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Potential health benefits of blueberries may be due to vascular effects of anthocyanins which predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation (FMD). The effects were similar to those of blueberries containing similar amounts of anthocyanins while control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month blueberry consumption increased FMD and lowered 24hambulatory-systolic-blood-pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 17 correlated with acute and chronic FMD improvements, respectively. Injection of these metabolites improved FMD in mice. Daily blueberry consumption led to differential expression (>1.2fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs.

Coffee is a relatively rich source of chlorogenic acids (CGA), which, as other polyphenols, have been postulated to exert preventive effects against CVD and type 2 diabetes. As a considerable proportion of ingested CGA reaches the large intestine, CGA may be capable of exerting beneficial effects in the large gut. Here, we utilise a stirred, anaerobic, pH-controlled, batch culture fermentation model of the distal region of the colon in order to investigate the impact of coffee and CGA on the growth of the human faecal microbiota. Incubation of coffee samples with the human faecal microbiota led to the rapid metabolism of CGA (4 h) and the production of dihydrocaffeic acid and dihydroferulic acid, while caffeine remained unmetabolised. The coffee with the highest levels of CGA (P, 0·05, relative to the other coffees) induced a significant increase in the growth of Bifidobacterium spp. relative to the control vessel at 10 h after exposure (P, 0·05). Similarly, an equivalent quantity of CGA (80·8 mg, matched with that in high-CGA coffee) induced a significant increase in the growth of Bifidobacterium spp. (P, 0·05). CGA alone also induced a significant increase in the growth of the Clostridium coccoides -Eubacterium rectale group (P,0·05). This selective metabolism and subsequent amplification of specific bacterial populations could be beneficial to host health.

The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2 = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

Dietary nitrate (found in green leafy vegetables such as rocket and in beetroot) is now recognized to be an important source of nitric oxide, via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. Having described key twists and turns in the elucidation of the pathway and the underlying mechanisms in Part I, we explore the more recent developments which have served to confirm mechanisms, extend our understanding, and discover new properties and potential therapeutic uses of the pathway in Part II. Even the established dependency on low oxygen states for bioactivation of nitrite has recently been challenged. Dietary nitrate appears to be an important component of 'healthy diets', such as the DASH diet to lower blood pressure and the Mediterranean diet, with its potential to lower cardiovascular risk, possibly through beneficial interactions with a range of other constituents. The World Cancer Research Foundation report strong evidence for vegetables including spinach and lettuce (high nitrate-containing) decreasing cancer risk (mouth, pharynx, larynx, oesophagus and stomach), summarized in a 'NitrateCancer Risk Veg- Table'. The European Space Agency recommends that beetroot, lettuce, spinach and rocket (high-nitrate vegetables) are grown to provide food for long-term space missions. Nitrate, an ancient component of rocket fuel, could support sustainable crops for healthy humans. IntroductionIn Part I we described how the nitrate-nitrite-NO pathway was initially established. In Part II we address the more recent developments that have served to confirm mechanisms, extend our understanding, and discover new properties and potential therapeutic uses of the pathway. Is nitrate protective in ischaemia-reperfusion injury (IRI)?Having previously discovered the protective effects of inorganic nitrite in a model of ischaemia-reperfusion injury (IRI) in the isolated perfused rat heart (Langendorff preparation)

Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects. RESEARCH DESIGN AND METHODS The European Society of Cardiology's European Observational Research Programme (ESC EORP) European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V (2016-2017) included 8,261 CAD patients, aged 18-80 years, from 27 countries. If the glycemic state was unknown, patients underwent an oral glucose tolerance test (OGTT) and measurement of glycated hemoglobin A 1c. Lifestyle, risk factors, and pharmacological management were investigated. RESULTS A total of 2,452 patients (29.7%) had known diabetes. OGTT was performed in 4,440 patients with unknown glycemic state, of whom 41.1% were dysglycemic. Without the OGTT, 30% of patients with type 2 diabetes and 70% of those with IGT would not have been detected. The presence of dysglycemia almost doubled from that selfreported to the true proportion after screening. Only approximately one-third of all coronary patients had completely normal glucose metabolism. Of patients with known diabetes, 31% had been advised to attend a diabetes clinic, and only 24% attended. Only 58% of dysglycemic patients were prescribed all cardioprotective drugs, and use of sodium-glucose cotransporter 2 inhibitors (3%) or glucagon-like peptide 1 receptor agonists (1%) was small. CONCLUSIONS Urgent action is required for both screening and management of patients with CAD and dysglycemia, in the expectation of a substantial reduction in risk of further cardiovascular events and in complications of diabetes, as well as longer life expectancy.

Dietary nitrate (found in green leafy vegetables, such as rocket, and in beetroot) is now recognized to be an important source of nitric oxide (NO), via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. While this pathway may now seem obvious, its realization followed a rather tortuous course over two decades. Early steps included the discovery that nitrite was a source of NO in the ischaemic heart but this appeared to have deleterious effects. In addition, nitrate-derived nitrite provided a gastric source of NO. However, residual nitrite was not thought to be absorbed systemically. Nitrite was also considered to be physiologically inert but potentially carcinogenic, through N-nitrosamine formation. In Part 1 of a two-part Review on the nitrate-nitrite-NO pathway we describe key twists and turns in the elucidation of the pathway and the underlying mechanisms. This provides the critical foundation for the more recent developments in the nitrate-nitrite-NO pathway which are covered in Part 2.

The National Institutes of Health (NIH) on ClinicalTrials.govNCT01813981 and NCT01772784.