Volume 57, Issue 5 pp. 784-801

Review

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Effect of flavonoids on circulating levels of TNF-α and IL-6 in humans: A systematic review and meta-analysis

Ilaria Peluso,

Ilaria Peluso

Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Rome, Italy

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Anna Raguzzini,

Anna Raguzzini

Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Rome, Italy

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Mauro Serafini,

Corresponding Author

Mauro Serafini

Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Rome, Italy

Correspondence: Dr. Mauro Serafini, Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Via Ardeatina, 546, 00178 Rome, Italy

E-mail:[email protected]

Fax: +39-0651494550

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Ilaria Peluso,

Ilaria Peluso

Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Rome, Italy

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Anna Raguzzini,

Anna Raguzzini

Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Rome, Italy

Search for more papers by this author

Mauro Serafini,

Corresponding Author

Mauro Serafini

Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Rome, Italy

Correspondence: Dr. Mauro Serafini, Agricultural Research Council (CRA), Ex National Institute for Food and Nutrition Research (INRAN), Via Ardeatina, 546, 00178 Rome, Italy

E-mail:[email protected]

Fax: +39-0651494550

Search for more papers by this author

First published: 08 March 2013

https://doi.org/10.1002/mnfr.201200721

Citations: 70

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Abstract

Epidemiological or in vitro evidence suggests a potential role for flavonoids as anti-inflammatory agents; we investigated the effect of flavonoids-rich foods or supplements on tumor necrosis factor- alpha (TNF-α) and interleukin-6 (IL-6) in long-term placebo-controlled human intervention trials. From 110 human intervention studies selected (MEDLINE, EMBASE, CHORANE, and FSTA databases), 32 long-term placebo-controlled trials were suitable for meta-analysis. After sensitivity analysis, seven studies imputed of bias were excluded and 25 studies were analyzed (TNF-α, n = 2404; IL-6, n = 2174). Levels of TNF-α decreased after flavonoid consumption in the fixed model only (mean difference (MD) (95% CI): −0.098 (−0.188, –0.009), p = 0.032), but metaregression results showed that neither higher dose, nor a longer duration of intervention were associated with a greater effect size. Subgroup analysis did not reveal any significant effect for quercetin and soy, but other sources (red wine, pomegranate, and tea extracts) showed a significant effect size both in fixed (MD (95% CI): TNF-α −0.449 (−0.619, –0.280), p < 0.001; IL-6 −0.346 (−0.612, –0.079), p = 0.011) and random (MD (95% CI): TNF-α −0.783 (−1.476, –0.090), p = 0.027; IL-6, −0.556 (−1.062, –0.050), p = 0.031) effect models. High-quality placebo-controlled trials are needed in order to identify flavonoids as the active ingredients.

Abbreviations

ApoE: apolipoprotein E
CVD: cardiovascular disease
EGCG: epigallocatechin 3-gallate
IL-6: interleukin-6
MD: mean difference
TNF-α: tumor necrosis factor-alpha

1 Introduction

Chronic low-grade inflammation is a common pathogenetic denominator in many diseases 1-3 and inflammatory markers are significant predictors of mortality in humans 1. Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are important mediators of chronic low-grade systemic inflammation, which plays a central role in several pathologies, such as diabetes, metabolic syndrome, and cardiovascular disease (CVD) 4-6. Besides, these cytokines have been also implicated in complication related to obesity 6, as well as in geriatric 7 and cancer-induced cachexia 8. Therapeutic blockade of IL-6 9 and TNF-α 10 signaling are emerging in clinical management of immune-related inflammatory diseases. Following that, the effect of dietary habit on TNF-α and IL-6 represents an important subject with significant clinical implications.

A large body of evidence suggests a primary role for plant food-based diet in reducing risk of mortality from inflammatory stress-mediated diseases. Studies have suggested an inverse correlation between fruit and vegetable consumption and serum levels of inflammatory markers 11-13. The molecules, contained in foods of plant origin, responsible for the protective action are not known, but flavonoids have been recognized as potential candidates 14, 15. Flavonoids, divided in different subclasses: flavonols (quercetin and kaempferol), flavones (luteolin and apigenin), flavanols (catechins and proanthocyanidins), anthocyanidins, flavanones (naringenin and hespertin), and isoflavones (genistein and daidzein), are widely present in the majority of food of plant origin 16, 17. Flavonoid-rich food intake was significantly and inversely related to TNF-α and IL-6 1, 18, 19. Mounting evidence suggests that flavonoids in vitro inhibit TNF-α 20-22 and IL-6 21, 23 productions. However, evidence in humans are limited and the results are contrasting, mainly due to the fact that only few studies measure flavonoid plasma levels 24. In fact, the health effects of flavonoids depend on their bioavailability, which is low in humans and is affected by several variables, such as intestinal absorption, metabolism by the microflora, intestinal and hepatic metabolism, nature of circulating metabolites, binding to albumin, cellular uptake, accumulation in tissues, and biliary and urinary excretion 17. Thus, the effects observed in vitro may not reflect the in vivo situation and the current knowledge remains limited and inconclusive. Moreover, the large majority of evidence is obtained with nonphysiological concentrations of flavonoids and without considering the nature of the metabolites found in bloodstream 21, 23, 24 compared to the scarce results obtained with metabolites 20, 22. The objective of this meta-analysis was to investigate the effect of flavonoids-rich foods or supplements on the more frequently studied inflammatory cytokines (TNF-α and IL-6). To this aim, a systematic review and meta-analysis of chronic intervention studies with flavonoids or flavonoid-rich foods and circulating concentrations of TNF-α or IL-6 with outcome has been conducted in this work.

2 Methods

2.1 Study selection

We performed a systematic search in the MEDLINE, EMBASE, COCHRANE, and FSTA databases for literature examining the effect of flavonoids or flavonoid-rich foods on TNF-α or IL-6 circulating levels, up to July 2012. The search terms and the limits are depicted in Fig. 1. Given that the aim of present review was to focus on the consumption of food-derived flavonoids, interventions that involved herbal extracts or sylimarin supplements were excluded.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Four-phase flow diagram of systematic review and meta-analysis. Studies are listed in [25–134].

Any study that met the following criteria was included for meta-analysis: studies that appear in an edited journal (peer-review criterion) and are written in English (language criterion), randomized placebo-controlled trials (research criterion), of a duration ≥7 d (duration criterion), focused on the effect of flavonoid-rich food or supplements on TNF-α or IL-6 levels (topic criterion), the plasma levels of cytokine were measured by ELISA before and after placebo and treatment (method criterion). All human chronic studies were included if they met the above criteria regardless of the flavonoids’ source and dose or the healthy status of subjects. First trials were identified through title or abstract. When a title and abstract could not be rejected with certainty, the full text of the article was obtained. Then, based on inclusion and exclusion criteria, eligible studies were included through full text and reviewed by two independent authors (I.P. and A.R.). Discrepancies were resolved by discussion with the third reviewer (M.S.).

Using the search criteria, after exclusion of irrelevant references, a total of 110 intervention studies after flavonoids-rich food and beverages consumption or pure molecules and food extracts administration were identified as suitable and were retrieved for complete review 25-134. Figure 1 depicts the flow of studies in this review and the four-phase diagram of meta-analysis, according to the PRISMA Statement 135. First, of the 110 reviewed, we excluded studies referring to single administration or addressing ex vivo cytokines production. Then, we excluded studies referring to not shown data, nonplacebo-controlled trials, not randomized studies and papers reporting posttreatment but not pretreatment values. Usually, normally distributed data are given as mean ± SD and not normally distributed variables as medians (25–75 percentiles). Thus we excluded studies with data presented as medians, as well as by figures, but retained them for discussion. The remaining 32 studies met our inclusion criteria and could provide data for the analyses. After this first meta-analysis, studies imputed of bias by Trim-and-fill sensitivity analysis (Fig. 2) were excluded and a second meta-analysis was performed on 25 studies, 12 of which reported data on both cytokines, seven only data on TNF-α and eight only data on IL-6. Meta regression and subgroup analysis were also performed on these 25 studies reporting 28 data sets from 19 studies for TNF-α and 28 data sets from 18 studies for IL-6.

