84 research outputs found
The Metabolic Fate and Bioactivity of Anthocyanins in Humans
Anthocyanins, the class of flavonoid responsible for giving a red hue to many berries, have
been associated with a decreased risk of cardiovascular disease. However, numerous
intervention studies feeding anthocyanin-rich foods report limited (<1%) bioavailability of
the parent anthocyanins in vivo. Due to the instability of anthocyanins at neutral pH, it is
postulated that degradation products and metabolites of anthocyanins may be responsible for
the perceived bioactive effects. The aims of the present thesis were: (1) To model and
establish analytical methods for the extraction and quantification of putative anthocyanin
metabolites in urine, serum and faecal samples. (2) To identify and explore the
pharmacokinetics of anthocyanin metabolites via the analysis of urine, serum and faecal
samples from two human interventions, feeding either (a) 500 mg of isotopically (13C5)
labelled anthocyanin or (b) 500 mg elderberry anthocyanins for 12 wks. (3) To explore the
impact of acute (500 mg) versus chronic (500 mg/day for 12 wks) anthocyanin consumption
on their metabolism and (4) To investigate the anti-inflammatory activity of six anthocyanin
metabolites at physiologically relevant concentrations (0.01 μM to 10 μM) using human
umbilical vein endothelial cells (HUVECs). Following the consumption of 500 mg
elderberry anthocyanins, 28 anthocyanin metabolites were identified in urine and 21 in
plasma, with the phenolic metabolites within plasma identified at 45 fold higher levels than
their parent compounds. Similar results were observed within the 13C-labelled anthocyanin
intervention, where 17 13C-labelled compounds were identified in serum and 31 in urine.
However, chronic consumption of anthocyanins had no impact on the formation of the
metabolites. The cardiovascular bioactivity of anthocyanins may be linked to the antiinflammatory
activity of their metabolites. IL-6 and VCAM-1 are cytokines and adhesion
molecules integral to the initiation and progression of inflammation. In vitro, anthocyanin
metabolites reduced CD40L and TNF-α stimulated expression of the inflammatory markers,
sVCAM-1 and IL-6, indicating that the anti-inflammatory effects of anthocyanins are likely
attributed to their metabolites. In conclusion, the present thesis provides a new
understanding into the metabolism and bioactivity of anthocyanins, which should provide an
informative insight into how the consumption of higher intakes of anthocyanins may
contribute to optimising human health
Anthocyanins do not influence long-chain n-3 fatty acid status:Studies in cells, rodents and humans
Increased tissue status of the long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) is associated with cardiovascular and cognitive benefits. Limited epidemiological and animal data suggest that flavonoids, and specifically anthocyanins, may increase EPA and DHA levels, potentially by increasing their synthesis from the shorter-chain n-3 PUFA, α-linolenic acid. Using complimentary cell, rodent and human studies we investigated the impact of anthocyanins and anthocyanin-rich foods/extracts on plasma and tissue EPA and DHA levels and on the expression of fatty acid desaturase 2 (FADS2), which represents the rate limiting enzymes in EPA and DHA synthesis. In experiment 1, rats were fed a standard diet containing either palm oil or rapeseed oil supplemented with pure anthocyanins for 8 weeks. Retrospective fatty acid analysis was conducted on plasma samples collected from a human randomized controlled trial where participants consumed an elderberry extract for 12 weeks (experiment 2). HepG2 cells were cultured with α-linolenic acid with or without select anthocyanins and their in vivo metabolites for 24 h and 48 h (experiment 3). The fatty acid composition of the cell membranes, plasma and liver tissues were analyzed by gas chromatography. Anthocyanins and anthocyanin-rich food intake had no significant impact on EPA or DHA status or FADS2 gene expression in any model system. These data indicate little impact of dietary anthocyanins on n-3 PUFA distribution and suggest that the increasingly recognized benefits of anthocyanins are unlikely to be the result of a beneficial impact on tissue fatty acid status
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Pelargonidin-3-O-glucoside and its metabolites have modest anti-inflammatory effects in human whole blood cultures
This study hypothesized that the predominant strawberry anthocyanin, pelargonidin-3-O-glucoside (Pg-3-glc), and three of its plasma metabolites (4-hydroxybenzoic acid, protocatechuic acid and phloroglucinaldehyde [PGA]) would affect phagocytosis, oxidative burst and the production of selected pro- and anti-inflammatory cytokines in a whole blood culture model. For the assessment of phagocytosis and oxidative burst activity of monocytes and neutrophils, whole blood was pre-incubated in the presence or absence of the test compounds at concentrations up to 5 μM, followed by analysis of phagocytic and oxidative burst activity using commercially available test kits. For the cytokine analysis, diluted whole blood was stimulated with lipopolysaccharide in the presence or absence of the test compounds at concentrations up to 5 μM. Concentrations of selected cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, IL-6, IL-8 and IL-10) were determined using a cytometric bead array kit. There were no effects of any of the test compounds on phagocytosis of opsonized or non-opsonized E. coli or on oxidative burst activity. Pg-3-glc and PGA at 0.08 μM increased the concentration of IL-10 (P<0.01 and P<0.001, respectively), but there was no effect on TNF-α, IL-1β, IL-6 and IL-8 and there were no effects of the other compounds. In conclusion, this study demonstrated a lack of effect of these compounds on the opsonization, engulfment and subsequent destruction of bacteria. Pg-3-glc and PGA, at physiologically relevant concentrations, had anti-inflammatory properties; however, effects were modest, only observed at the lowest dose tested and limited to IL-10
Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo:Sulforaphane is protective in the articular Joint
Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis
Adaptation of the Human Gut Microbiota Metabolic Network During the First Year After Birth
Predicting the metabolic behavior of the human gut microbiota in different contexts is
one of the most promising areas of constraint-based modeling. Recently, we presented
a supra-organismal approach to build context-specific metabolic networks of bacterial
communities using functional and taxonomic assignments of meta-omics data. In this
work, this algorithm is applied to elucidate the metabolic changes induced over the
first year after birth in the gut microbiota of a cohort of Spanish infants. We used
metagenomics data of fecal samples and nutritional data of 13 infants at five time
points. The resulting networks for each time point were analyzed, finding significant
alterations once solid food is introduced in the diet. Our work shows that solid food
leads to a different pattern of output metabolites that can be potentially released from
the gut microbiota to the host. Experimental validation is presented for ferulate, a
neuroprotective metabolite involved in the gut-brain axis.IA was supported by a Basque Government predoctoral
grant (PRE_2017_2_0028). SP-B was supported by a Spanish
Government predoctoral grant (FPU14/01192). This manuscript
will form part of the doctoral thesis of SP-B conducted within
the context of the “Nutrition and Food Sciences Programme”
at the University of Granada. This work was supported by
the EU Project STANCE4HEALTH (contract number 816303)
and the Ministry of Economy and Competitiveness of Spain
(BIO2016-77998-R, SAF2009-13032-C02-02, CSD2009-00006
and SAF2012-31187)
Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells
Background: Flavonoids have been implicated in the prevention of cardiovascular disease; however, their mechanisms of action have yet to be elucidated, possibly because most previous in vitro studies have used supraphysiological concentrations of unmetabolized flavonoids, overlooking their more bioavailable phenolic metabolites.
Objective: We aimed to explore the effects of phenolic metabolites and their precursor flavonoids at physiologically achievable concentrations, in isolation and combination, on soluble vascular cellular adhesion molecule-1 (sVCAM-1).
Method: Fourteen phenolic acid metabolites and 6 flavonoids were screened at 1 μM for their relative effects on sVCAM-1 secretion by human umbilical vein endothelial cells stimulated with tumor necrosis factor alpha (TNF-α). The active metabolites were further studied for their response at different concentrations (0.01 μM–100 μM), structure-activity relationships, and effect on vascular cellular adhesion molecule (VCAM)-1 mRNA expression. In addition, the additive activity of the metabolites and flavonoids was investigated by screening 25 unique mixtures at cumulative equimolar concentrations of 1 μM.
Results: Of the 20 compounds screened at 1 μM, inhibition of sVCAM-1 secretion was elicited by 4 phenolic metabolites, of which protocatechuic acid (PCA) was the most active (−17.2%, P = 0.05). Investigations into their responses at different concentrations showed that PCA significantly reduced sVCAM-1 15.2–36.5% between 1 and 100 μM, protocatechuic acid-3-sulfate and isovanillic acid reduced sVCAM-1 levels 12.2–54.7% between 10 and 100 μM, and protocatechuic acid-4-sulfate and isovanillic acid-3-glucuronide reduced sVCAM-1 secretion 27.6% and 42.8%, respectively, only at 100 μM. PCA demonstrated the strongest protein response and was therefore explored for its effect on VCAM-1 mRNA, where 78.4% inhibition was observed only after treatment with 100 μM PCA. Mixtures of the metabolites showed no activity toward sVCAM-1, suggesting no additive activity at 1 μM.
Conclusions: The present findings suggest that metabolism of flavonoids increases their vascular efficacy, resulting in a diversity of structures of varying bioactivity in human endothelial cells
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Orange juice–derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: a randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease
Background: Epidemiological data suggest inverse associations between citrus flavanone intake and cardiovascular disease (CVD) risk. However, insufficient randomized controlled trial (RCT) data limit our understanding of mechanisms by which flavanones and their metabolites potentially reduce cardiovascular (CV) risk factors.
Objective: We examined the effects of orange juice or a dose-matched hesperidin supplement on plasma concentrations of established and novel flavanone metabolites and their effects on CV risk biomarkers in men at moderate CVD risk.
