Identification of (poly)phenol treatments that modulate the release of pro-inflammatory cytokines by human lymphocytes

Diets rich in fruits and vegetables (FV), which contain (poly)phenols, protect against age-related inflammation and chronic diseases. T-lymphocytes contribute to systemic cytokine production and are modulated by FV intake. Little is known about the relative potency of different (poly)phenols in modulating cytokine release by lymphocytes. We compared thirty-one (poly)phenols and six (poly)phenol mixtures for effects on pro-inflammatory cytokine release by Jurkat T-lymphocytes. Test compounds were incubated with Jurkat cells for 48 h at 1 and 30 µm, with or without phorbol ester treatment at 24 h to induce cytokine release. Three test compounds that reduced cytokine release were further incubated with primary lymphocytes at 0·2 and 1 µm for 24 h, with lipopolysaccharide added at 5 h. Cytokine release was measured, and generation of H2O2 by test compounds was determined to assess any potential correlations with cytokine release. A number of (poly)phenols significantly altered cytokine release from Jurkat cells (P<0·05), but H2O2 generation did not correlate with cytokine release. Resveratrol, isorhamnetin, curcumin, vanillic acid and specific (poly)phenol mixtures reduced pro-inflammatory cytokine release from T-lymphocytes, and there was evidence for interaction between (poly)phenols to further modulate cytokine release. The release of interferon-γ induced protein 10 by primary lymphocytes was significantly reduced following treatment with 1 µm isorhamnetin (P<0·05). These results suggest that (poly)phenols derived from onions, turmeric, red grapes, green tea and açai berries may help reduce the release of pro-inflammatory mediators in people at risk of chronic inflammation

Regular Consumption of a Flavanol-rich Chocolate can Improve Oxidant Stress in Young Soccer Players

The consumption of a diet rich in certain flavonoids, including the flavanol sub-class, has been associated with a reduced risk for vascular disease. We evaluated the effects of the regular consumption (14 d) of a flavanol-containing milk chocolate (FCMC) or cocoa butter chocolate (CBC) on variables related to vascular disease risk, oxidative stress and physical activity. Twenty-eight free-living, young (18–20 years old) male soccer players consumed daily 105 g of FCMC (168 mg of flavanols) or CBC (<5 mg of flavanols), as part of their normal diet. The consumption of FCMC was significantly associated with a decrease in diastolic blood pressure (-5 mm Hg), mean blood pressure (-5 mm Hg), plasma cholesterol (-11%), LDL-cholesterol (-15%), malondialdehyde (-12%), urate (-11%) and lactate dehydrogenase (LDH) activity (-11%), and an increase in vitamin E/cholesterol (+12%). No relevant changes in these variables were associated with CBC consumption. No changes in the plasma levels of (-)-epicatechin were observed following analysis of fasting blood samples. In conclusion, FCMC consumption was associated with changes in several variables often associated with cardiovascular health and oxidant stress. The presence of significant quantities of flavanols in FCMC is likely to have been one of the contributing factors to these results

Data of oxygen- and pH-dependent oxidation of resveratrol

AbstractWe show here if under physiologically relevant conditions resveratrol (RSV) remains stable or not. We further show under which circumstances various oxidation products of RSV such as ROS can be produced. For example, in addition to the widely known effect of bicarbonate ions, high pH values promote the decay of RSV. Moreover, we analyse the impact of reduction of the oxygen partial pressure on the pH-dependent oxidation of RSV. For further interpretation and discussion of these focused data in a broader context we refer to the article “Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress” (Plauth et al., in press) [1]

Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress

AbstractResveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general <50µM), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61mVmmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells. In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress

Metabolic Response to Decaffeinated Green Tea Extract during Rest and Moderate-Intensity Exercise

We previously reported that a 7 day ingestion of caffeinated green tea extract (cGTE) induced marked metabolic differences during rest and exercise. Here, we report the metabolic effects of 1, 7, and 28 day ingestions of decaffeinated GTE (dGTE). In this crossover placebo-controlled study, 19 healthy males ingested dGTE or placebo (PLA) for 28 days, separated by a 28 day wash-out period. On days 1, 7, and 28, participants completed a 30 min cycling exercise 2 h after the ingestion of dGTE or PLA. Blood samples were collected at rest (<i>t</i> = 0 and 120 min) and during exercise (<i>t</i> = 150 min). Plasma was analyzed using untargeted four-phase metabolite profiling and targeted profiling of catecholamines and catechins. dGTE abolished several metabolic effects when compared to our previous study with cGTE. However, following 7 and 28 day dGTE ingestions, increases in 3-hydroxybutyrate, a metabolic marker of fat oxidation, were observed at <i>t</i> = 0 min. dGTE ingestion did not induce significant acute or acute-on-chronic effects on endogenous metabolites just prior to and during exercise