2.2 Data extraction and analysis

A data extraction form including quality characteristics was designed for the review (Table 1) and piloted by all of those involved in the meta-analysis (I.P., A.R., and M.S.). All data extraction and quality assessment were performed independently by two reviewers (I.P. and A.R.) to ensure uniformity, and all data were entered by these reviewers, who checked the extracted data and validity criteria against the original published report. Discrepancies were resolved by discussion between the two reviewers and unresolved disagreement was referred to a third reviewer (M.S.).

Table 1. Data extraction form

General checklist		Data extracted		Subgroup and metaregression		Quality score (values between 0–1)
Reference	Year, authors, journal	Controls	Number	Type of intervention	Pure molecule, extract, food, or beveragea	Proper placebo	0.30
Male	Number	Pg/mL before treatment	Mean ± SD/SEM	Dose	Mg/die of flavonoid	Intra and interstudy baseline comparability	0.30
Female	Number	Pg/mL after treatment	Mean ± SD/SEM	Duration	Days	Compliance assessment	0.10
Dropout	%	Treated	Number	Status	Healthy, risk: menopausal, overweight, dislipidemia disease	Dietary record (Food records or food-frequency questionnaires throughout the study)	0.06
Body mass index (BMI)	Mean	Pg/mL before treatment	Mean ± SD/SEM			Food antioxidant intake in subjects selection criteria (Flavonoid-rich food or antioxidant supplement consumption)	0.05
Age	Mean	Pg/mL after treatment	Mean ± SD/SEM			Wash out/run-in period	0.05
Study design	Crossover, parallel	Delta pg/mL	Mean ± SD/SEM			Marker of bioavailability	0.05
						Double blinding	0.05
						No funding support	0.03
						No food donation	0.01

^a Due to the low number of intervention, data are subgrouped in: quercetin, soy, and other sources.

We were interested in the following outcomes or endpoints, pre- and post-IL-6 and TNF-α concentration for both treatment and control. Also other data were extracted to assess each trial's risk of bias and perform a validity assessment as described in Table 1. Considering that restriction to high-quality studies may exclude much information, while inclusion of low-quality studies may bias the summary effect estimate, we assigned a quality score as described in Table 1. Withdrawal was not considered as a bias because in dietary or flavonoid-based intervention, the compliance of subjects is generally due to factors not imputable to treatments or researchers.

For the meta-analysis, we calculated the mean change of plasma concentrations of selected cytokines from baseline to follow-up for each intervention and control group, if not reported, and the SD of delta concentration was estimated as previously described 136. All values were converted to pg/mL, if necessary. If more than one time point for follow-up was reported, we included the value corresponding to the longer treatment. For each study with more than one intervention group, we divided the control group evenly according to the number of intervention groups 137. When the data were presented as SEMs, SD was obtained by multiplying SEM by the square root of the sample size.

Statistical analysis has been performed with MIX software 138 and meta-analyst software 139. Mean difference (MD) and confidence intervals 95% (CI 95%) were calculated by fixed (inverse variance, unequal, small sample corrected) random (DerSimonian & Laird, unequal, small sample corrected) and quality effect (inverse variance, unequal, small sample corrected) models for continuous data. We used the quality score as probability modifier to perform quality effect model analysis, with modifier multiplication as additional weighting scheme with inverse variance as weighting method.

Visual inspection of funnel plots and Egger's weighted regression statistics were used to determine the presence of publication bias. Symmetry or asymmetry of funnel plots was defined through visual examination. In addition, trim-and-fill sensitivity analysis was conducted. Statistical heterogeneity was assessed by using the I², τ², and Q statistics, for fixed, random, and quality models, respectively.

Investigation of sources of heterogeneity will increase both the scientific and the clinical relevance of the results of meta-analyses. Subgroup analysis and metaregression are usual methods to explore heterogeneity of effect. To explore the effects of modifier factors on the primary outcomes, metaregression was performed when at least ten studies were available, while subgrouping was used when data from ≥ three studies and ≥ five interventions were included. These factors were the type of intervention, the participants’ characteristics, the dose and the duration of intervention.

3 Results

3.1 Description of included studies

Studies characteristics and the results of the assessment of risk of bias of the included trials (quality assessment) are shown in Table 2. Average length is 7–730 days and the number of participants in individual trials ranged from 11 to 672. Six studies selected only females and four only males. The remaining trials included percentage of male participants from five to 85. Mean age ranged between 23 and 66 years and mean body mass index between 22 and 40 kg/m². Participant withdrawal rate from the trial was between 0 and 37%.