Methods: In an acute, randomized, placebo-controlled crossover trial, 16 fasted participants (aged 51-69 y) received orange juice or a hesperidin supplement (both providing 320 mg hesperidin) or control (all matched for sugar and vitamin C content). At baseline and 5 h post-intake, endothelial function (primary outcome), further CV risk biomarkers (i.e. blood pressure, arterial stiffness, cardiac autonomic function, platelet activation and NADPH oxidase gene expression) and plasma flavanone metabolites were assessed. Prior to each intervention, a diet low in flavonoids, nitrate/nitrite, alcohol and caffeine was followed and a standardized low-flavonoid evening meal was consumed.
Results: Orange juice intake significantly elevated mean (± SEM) plasma concentrations of 8 flavanone (1.75 ± 0.35 µmol/L, P < 0.0001) and 15 phenolic metabolites (13.27 ± 2.22 µmol/L, P < 0.0001) compared with control at 5 h post-consumption. Despite increased plasma flavanone and phenolic metabolite concentrations, CV risk biomarkers were unaltered. Following hesperidin supplement intake, flavanone metabolites were not different to control, suggesting altered absorption/metabolism compared with the orange juice matrix.
Conclusions: Following single-dose flavanone intake within orange juice, we detected circulating flavanone and phenolic metabolites collectively reaching a concentration of 15.20 ± 2.15 µmol/L but observed no effect on CV risk biomarkers. Longer-duration RCTs are required to further examine the previous associations between higher flavanone intakes and improved cardiovascular health and to ascertain the relative importance of food matrix and flavanone-derived phenolic metabolites
Habitual intake of anthocyanins and flavanones and risk of cardiovascular disease in men
Background: Although increased fruit intake reduces cardiovascular disease (CVD) risk, which fruits are most beneficial and what key constituents are responsible are unclear. Habitual intakes of flavonoids, specifically anthocyanins and flavanones, in which >90% of habitual intake is derived from fruit, are associated with decreased CVD risk in women, but associations in men are largely unknown. Objective: We examined the relation between habitual anthocyanin and flavanone intake and coronary artery disease and stroke in the Health Professionals Follow-Up Study. Design: We followed 43,880 healthy men who had no prior diagnosed CVD or cancer. Flavonoid intake was calculated with the use of validated food-frequency questionnaires. Results: During 24 y of follow-up, 4046 myocardial infarction (MI) and 1572 stroke cases were confirmed by medical records. Although higher anthocyanin intake was not associated with total or fatal MI risk, after multivariate adjustment an inverse association with nonfatal MI was observed (HR: 0.87; 95% CI: 0.75, 1.00; P = 0.04; P-trend = 0.098); this association was stronger in normotensive participants (HR: 0.81; 95% CI: 0.69, 0.96; P-interaction = 0.03). Anthocyanin intake was not associated with stroke risk. Although flavanone intake was not associated with MI or total stroke risk, higher intake was associated with a lower risk of ischemic stroke (HR: 0.78; 95% CI: 0.62, 0.97; P = 0.03, P-trend = 0.059), with the greatest magnitude in participants aged ≥65 y (P-interaction = 0.04). Conclusions: Higher intakes of fruit-based flavonoids were associated with a lower risk of nonfatal MI and ischemic stroke in men. Mechanistic studies and clinical trials are needed to unravel the differential benefits of anthocyanin- and flavanone-rich foods on cardiovascular health
Bioavailability of wild blueberry (poly)phenols at different levels of intake
BACKGROUND: Data from human intervention studies have highlighted potential cardiovascular benefits of blueberry (poly)phenols. However, such biological effects are dependent on their bioavailability and, as such, information on the absorption, metabolism and excretion of such compounds is necessary. OBJECTIVE: To investigate whether the bioavailability of blueberry (poly)phenols is intake-dependent, a group of nine healthy volunteers consumed three wild blueberry drinks containing 766mg (lower), 1278mg (medium) and 1791mg (higher) total (poly)phenols, corresponding to 34, 56 and 80g, respectively, freeze-dried blueberry powder. METHODS: Plasma levels of (poly)phenol metabolites were assessed at baseline and at 1, 2, 4 and 6 hours post-consumption, using UPLC-Q-TOF mass spectrometry. RESULTS: Twenty-three phenolic acid metabolites were quantified in plasma after blueberry consumption. Increases in plasma (poly)phenol metabolites were observed in all the interventions tested. The area under the curve of the concentration over time (AUC) significantly increased when comparing the lower and higher (poly)phenol interventions. Linear dose-response regressions were obtained for 11 metabolites, while the plasma concentration of the remaining 12 metabolites was not affected by increasing amounts of (poly)phenols in the blueberry interventions. CONCLUSION: Absorption and metabolism of blueberry (poly)phenols are not exclusively intake-dependent at the amounts tested, evidencing a complex metabolic fate of these compounds.</p
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