changes concerning vascular and myocardial function.