Table 2. Long-term studies included in the meta-analyses

Reference	Subjects	Study design	Treatment	Days	Bioavailability	Bias	Score	Outcomes
Asghari 2012	Dyslipidemic 45 D12% BMI ≤ 35 Age 53	Randomized, double-blind, parallel	Pomegranate seed oil capsule (800 mg)	28		1. No antioxidant or food consumption in selection criteria 2. No wash out or run in 3. Capsule supplied by Vitane Pharma	0.84	TNF ↓ Baseline levels: TNF-α 12–15 pg/mL
Bae 2009	Rheumatoid arthritis 1M, 19W D37% BMI 22 Age 52	Randomized, double-blind, cross-over	Quercetin (498 mg) + vitamin C 399 mg	28		1. No compliance 2. Vitamin C dosage differs between treatment	0.55	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 3–4 pg/mL IL-6 3–4 pg/mL
Basu 2011a	Obese with metabolic syndrome 27M, 8W D17% BMI 36 Age 43	Randomized, blind, parallel	1. Green tea (928 mg) 2. Green tea extract (870 mg)	56		1. Funding by WhiteWave Foods	0.49	IL-6 ↔ Baseline levels 19–26 μg/L
Basu 2011b	Obese with metabolic syndrome 31W D11% BMI 40 Age 52	Randomized, double-blind, parallel	Cranberry juice (458 mg)	56		1. No wash out or run in 2. No dietary record	0.6	IL-6 ↔ Baseline levels 19–26 μg/L
Beavers 2009	Healthy 31W D6% BMI 26 Age 54	Randomized, blind, parallel	Soy milk (98 mg)	28		1. No wash out or run in	0.86	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 2–4 pg/mL IL-6 2–3 pg/mL
Bogdanski 2012	Obese hypertensive 28M, 28W D0% BMI 33 Age 50	Randomized, double-blind, parallel	Green tea extract (379 mg; 208 mg EGCG)	93		1. No wash out or run in	0.9	TNF ↓ Baseline levels: TNF-α 5.2–5.5 ng/L
Buscemi 2012	High risk of CVD 10M, 9F D0% BMI 32 Age 48	Randomized, single-blind, cross-over	Red orange juice (500 mL/209.5 mg)	7		1. No wash out or run in	0.55	TNF ↓ IL-6 ↓ Baseline levels: TNF-α 100–200 pg/mL IL-6 30–37 pg/mL
Chiva-Blanch 2012	High risk of CVD 67M D8% BMI 29 Age 60	Randomized, cross-over	Red wine (2933 mg) Dealcoholized red wine (2695 mg)	28		1. A unique basal value for both groups	0.6	TNF ↔ IL-6 ↓ Baseline levels: TNF-α 3–7 pg/mL IL-6 2–3 pg/mL
Chu 2011	Metabolic syndrome 41M, 49W D1% BMI 29 Age 51	Randomized, double-blind, parallel	Tea extract (1000 mg)	93		1. No compliance 2. No wash out or run in 3. No dietary record 4. No antioxidant or food consumption in selection criteria	0.39	TNF ↓ IL-6 ↓ Baseline levels: TNF-α 19–25 pg/mL IL-6 25–35 pg/mL
Deibert 2011	Middle aged 35M D12% BMI 27 Age 57	Randomized, parallel	Soy	84		1. No wash out or run in 2. No dietary record 3. No antioxidant or food consumption in selection criteria 4. Funding by Almased Wellness Corp	0.4	IL-6 ↔ Baseline levels: 1–4 pg/mL
Egert 2009	Obese with metabolic syndrome 42M, 51W D2% BMI 30 Age 45	Randomized, double-blind, cross-over	Quercetin 150 mg	42	Plasma quercetin 250 nM Flavonols 350 nM	No bias	1.00	TNF ↓ Baseline levels: 2–3 pg/mL
Egert 2010	Overweight/obese Apo E 3 (24M, 36F) Apo E 4 (15M, 11F) D2% BMI 31 Age 46	Randomized, double-blind, cross-over	Quercetin 150 mg	42	Plasma n = 60 Q 262.7 nM Kaempherol 30.6 Isorhamnetin 30.6 Total flavonols 347.8	No bias	1.00	TNF-α ↓ Apo E 3 TNF-α ↓ Apo E 4 Baseline levels: 2–4 pg/mL
Ellis 2011	Overweight/obese 10M, 14W D8% BMI 29 Age 60	Randomized, blind, parallel	Strawberry beverage 94.7 mg	42		1. No compliance 2. No dietary record	0.74	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 1–2 pg/mL IL-6 1–2 pg/mL
Estruch 2004	Healthy 40M D5% BMI nr Age 38	Randomized, blind, cross-over	Red wine 201mg (Control gin)	28	Plasma epicatechin 42 μg/L	No bias	0.65	TNF ↔ Baseline levels of 70–80 pg/mL
Heinz 2010	Healthy 120W D0% BMI 26 Age 47	Randomized, double-blind, parallel	1 Quercetin (500 mg) 2 Quercetin (1000 mg)	84	Plasma quercetin 350 μg/L 500 μg/L	1. No dietary record 2. No antioxidant or food consumption in selection criteria 3. Funding by Coca-Cola and Quercegen Pharma.	0.85	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 1–2 pg/mL IL-6 1–3 pg/mL
Hermansen 2005	Hypercholesterolemic 58 M, 42W D11% BMI 25 Age 59	Randomized, double-blind, parallel	Soy (100 mg isoflavones)	168		1. Funding by Nutripharma	0.91	TNF ↔ Baseline levels: TNF-α 4–5 pg/mL
Jenkins 2002	Hypercholesterolemic + menopausal 23M, 18W D2 0% BMI 25 Age 62	Randomized, blind, cross-over	Soy 1 M (70 mg) 2 W (70 mg) 3 M (10 mg) 3 W (10 mg)	28		1. No antioxidant or food consumption in selection criteria	0.82	TNF ↔ IL-6 ↑ W Baseline levels: TNF-α 1–2 pg/mL IL-6 0–2 pg/mL
Knab 2011	Healthy overweight 260M, 412W D3% BMI 27 Age 45	Randomized, double-blind, parallel	1 Quercetin (500 mg) 2 Quercetin (1000 mg)	84	Plasma quercetin 400 μg/L 600 μg/L	1. Vitamin C dosage differs between treatment 2. No dietary record 3. No antioxidant or food consumption in selection criteria 4. Funding by Coca-Cola and Quercegen Pharma.	0.55	TNF ↔ IL-6 ↓ Q1000 Baseline levels: TNF-α 1–2 pg/mL IL-6 1–2 pg/mL
Lenn 2002	Healthy 6M, 5W D27% BMI 24 Age 23	Randomized, parallel	Soy isoflavones (120 mg)	30		1. No compliance 2. No dietary record 3. No antioxidant or food consumption in selection criteria	0.39	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 0–2 pg/mL IL-6 1–11 pg/mL
Llanezaa 2011	Obese postmenopausal women 70 W D19% BMI 35 Age 57	Randomized, double-blind, parallel	Soy isoflavones extract (Fisiogen® 80 mg)	180		1. No antioxidant or food consumption in selection criteria	0.9	TNF ↔ Baseline levels: 6–8 pg/mL
Maskarinec 2009a	Healthy overweight 183W D8% BMI 26 Age 43	Randomized, double-blind, parallel	Soy (100 mg)	730	Urinary isoflavone 59.8 nmol/mg creatinine	1. Support through food donations from The Solae Company,	0.99	IL-6 ↔ Baseline levels: 1–2 pg/mL
Maskarinec 2009b	Healthy overweight 24M D17% BMI 28 Age 59	Randomized, blinded, cross-over	Soy (70 mg)	93		1. Support through food donations from Aloha Tofu Factory, DrSoy Nutrition, and The Solae Company	0.89	IL-6 ↔ Baseline levels: 0 pg/mL
Miraghajani 2012	Type II diabetic 25 (60%W) D13% BMI 28 Age 51	Randomized, cross-over	Soy milk (240 mL)	28		1. No antioxidant or food consumption in selection criteria	0.85	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 1.7–1.9 pg/mL IL-6 1.3–1.6 pg/mL
Mukamal 2009	Diabetics 10M, 18W D10% BMI 29 Age 55	Randomized, blind, parallel	Black tea (318 mg)	180	Urinary 4-O-methylgallic acid 13 μM	1. No antioxidant or food consumption in selection criteria 2. Support through food donations from Templar Foods	0.89	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 1–3 pg/mL IL-6 1–2 pg/mL
Naruszewicz 2007	After myocardial infarction 33M, 11W D0% BMI 27 Age 66	Randomized, double-blind, parallel	Chokeberry extract (255 mg)	42		1. No compliance 2. No dietary record 3. No antioxidant or food consumption in selection criteria 4. Funding by Agropharm	0.35	IL-6 ↔ Baseline levels: IL-6 4–6 ng/mL
Nieman 2009	Healthy 32M, 7W D0% BMI nr Body composition 15% fat Age 26	Randomized, double-blind, parallel	1. Quercetin (1000 mg) 2. (Quercetin 1000 mg + EGCG 120 mg + isoquercetin 400 mg)	14	Plasma quercetin 550 μg/L 700 μg/L	1. Vitamin C dosage differs between treatment 2. No dietary record 3. No antioxidant or food consumption in selection criteria 4. Funding by Quercegen Pharma	0.56	TNF ↔ Baseline levels: 3–5 pg/mL IL-6 (fig) ↔
Rajaram 2010	Healthy 17M, 14W D7% BMI<30 Age 41	Randomized, blinded, crossover	1. Low-almond diet 2. High-almond diet	28		1. A unique basal value for both groups	0.60	IL-6 ↔ Baseline levels 1, 18 ng/L
Ryan-Borchers 2006	Healthy overweight postmenopausal 52W D9% BMI 27 Age 56	Randomized, double-blind, parallel	1. Soy (71.6 mg) 2. Isoflavone tablets (70 mg)	112	Soy: Plasma: daidzein ↔; genistein ↑ (0.15 μM); equol ↑ (0.1 μM); Urine: daidzein ↑ (13 μM); genistein ↑ (5 μM); equol ↑ (18 μM); Supplement: Plasma: daidzein ↔; genistein ↑ (0.35 μM); equol ↑ (0.03 μM); Urine: daidzein ↑ (24 μM); genistein ↑ (18 μM); equol ↑ (10 μM)	1. No compliance	0.64	TNF-α ↔ Baseline levels 2–2.5 ng/mL
Rytter 2010	Diabetes 18M, 22W D15% BMI 28 Age 62	Randomized, double-blind, parallel	Fruit, berries, and vegetable supplement 1 (736 mg) 2 (1472 mg)	56		1. Support through food donations from White Wave, Inc. (Boulder, CO) and Archer Daniels Midland Co. (Decatur, IL, USA).	0.85	IL-6 ↔ Baseline levels: 2–3 ng/L
Tome-Carneiro 2012	CVD 34M, 41W D0% BMI 31 Age 60	Randomized, triple-blind, parallel	1. Grape extract (66.8mg/6 months + 133.6 mg/6 months) 2. Grape extract + resveratrol (66.8 mg + 8 mg/6 months + 133.6 mg + 16 mg/6 months)	365		1. No wash out or run in 2. Product provided by Actapharma	0.89	TNF ↔ IL-6 ↔ Baseline levels: TNF-α 1.7–1.9 pg/mL IL-6 1.3–1.6 pg/mL
Urpi-Sarda 2012	High risk of CVD 106 Registration number: NCT01449110	PREDIMED study	1. Virgin oil (1L/week) 2. Nuts (30 g/d)	93		No bias	1	IL-6 ↓ Baseline levels: IL-6 5–7 pg/mL
Zemel 2010	Overweight and obese 14M, 6W D2% BMI 28 and 32 Age 31	Randomized blinded, crossover	1. Soy (overweight) 2. Soy (obese)	28		1. No compliance 2. No dietary record 3. No antioxidant or food consumption in inclusion criteria	0.39	TNF ↑ IL-6 ↑ obese Baseline levels: TNF-α 440–460 pg/mL IL-6 83–90 pg/mL