Acute Effects of Green Tea Extract Intake on Exogenous and Endogenous Metabolites in Human Plasma

The acute effects of green tea extract (GTE) on plasma metabolites in vivo are largely unknown. In this parallel, double-blind study, the transient changes in total and free concentrations of catechins were measured in plasma from healthy males following the consumption of a single GTE dose (559.2 mg total catechins, 120.4 mg caffeine). Furthermore, the acute effects on endogenous metabolites were assessed 2 h after GTE intake using four-phase metabolite profiling. The ratios of the catechin concentrations in plasma to those in the GTE followed the order ECG/CG > EC > GCG > EGCG > EGC > C > GC. The gallated catechins EGCG, CG/ECG, GC, and GCG were also present in their free form. Sixteen out of 163 mostly endogenous metabolites were affected by acute GTE ingestion, when compared to placebo. These included caffeine, salicylate, hippurate, taurine, 3,4-dihydroxyphenylethylene-glycol, serotonin, some cholesterylesters, fatty acids, triglycerides, and sphingosines. Our results on the exogenous metabolites largely confirm previous studies, while our findings on the endogenous metabolites are novel and may suggest specific biological targets

Metabolic conversion of dietary flavonoids alters their anti-inflammatory and antioxidant properties

The notion that dietary flavonoids exert beneficial health effects in humans is often based on in vitro studies using the glycoside or aglycone forms of these flavonoids. However, flavonoids are extensively metabolized in humans, resulting in the formation of glucuronide, methyl, and sulfate derivatives, which may have different properties than their parent compounds. The goal of this study was to investigate whether different chemical modifications of the same flavonoid molecule affect its biological and antioxidant activities. Hence, we studied the anti-inflammatory effects of several major human metabolites of quercetin and (-)-epigallocatechin-3-O-gallate (EGCG) by assessing their inhibitory effects on tumor necrosis factor a (TNF alpha)-induced protein expression of cellular adhesion molecules in human aortic endothelial cells (HAEC). HAEC were incubated with 1-30 mu M quercetin, 3'- or 4'-O-methyl-quercetin, quercetin-3-O-glucuronide, and quercetin-3'-O-sulfate or 20-100 mu M EGCG, 4 ''-O-methyl-EGCG, and 4',4 ''-di-O-methyl-EGCG, prior to coincubation with 100 U/ml of TNF alpha. 3'-O-Methyl-quercetin, 4'-O-methyl-quercetin, and their parent aglycone compound, quercetin, all effectively inhibited expression of intercellular adhesion molecule-1 (ICAM-1) with IC50 values (concentration required for 50% inhibition) of 8.0, 5.0, and 4.4 mu M, respectively: E-selectin expression was suppressed to a somewhat lesser but still significant degree by all three compounds, whereas vascular cell adhesion molecule-1 (VCAM-1) was not affected. In contrast, quercetin-3-O-glucuronide (20-100 mu M), quercetin-3'-O-sulfate (10-30 mu M), and phenolic acid metabolites of quercetin (20-100 mu M) did not inhibit adhesion molecule expression. 4',4 ''-Di-O-methyl-EGCG selectively inhibited ICAM-1 expression with an IC50 value of 94 mu M, whereas EGCG (20-60 mu M) and 4 ''-O-methyl-EGCG (20-100 mu M) had no effect. The inhibitory effects of 3'-O-methyl-quercetin and 4',4 ''-di-O-methyl-EGCG on adhesion molecule expression were not related either to inhibition of NF-kappa B activation or to their antioxidant reducing capacity. Our data indicate that flavonoid metabolites have different biological and antioxidant properties than their parent compounds, and suggest that data from in vitro studies using nonmetabolites of flavonoids are of limited relevance in vivo. (C) 2011 Elsevier Inc. All rights reserve