Wai Mun Loke

Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction.

Objective—Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (−)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE)−/− gene–knockout mouse. Methods and Results—Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta (P<0.05 versus ApoE−/− control mice). Quercetin significantly reduced aortic F2-isoprostane, vascular superoxide, vascular leukotriene B4, and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion (P<0.05 versus control ApoE−/− mice). Theaflavin showed similar, although less extensive, significant effects. Although (−)-epicatechin significantly reduced F2-isoprostane, superoxide, and endothelin-1 production (P<0.05 versus control ApoE−/− mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (−)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE−/− controls. Conclusion—Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE−/− gene–knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

HDL is the major lipoprotein carrier of plasma F2-isoprostanes

Enhanced oxidative stress is implicated in the development of atherosclerosis in humans and animal models. F2-isoprostanes are formed in vivo via free radical peroxidation of arachidonic acid, and their quantification has allowed assessment of oxidative stress in vivo. F2-isoprostanes associate with lipids, although their distribution in human plasma lipoproteins is unknown. Our aim was to determine the distribution and levels of F2-isoprostanes in lipoproteins isolated from human plasma by ultracentrifugation and fast protein liquid chromatography (FPLC). F2-isoprostanes were significantly higher in HDL compared with LDL or VLDL after isolation by ultracentrifugation or FPLC. Furthermore, HDL3 particles contained elevated levels of F2-isoprostanes compared with HDL2. Platelet activating factor acetylhydrolase (PAF-AH), which hydrolyses esterified F2-isoprostanes from phospholipids, was predominantly associated with LDL. Reduced F2-isoprostanes in LDL may be related to higher PAF-AH activity in LDL. Paraoxonase 1 (PON-1) activity was associated with HDL2 and may be a contributing factor to the lower F2-isoprostanes in HDL2 compared with HDL3. Further studies are required to establish the implications of these findings on HDL function.

A Metabolite Profiling Approach to Identify Biomarkers of Flavonoid Intake in Humans

Flavonoids are phytochemicals that are widespread in the human diet. Despite limitations in their bioavailability, experimental and epidemiological data suggest health benefits of flavonoid consumption. Valid biomarkers of flavonoid intake may be useful for estimating exposure in a range of settings. However, to date, few useful flavonoid biomarkers have been identified. In this study, we used a metabolite profiling approach to examine the aromatic and phenolic profile of plasma and urine of healthy men after oral consumption of 200 mg of the pure flavonoids, quercetin, (-)-epicatechin, and epigallocatechin gallate, which represent major flavonoid constituents in the diet. Following enzymatic hydrolysis, 71 aromatic compounds were quantified in plasma and urine at 2 and 5 h, respectively, after flavonoid ingestion. Plasma concentrations of different aromatic compounds ranged widely, from 0.01 to 10 micromol/L, with variation among volunteers. None of the aromatic compounds was significantly elevated in plasma 2 h after consumption of either flavonoid compared with water placebo. This indicates that flavonoid-derived aromatic compounds are not responsible for the acute physiological effects reported within 2 h in previous human intervention studies involving flavonoids or flavonoid-rich food consumption. These effects are more likely due to absorption of the intact flavonoid. Our urine analysis suggested that urinary 4-ethylphenol, benzoic acid, and 4-ethylbenzoic acid may be potential biomarkers of quercetin intake and 1,3,5-trimethoxybenzene, 4-O-methylgallic acid, 3-O-methylgallic acid, and gallic acid may be potential markers of epigallocatechin gallate intake. Potential biomarkers of (-)-epicatechin were not identified. These urinary biomarkers may provide an accurate indication of flavonoid exposure.

Does Influenza A Infection Increase Oxidative Damage

Considerable data implicate oxidative damage in influenza pathogenesis. We examined temporal changes in oxidative damage using accurate biomarkers in an adult cohort with acute influenza infection and their relationships with clinical parameters. Clinical information and blood samples were collected during their acute illness and 3 months later. A fatigue questionnaire was administered 3 months following influenza infection. Thirty-five patients (mean age, 34 years) with polymerase chain reaction-confirmed influenza A infection were included; all patients returned for follow-up assessments. Adjusted levels of plasma F2-isoprostanes, total hydroxyeicosatetraenoic products (HETEs), 7β-hydroxycholesterol and 7-ketocholesterol, serum gamma-glutamyltransferase, and high-sensitivity C-reactive protein (hsCRP) were increased during the acute illness compared with age-matched controls. Despite clinical recovery, levels of these biomarkers remained higher at month 3 compared with controls. A proportion of patients had persistent symptoms such as fatigue (23%), myalgia (14%), and arthralgia (11%) at month 3. Patients with significant fatigue had higher baseline levels of plasma F2-isoprostanes, F4-neuroprostanes, and total HETEs compared to those without fatigue. By contrast, patients with persistent arthralgia and myalgia had higher baseline levels of serum hsCRP compared to those without these symptoms. Our observations lead to the hypothesis that oxidative damage participates in the pathogenesis of influenza infection and postinfectious fatigue.