D: dropout (when not reported it has been calculated confronting the numbers in methods and in results).

The characteristics and comorbidity status of the participants varied. Eleven studies recruited only healthy participants. The remaining studies evaluated the effect of the intervention among patients with rheumatoid arthritis, diabetes, and metabolic syndrome or subjects with risk factors of CVD.

All the 32 studies were randomized placebo-controlled trials (10 blinded and 18 double blinded), 11 of which had a crossover design.

The more frequent limitation was incomplete food or antioxidant monitoring (19/32) and funding source or support by profit-making companies (12/32). In three studies, vitamin C differs between treatment and control, however this factor has been taken into account in score assignment (no proper placebo) (Table 1). All but five studies described flavonoid concentration of ingested food (soy, almond, nuts, virgin oil), beverage (teas, red wine, and fruit juice) or supplement (quercetin, pomegranate seed oil capsules, isoflavones supplements, tea, grape, and chokeberry extracts), with a flavonoids intake ranging from 10 to 2933 mg/d, but only nine assessed polyphenols bioavailability with both plasma and urinary levels in the range of micromolar concentrations. However, in these studies, bioavailability was unrelated to anti-inflammatory effect. In diabetic subjects, IL-6 and TNF-α were unaffected by a daily ingestion of three cup of black tea, despite urinary 4-O-methylgallic acid was excreted in urine 98. Estruch 65 et al. found unchanged levels of TNF-α after 4 weeks of red wine consumption but increased epicatechin gallate plasma concentrations.

The sources of flavonoids used in the selected studies are shown in Table 2 and quercetin is the only pure molecule used in these interventions. The inflammatory cytokines IL-6 30, 104 and TNF-α 30 were unaffected by quercetin supplementation, also when taken in combination with vitamin C 30 or epigallocatechin 3-gallate 104. To the contrary, quercetin alone decreased TNF-α in subjects with metabolic syndrome 58 and with apolipoprotein E (ApoE) genotype ApoE3 and ApoE4 57. All but one of these studies reported also data of bioavailability but the absorption of quercetin in the mainstream was not related to any reduction in circulating cytokines. However, Knab 83 reported no effects on TNF-α, but reduced levels of IL-6 concomitantly with increased concentrations of plasma quercetin.

The majority of chronic intervention studies using flavonoid-rich food or extract as source of bioactive molecules showed no changes in TNF-α and IL-6 levels. Besides, Zemel 133, in an intervention study providing 10 g of soy proteins, reported increased levels of TNF-α in both obese and overweight subjects and increased levels of IL-6 in obese only. Similarly, Jenkins 78 observed, after soy consumption, increased levels of IL-6 in hypercholesterolemic postmenopausal women. Contrarily, recent studies, conducted in subjects at high risk of CVD 28, 37, 44, 48, 122 or with metabolic syndrome 49, reported decreased levels of TNF-α 28, 37, 44 and IL-6 44, 48, 122 after consumption of red wine 48, tea extract 37, 49, pomegranate capsules 28, red orange juice 44, olive oil 122, and nuts 122.

3.2 Data synthesis

Since there were 13 studies with different treatment groups or with different sources of subjects, 34 datasets from 23 studies for TNF-α and 35 datasets from 23 studies for IL-6 were analyzed in this meta-analysis. The number of subjects was: for TNF-α 2163 of which 448 in crossover for a total of 2611: 1575 received flavonoids and 1036 placebo; for IL-6 2078 of which 275 in crossover for a total of 2353 (1467 treated and 886 controls).

No significant difference was detected with meta-analysis for the change of plasma concentration between flavonoid ingestion and control for both TNF-α and IL-6 in random (MD (95%CI): TNF-α –0.160 (−0.374, 0.055); IL-6 −0.064 (−0.225, 0.096)) and quality (MD (95%CI): TNF-α −0.108 (−45.155, 44.940); IL-6 0.015 (−184.585, 184.614)) effect models. On the other hand, decreased levels of TNF-α (MD (95%CI): −0.097 (−0.187, −0.008), p = 0.033) but not of IL-6 (MD (95% CI): 0.014 (−0.004, 0.033)) were found after flavonoid consumption in fixed effect model. From low to medium, statistical heterogeneity was found for TNF-α (I² 65%, τ² 0.15, Q 20%, Egger intercept −0.882, p = 0.461) and IL-6 (I² 60%, τ² 0.06, Q 12%, Egger intercept 0.869, p = 0.003), respectively. Funnel plots showed asymmetric distribution of results and Trim-and-fill analysis suggesting potential publication bias TNF-α (4 bias) and IL-6 (3 bias) (Fig. 2). After this sensitivity analysis, seven studies 32, 33, 44, 65, 100, 113, 133 have been excluded for higher baseline levels compared with other studies.

Thus, 28 datasets from 19 studies for TNF-α (n = 2404: 1464 treated and 940 controls) and 28 datasets from 18 studies for IL-6 (n = 2174: 1374 treated and 800 controls) were analyzed. Trim-and-fill analysis showed no publication bias for both TNF-α and IL-6 (not shown). Also this analysis revealed, in fixed effect model, decreased levels of TNF-α after flavonoid consumption but not for IL-6 (Table 3). No significant difference was detected with meta-analysis for the change of plasma concentration between flavonoid ingestion and control for both TNF-α and IL-6 in random and quality effect models (Table 3).

Table 3. Combined Effect Estimate on TNF-α and IL-6 of selected studies and subgrouping for source of flavonoids and “health status” of subjects

	Studies/interventions	Fixed effect	Random effect	Quality effect
	(subjects)	MD (95% CI)	MD (95% CI)	MD (95% CI)
		p (I²%)	p (τ²)	p (Q%)
TNF-α	19/28 (2404)	−0.098 (−0.188 to –0.009)	−0.151 (−0.350 to 0.048)	−0.108 (−0.287 to 0.070)
		0.032 (64%)	0.138 (0.12)	0.191 (20%)
Quercetin	6/10 (1494)	−0.032 (−0.196 to 0.133)	−0.032 (−0.196 to 0.133)	−0.052 (−0.353 to 0.249)
		0.707 (0%)	0.707 (0)	0.609 (32%)
Soy	6/9 (391)	0.087 (−0.051 to 0.224)	0.087 (−0.051 to 0.224)	0.087 (−0.157 to 0.332)
		0.216 (0%)	0.216 (0)	0.253 (15%)
Other sources	7/9 (519)	−0.449 (−0.619 to −0.280)	−0.783 (−1.476 to –0.090)	−0.456 (−0.779 to −0.113)
		<0.001 (82%)	0.027 (0.51)	0.109 (16%)
Disease	7/8 (525)	−0.186 (−0.316 to −0.055)	−0.505 (−1.118 to 0.108)	−0. 184 (−0.472 to 0.104)
		0.005 (89%)	0.107 (0.44)	0.308 (13%)
Risk	8/14 (1678)	0.021 (−0.115 to 0.157)	0.021 (−0.115 to 0.157)	0.018 (−0.228 to 0.264)
		0.763 (0%)	0.763 (0)	0.828 (29%)
Healthy	4/6 (201)	−0.209 (−0.497 to 0.080)	−0.209 (−0.497 to 0.080)	−0.209 (−0.664 to 0.245)
		0.157 (0%)	0.157 (0)	0.194 (16%)
IL-6	18/28 (2174)	0.015 (−0.004 to 0.034)	−0.033 (−0.180 to 0.114)	0.015 (−0.059 to 0.089)
		0.122 (57%)	0.659 (0.04)	0.869 (12%)
Quercetin	3/5 (1097)	−0.064 (−0.236 to 0.107)	−0.064 (−0.236 to 0.107)	–0.056 (−0.560 to 0.448)
		0.463 (0%)	0.463 (0%)	0.629 (43%)
Soy	7/10 (438)	0.017 (−0.001 to 0.036)	0.132 (−0.018 to 0.281)	0.017 (−0.171 to 0.205)
		0.069 (48%)	0.085 (0.02)	0.091 (11%)
Other sources	9/13 (639)	−0.346 (−0.612 to −0.079)	−0.556 (−1.062 to −0.050)	−0.383 (−0.775 to 0.009)
		0.011 (65%)	0.031 (0.48)	0.046 (26%)
Disease	6/8 (323)	0.122 (−0.014 to 0.257)	−0.135 (−0.567 to 0.297)	0.129 (−0.070 to 0.327)
		0.078 (45%)	0.541 (0.14)	0.087 (15%)
Risk	8/14 (1614)	0.013 (−0.006 to 0.032)	−0.051 (−0.269 to 0.167)	0.013 (−0.031 to 0.057)
		0.180 (68%)	0.646 (0.07)	0.592 (11%)
Healthy	4/6 (237)	−0.060 (−0.385 to 0.265)	−0.058 (−0.470 to 0.355)	−0.060 (−1.306 to 1.185)
		0.719 (27%)	0.784 (0.07)	0.761 (30%)

MD, mean difference.

We evaluated the effect of dose and duration of supplementation of flavonoids with metaregression on TNF-α concentration, however neither a higher dose (range 10–2933 mg) nor a longer duration (range 14–365 days) of treatment were associated with a greater effect (Fig. 3).

To differentiate between the effect of whole foods with respect to flavonoids, we did subgroups analyses. However, due to the low number of studies, we could subgroup only soy for foods and quercetin for supplements, from the other sources of flavonoids (foods, beverages, or extracts) as described in Table 3. Not statistically significant differences between treated and controls have been observed with quercetin or soy for both TNF-α and IL-6 (Table 3). On the contrary, other sources subgroup revealed a significant effect size on TNF-α in fixed and random effect models, and IL-6, in fixed, random and quality effect models (Table 3). When subjects were stratified on the basis of their “health status”, a significant effect on TNF-α was revealed in disease subjects as described in Table 3.

4 Discussion

Results of meta-analysis, including all the 32 selected studies, show a decrease of TNF-α, but not of IL-6 circulating levels, following flavonoid chronic consumption. With Trim-and-fill sensitivity analysis, we were able to remove publication bias excluding seven studies from the meta-analysis. The second analysis confirmed the effect only for TNF-α, but neither the administration of higher doses, nor longer duration of intervention were related to this effect. However, subsequent subgroup analysis showed that sources of flavonoids different from soy and quercetin reduce plasma levels of TNF-α and IL-6 in humans.

The major limitation of this meta-analysis is that it excludes studies that presented data as figures, medians, or geometric means 29, 36, 42, 47, 51, 53, 55, 72, 74, 80, 89, 90, 97, 110, 125. However, the exclusion of these studies did not affect the results considering that also these studies suggest that chronic ingestion of fruit 36, 52, 80, 90, wine 55, 89, 125, 90, 72 and tea 53, 72 reduces TNF-α 72, 80, 89 and IL-6 36, 80, 89, 125, while results on soy intervention are more contrasting 29, 47, 74 and none of these studies used quercetin as pure molecule.

To understand the impact of flavonoids on human health, it is essential to know the nature of the main compounds ingested and their bioavailability, which is known to be low in humans, because they are substrates of phase I (cytochrome P450), phase II (conjugation) and phase III (transporters) drug metabolism/transport systems 140. First, only about 28% of the selected studies reported data of bioavailability. Second, investigators rarely (only in 41% of cases) consider other dietary origin and the amounts consumed during the study. Third, potential limitations of included trials included short duration of follow-up and a small sample size. Again, all the included trials varied in terms of study population, source, and amount of flavonoids ingestion. In addition, the number of studies contributing substantial data to the meta-analysis were limited, thus we did not perform a subgroup analysis for different food sources other than soy.

The only pure molecule used in the selected studies was quercetin and almost all of these studies (5/6) reported data of bioavailability, however this flavonol did not affect both TNF-α and IL-6 levels. Also, treatment with soy, containing primarily isoflavones 16, unaffected both TNF-α and IL-6 levels.

On the other hand, results suggest that sources different from quercetin and soy, such as tea extract 37, 49 and red wine 48, both rich in flavanols 16, or fruit extract 28, containing a wide variety of flavonoids including flavanones 16, may decrease both TNF-α and IL-6 circulating levels. In the group “other sources”, only one of the studies included in this subgroup analysis was conducted with healthy subjects. Inflammation states may interfere with flavonoid metabolism, due to modulating effects of inflammatory cytokines on cytochrome P450 141 and transporter gene expression 142, thus healthy and disease-affected subjects may metabolize flavonoids differently. On the other hand, the interaction of flavonoid-rich foods or beverages with some drugs commonly used in clinical management of chronic patients is well known 143-150. Thus, in order to understand if there was an anti-inflammatory effect of flavonoids supplementation linked to the presence of diseases in the subjects, we performed subgroup meta-analysis in healthy or pathological subjects. Statistically significant effects were found for TNF-α in subjects affected by different diseases, but only in fixed effect model and with high heterogeneity, making difficult to draw any conclusions. The high variability in terms of different pathologies 30, 37, 49, 58, 96, 98, 119, treatments, duration, and dosage, make unfeasible a further stratification of the data to clarify if flavonoids might be more effective in certain disease state with respect to others.

We could not assess the effects of important clinical factors that might influence outcomes of flavonoid consumption. For example, we could not adequately investigate sex, age, and body mass index differences, due to the low number of subjects. We could not analyze also the effects of different study designs (crossover/parallel). For the parallel design studies, the small sample sizes could have led to ineffective randomization and potential confounding, while without complete information about bioaccumulation and pharmacokinetic of flavonoids, the correct wash out period for crossover design is difficult to establish. Last, due to the lack of a proper placebo with same aspect and same taste of the treatment, blinding of subjects in dietary interventions trials is also difficult to obtain.

In conclusion, results of our subgroup meta-analysis suggest an effect of grouped dietary sources of flavonoids (wine, pomegranate, and tea extracts), but not for soy and quercetin subgroups, on TNF-α and IL-6 plasma levels in humans. Due to the high heterogeneity of intervention, the low number of evidences and the lack of data on bioavailability, high-quality double-blind randomized trials with proper placebo are needed in order to identify flavonoids as the active ingredients involved in the anti-inflammatory effect of plant foods.

Acknowledgment

We thank Dr. Claudio Andrew Gobbi for English revision of the manuscript.

The authors have declared no conflict of interest.

5 References

1Candore, G., Caruso, C., Jirillo, E., Magrone, T. et al., Low grade inflammation as a common pathogenetic denominator in age-related diseases: novel drug targets for anti-ageing strategies and successful ageing achievement. Curr. Pharm. Des. 2010, 16, 584–596.
10.2174/138161210790883868
CAS PubMed Web of Science® Google Scholar
2Ford, A. C., Talley, N. J., Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review. J. Gastroenterol 2011, 46, 421–431.
10.1007/s00535-011-0379-9
PubMed Web of Science® Google Scholar
3Wouters, E. F., Reynaert, N. L., Dentener, M. A., Vernooy, J. H., Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc. Am. Thorac. Soc. 2009, 6, 638–647.
10.1513/pats.200907-073DP
CAS PubMed Google Scholar
4Gustafson, B., Hammarstedt, A., Andersson, C. X., Smith, U., Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 2276–2283.
10.1161/ATVBAHA.107.147835
CAS PubMed Web of Science® Google Scholar
5Adibhatla, R. M., Dempsy, R., Hatcher, J. F., Integration of cytokine biology and lipid metabolism in stroke. Front Biosci. 2008, 13, 1250–1270.
10.2741/2759
CAS PubMed Web of Science® Google Scholar
6Graves, D. T., Kayal, R. A., Diabetic complications and dysregulated innate immunity. Front Biosci. 2008, 13, 1227–1239.
10.2741/2757
CAS PubMed Web of Science® Google Scholar
7Yeh, S. S., Schuster, M. W., Geriatric cachexia: the role of cytokines. Am. J. Clin. Nutr. 1999, 70, 183–197.
10.1093/ajcn.70.2.183
CAS PubMed Web of Science® Google Scholar
8Noguchi, Y., Yoshikawa, T., Matsumoto, A., Svaninger, G. et al., Are cytokines possible mediators of cancer cachexia? Jpn. J. Surg. 1996, 26, 467–475.
CAS PubMed Web of Science® Google Scholar
9Jones, S. A., Scheller, J., Rose-John, S., Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 2011, 121, 3375–3383.
10.1172/JCI57158
CAS PubMed Web of Science® Google Scholar
10Baeten, D., van Hagen, P. M., Use of TNF blockers and other targeted therapies in rare refractory immune-mediated inflammatory diseases: evidence-based or rational? Ann. Rheum. Dis. 2010, 69, 2067–2073.
10.1136/ard.2009.126813
CAS PubMed Web of Science® Google Scholar
11Hermsdorff, H. H., Zulet, M. A., Puchau, B., Martínez, J. A., Fruit and vegetable consumption and proinflammatory gene expression from peripheral blood mononuclear cells in young adults: a translational study. Nutr. Metab. (Lond) 2010, 7, 42, doi:10.1186/1743-7075-7-42.
10.1186/1743‐7075‐7‐42
CAS PubMed Web of Science® Google Scholar
12Panagiotakos, D. B., Dimakopoulou, K., Katsouyanni, K., Bellander, T. et al., Mediterranean diet and inflammatory response in myocardial infarction survivors. Int. J. Epidemiol. 2009, 38, 856–866.
10.1093/ije/dyp142
PubMed Web of Science® Google Scholar
13Salas-Salvadó, J., Garcia-Arellano, A., Estruch, R., Marquez-Sandoval, F. et al., Components of the Mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease. Eur. J. Clin. Nutr. 2008, 62, 651–659.
10.1038/sj.ejcn.1602762
CAS PubMed Web of Science® Google Scholar
14Crozier, A., Jaganath, I. B., Clifford, M. N., Dietary phenolics: chemistry, bioavailability and effects on health. Nat. Prod. Rep. 2009, 26, 1001–1043.
10.1039/b802662a
CAS PubMed Web of Science® Google Scholar
15Calder, P. C., Albers, R., Antoine, J. M., Blum, S. et al., Inflammatory disease processes and interactions with nutrition. Br. J. Nutr. 2009, 101(Suppl 1), S1–S45.
PubMed Google Scholar
16Pérez-Jiménez, J., Neveu, V., Vos, F., Scalbert, A., Systematic analysis of the content of 502 polyphenols in 452 foods and beverages: an application of the phenol-explorer database. J. Agric. Food Chem. 2010, 58, 4959–4969.
10.1021/jf100128b
CAS PubMed Web of Science® Google Scholar
17D'Archivio, M., Filesi, C., Di Benedetto, R., Gargiulo, R. et al., Polyphenols, dietary sources and bioavailability. Ann. Ist Super Sanita 2007, 43, 348–361.
CAS PubMed Google Scholar
18Holt, E. M., Steffen, L. M., Moran, A., Basu, S. et al., Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. J. Am. Diet Assoc. 2009, 109, 414–421.
10.1016/j.jada.2008.11.036
CAS PubMed Web of Science® Google Scholar
19Song, Y., Manson, J. E., Buring, J. E., Sesso, H. D., Liu, S., Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis. J. Am. Coll. Nutr. 2005, 24, 376–384.
10.1080/07315724.2005.10719488
CAS PubMed Web of Science® Google Scholar
20Monagas, M., Khan, N., Andrés-Lacueva, C., Urpí-Sardá, M. et al., Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells. Br. J. Nutr. 2009, 102, 201–206.
10.1017/S0007114508162110
CAS PubMed Web of Science® Google Scholar
21Nair, M. P., Mahajan, S., Reynolds, J. L., Aalinkeel, R. et al., The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system. Clin. Vacc. Immunol 2006, 13, 319–328.
10.1128/CVI.13.3.319-328.2006
CAS PubMed Web of Science® Google Scholar
22Okoko, T., Oruambo, I. F., Inhibitory activity of quercetin and its metabolite on lipopolysaccharide-induced activation of macrophage U937 cells. Food Chem. Toxicol. 2009, 47, 809–812.
10.1016/j.fct.2009.01.013
CAS PubMed Web of Science® Google Scholar
23Liu, J., Li, X., Yue, Y., Li, J. et al., The inhibitory effect of quercetin on IL-6 production by LPS-stimulated neutrophils. Cell Mol. Immunol. 2005, 2, 455–460.
CAS PubMed Web of Science® Google Scholar
24Serafini, M., Peluso, I., Raguzzini, A., Flavonoids as anti-inflammatory agents. Proc. Nutr. Soc. 2010, 69, 273–278.
10.1017/S002966511000162X
CAS PubMed Web of Science® Google Scholar
25Alexopoulos, N., Vlachopoulos, C., Aznaouridis, K., Baou, K. et al., The acute effect of green tea consumption on endothelial function in healthy individuals. Eur. J. Cardiovasc. Prev. Rehabil. 2008, 15, 300–305.
10.1097/HJR.0b013e3282f4832f
PubMed Web of Science® Google Scholar
26Alvarez, P., Alvarado, C., Mathieu, F., Jiménez, L. et al., Diet supplementation for 5 weeks with polyphenol-rich cereals improves several functions and the redox state of mouse leucocytes. Eur. J. Nutr. 2006, 45, 428–438.
10.1007/s00394-006-0616-9
CAS PubMed Web of Science® Google Scholar
27Arent, S. M., Senso, M., Golem, D. L., McKeever, K. H., The effects of theaflavin-enriched black tea extract on muscle soreness, oxidative stress, inflammation, and endocrine responses to acute anaerobic interval training: a randomized, double-blind, crossover study. J. Int. Soc. Sports Nutr. 2010, 7, 11, doi:10.1186/1550-2783-7-11.
10.1186/1550‐2783‐7‐11
CAS PubMed Web of Science® Google Scholar
28Asghari, G., Sheikholeslami, S., Mirmiran, P., Chary, A. et al., Effect of pomegranate seed oil on serum TNF-α level in dyslipidemic patients. Int. J. Food Sci. Nutr. 2012, 63, 368–371.
10.3109/09637486.2011.631521
CAS PubMed Web of Science® Google Scholar
29Azadbakht, L., Kimiagar, M., Mehrabi, Y., Esmaillzadeh, A. et al., Soy consumption, markers of inflammation, and endothelial function: a cross-over study in postmenopausal women with the metabolic syndrome. Diabetes Care. 2007, 30, 967–973.
10.2337/dc06-2126
CAS PubMed Web of Science® Google Scholar
30Bae, S. C., Jung, W. J., Lee, E. J., Yu, R. et al., Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients. J. Am. Coll. Nutr. 2009, 28, 56–62.
10.1080/07315724.2009.10719762
CAS PubMed Web of Science® Google Scholar
31Bakker, G. C., van Erk, M. J., Pellis, L., Wopereis, S. et al., An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am. J. Clin. Nutr. 2010, 91, 1044–1059.
10.3945/ajcn.2009.28822
CAS PubMed Web of Science® Google Scholar
32Basu, A., Betts, N. M., Ortiz, J., Simmons, B. et al., Low-energy cranberry juice decreases lipid oxidation and increases plasma antioxidant capacity in women with metabolic syndrome. Nutr. Res. 2011a, 31, 190–196.
10.1016/j.nutres.2011.02.003
CAS PubMed Web of Science® Google Scholar
33Basu, A., Du, M., Sanchez, K., Leyva, M. J. et al., Green tea minimally affects biomarkers of inflammation in obese subjects with metabolic syndrome. Nutrition 2011b, 27, 206–213.
10.1016/j.nut.2010.01.015
CAS PubMed Web of Science® Google Scholar
34Beavers, K. M., Serra, M. C., Beavers, D. P., Cooke, M. B. et al., Soymilk supplementation does not alter plasma markers of inflammation and oxidative stress in postmenopausal women. Nutr. Res. 2009, 29, 616–622.
10.1016/j.nutres.2009.09.002
CAS PubMed Web of Science® Google Scholar
35Beavers, K. M., Serra, M. C., Beavers, D. P., Cooke, M. B. et al., Soy and the exercise-induced inflammatory response in postmenopausal women. Appl. Physiol. Nutr. Metab. 2010, 35, 261–269.
10.1139/H10-015
CAS PubMed Web of Science® Google Scholar
36Bobe, G., Albert, P. S., Sansbury, L. B., Lanza, E. et al., Interleukin-6 as a potential indicator for prevention of high-risk adenoma recurrence by dietary flavonols in the polyp prevention trial. Cancer Prev. Res. (Phila) 2010, 3, 764–775.
10.1158/1940-6207.CAPR-09-0161
CAS PubMed Web of Science® Google Scholar
37Bogdanski, P., Suliburska, J., Szulinska, M., Stepien, M. et al., Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutr. Res. 2012, 32, 421–427.
10.1016/j.nutres.2012.05.007
CAS PubMed Web of Science® Google Scholar
38Boots, A. W., Drent, M., de Boer, V. C., Bast, A. et al., Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin. Nutr. 2011, 30, 506–512.
10.1016/j.clnu.2011.01.010
CAS PubMed Web of Science® Google Scholar
39Boots, A. W., Wilms, L. C., Swennen, E. L., Kleinjans, J. C. et al., In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers. Nutrition 2008, 24, 703–710.
10.1016/j.nut.2008.03.023
CAS PubMed Web of Science® Google Scholar
40Bowtell, J. L., Sumners, D. P., Dyer, A., Fox, P. et al., Montmorency cherry juice reduces muscle damage caused by intensive strength exercise. Med. Sci. Sports Exerc. 2011, 43, 1544–1551.
10.1249/MSS.0b013e31820e5adc
CAS PubMed Web of Science® Google Scholar
41Briviba, K., Kulling, S. E., Möseneder, J., Watzl, B. et al., Effects of supplementing a low-carotenoid diet with a tomato extract for 2 weeks on endogenous levels of DNA single strand breaks and immune functions in healthy non-smokers and smokers. Carcinogenesis 2004, 25, 2373–2378.
10.1093/carcin/bgh249
CAS PubMed Web of Science® Google Scholar
42Broekhuizen, L. N., van Wijk, D. F., Vink, H., Stalmach, A. et al., Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors. Br. J. Nutr. 2011, 106, 1416–1422.
10.1017/S0007114511002431
CAS PubMed Web of Science® Google Scholar
43Bub, A., Watzl, B., Blockhaus, M., Briviba, K. et al., Fruit juice consumption modulates antioxidative status, immune status and DNA damage. J. Nutr. Biochem. 2003, 14, 90–98.
10.1016/S0955-2863(02)00255-3
CAS PubMed Web of Science® Google Scholar
44Buscemi, S., Rosafio, G., Arcoleo, G., Mattina, A. et al., Effects of red orange juice intake on endothelial function and inflammatory markers in adult subjects with increased cardiovascular risk. Am. J. Clin. Nutr. 2012, 95, 1089–1095.
10.3945/ajcn.111.031088
CAS PubMed Web of Science® Google Scholar
45Casas-Agustench, P., López-Uriarte, P., Bulló, M., Ros, E. et al., Effects of one serving of mixed nuts on serum lipids, insulin resistance and inflammatory markers in patients with the metabolic syndrome. Nutr. Metab. Cardiovasc. Dis. 2011, 21, 126–135.
10.1016/j.numecd.2009.08.005
CAS PubMed Web of Science® Google Scholar
46Chang, W. H., Hu, S. P., Huang, Y. F., Yeh, T. S. et al., Effect of purple sweet potato leaves consumption on exercise-induced oxidative stress and IL-6 and HSP72 levels. J. Appl. Physiol. 2010, 109, 1710–1715.
10.1152/japplphysiol.00205.2010
CAS PubMed Web of Science® Google Scholar
47Charles, C., Yuskavage, J., Carlson, O., John, M. et al., Effects of high-dose isoflavones on metabolic and inflammatory markers in healthy postmenopausal women. Menopause 2009, 16, 395–400.
10.1097/gme.0b013e3181857979
PubMed Web of Science® Google Scholar
48Chiva-Blanch, G., Urpi-Sarda, M., Llorach, R., Rotches-Ribalta, M. et al., Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial. Am. J. Clin. Nutr. 2012, 95, 326–334.
10.3945/ajcn.111.022889
CAS PubMed Web of Science® Google Scholar
49Chu, S. L., Fu, H., Yang, J. X., Liu, G. X. et al., A randomized double-blind placebo-controlled study of Pu'er tea extract on the regulation of metabolic syndrome. Chin. J. Integr. Med. 2011, 17, 492–498.
10.1007/s11655-011-0781-4
PubMed Web of Science® Google Scholar
50Corella, D., González, J. I., Bulló, M., Carrasco, P. et al., Polymorphisms cyclooxygenase-2 -765G>C and interleukin-6 -174G>C are associated with serum inflammation markers in a high cardiovascular risk population and do not modify the response to a Mediterranean diet supplemented with virgin olive oil or nuts. J. Nutr. 2009, 139, 128–134.
10.3945/jn.108.093054
CAS PubMed Web of Science® Google Scholar
51Dalgård, C., Nielsen, F., Morrow, J. D., Enghusen-Poulsen, H. et al., Supplementation with orange and blackcurrant juice, but not vitamin E, improves inflammatory markers in patients with peripheral arterial disease. Br. J. Nutr. 2009, 101, 263–269.
10.1017/S0007114508995660
CAS PubMed Web of Science® Google Scholar
52Danielsson, G., Norgren, L., Truedsson, L., Andreasson, A. et al., Flavonoid treatment in patients with healed venous ulcer: flow cytometry analysis suggests increased CD11b expression on neutrophil granulocytes in the circulation. Vasc. Med. 2003, 8, 83–88.
10.1191/1358863x03vm471oa
PubMed Web of Science® Google Scholar
53de Maat, M. P., Pijl, H., Kluft, C., Princen, H. M., Consumption of black and green tea had no effect on inflammation, haemostasis and endothelial markers in smoking healthy individuals. Eur. J. Clin. Nutr. 2000, 54, 757–763.
10.1038/sj.ejcn.1601084
CAS PubMed Web of Science® Google Scholar
54Deibert, P., Solleder, F., König, D., Vitolins, M. Z. et al., Soy protein based supplementation supports metabolic effects of resistance training in previously untrained middle aged males. Aging Male 2011, 14, 273–279.
10.3109/13685538.2011.565091
CAS PubMed Web of Science® Google Scholar
55Djurovic, S., Berge, K. E., Birkenes, B., Braaten, Ø et al., The effect of red wine on plasma leptin levels and vasoactive factors from adipose tissue: a randomized crossover trial. Alcohol Alcohol 2007, 42, 525–528.
10.1093/alcalc/agm056
CAS PubMed Web of Science® Google Scholar
56Edirisinghe, I., Banaszewski, K., Cappozzo, J., Sandhya, K. et al., Strawberry anthocyanin and its association with postprandial inflammation and insulin. Br. J. Nutr. 2011, 106, 913–922.
10.1017/S0007114511001176
CAS PubMed Web of Science® Google Scholar
57Egert, S., Boesch-Saadatmandi, C., Wolffram, S., Rimbach, G. et al., Serum lipid and blood pressure responses to quercetin vary in overweight patients by apolipoprotein E genotype. J. Nutr. 2010, 140, 278–284.
10.3945/jn.109.117655
CAS PubMed Web of Science® Google Scholar
58Egert, S., Bosy-Westphal, A., Seiberl, J., Kürbitz, C. et al., Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br. J. Nutr. 2009, 102, 1065–1074.
10.1017/S0007114509359127
CAS PubMed Web of Science® Google Scholar
59Egert, S., Wolffram, S., Bosy-Westphal, A., Boesch-Saadatmandi, C. et al., Daily quercetin supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J. Nutr. 2008, 138, 1615–1621.
10.1093/jn/138.9.1615
CAS PubMed Web of Science® Google Scholar
60Eichenberger, P., Mettler, S., Arnold, M., Colombani, P. C., No effects of three-week consumption of a green tea extract on time trial performance in endurance-trained men. Int. J. Vitam. Nutr. Res. 2010, 80, 54–64.
10.1024/0300-9831/a000006
CAS PubMed Web of Science® Google Scholar
61Ellis, C. L., Edirisinghe, I., Kappagoda, T., Burton-Freeman, B., Attenuation of meal-induced inflammatory and thrombotic responses in overweight men and women after 6-week daily strawberry (Fragaria) intake: a randomized placebo-controlled Trial. J. Atheroscler Thromb 2011, 18, 318–327.
10.5551/jat.6114
CAS PubMed Web of Science® Google Scholar
62Esposito, K., Marfella, R., Ciotola, M., Di Palo, C. et al., Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004, 292, 1440–1446.
10.1001/jama.292.12.1440
CAS PubMed Web of Science® Google Scholar
63Esposito, K., Pontillo, A., Di Palo, C., Giugliano, G. et al., Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003, 289, 1799–1804.
10.1001/jama.289.14.1799
CAS PubMed Web of Science® Google Scholar
64Estruch, R., Martínez-González, M. A., Corella, D., Salas-Salvadó, J. et al., Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann. Intern. Med. 2006, 145, 1–11.
10.7326/0003-4819-145-1-200607040-00004
PubMed Web of Science® Google Scholar
65Estruch, R., Sacanella, E., Badia, E., Antúnez, E. et al., Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers. Atherosclerosis 2004, 175, 117–123.
10.1016/j.atherosclerosis.2004.03.006
CAS PubMed Web of Science® Google Scholar
66Fanti, P., Asmis, R., Stephenson, T. J., Sawaya, B. P. et al., Positive effect of dietary soy in ESRD patients with systemic inflammation–correlation between blood levels of the soy isoflavones and the acute-phase reactants. Nephrol. Dial. Transplant 2006, 21, 2239–2246.
10.1093/ndt/gfl169
CAS PubMed Web of Science® Google Scholar
67Ghanim, H., Sia, C. L., Korzeniewski, K., Lohano, T. et al., A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J. Clin. Endocrinol. Metab. 2011, 96, 1409–1414.
10.1210/jc.2010-1812
CAS PubMed Web of Science® Google Scholar
68Heinz, S. A., Henson, D. A., Nieman, D. C., Austin, M. D. et al., A 12-week supplementation with quercetin does not affect natural killer cell activity, granulocyte oxidative burst activity or granulocyte phagocytosis in female human subjects. Br. J. Nutr. 2010, 104, 849–857.
10.1017/S000711451000156X
CAS PubMed Web of Science® Google Scholar
69Hermansen, K., Hansen, B., Jacobsen, R., Clausen, P. et al., Effects of soy supplementation on blood lipids and arterial function in hypercholesterolaemic subjects. Eur. J. Clin. Nutr. 2005, 59, 843–850.
10.1038/sj.ejcn.1602151
CAS PubMed Web of Science® Google Scholar
70Hilpert, K. F., Kris-Etherton, P. M., West, S. G., Lipid response to a low-fat diet with or without soy is modified by C-reactive protein status in moderately hypercholesterolemic adults. J. Nutr. 2005, 135, 1075–1079.
10.1093/jn/135.5.1075
CAS PubMed Web of Science® Google Scholar
71Howatson, G., McHugh, M. P., Hill, J. A., Brouner, J. et al., Influence of tart cherry juice on indices of recovery following marathon running. Scand J. Med. Sci. Sports 2010, 20, 843–852.
10.1111/j.1600-0838.2009.01005.x
CAS PubMed Web of Science® Google Scholar
72Hsu, S. P., Wu, M. S., Yang, C. C., Huang, K. C. et al., Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am. J. Clin. Nutr. 2007, 86, 1539–1547.
10.1093/ajcn/86.5.1539
CAS PubMed Web of Science® Google Scholar
73Huang, P. H., Chen, Y. H., Tsai, H. Y., Chen, J. S. et al., Intake of red wine increases the number and functional capacity of circulating endothelial progenitor cells by enhancing nitric oxide bioavailability. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 869–877.
10.1161/ATVBAHA.109.200618
CAS PubMed Web of Science® Google Scholar
74Huang, Y., Cao, S., Nagamani, M., Anderson, K. E. et al., Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women during consumption of soy-containing isoflavones. J. Clin. Endocrinol. Metab. 2005, 90, 3956–3962.
10.1210/jc.2005-0161
CAS PubMed Web of Science® Google Scholar
75Huebbe, P., Giller, K., de Pascual-Teresa, S., Arkenau, A. et al., Effects of blackcurrant-based juice on atherosclerosis-related biomarkers in cultured macrophages and in human subjects after consumption of a high-energy meal. Br. J. Nutr. 2012, 108, 234–244.
10.1017/S0007114511005642
CAS PubMed Web of Science® Google Scholar
76Inoue, T., Komoda, H., Uchida, T., Node, K., Tropical fruit camu-camu (Myrciaria dubia) has anti-oxidative and anti-inflammatory properties. J. Cardiol. 2008 , 52, 127–132.
10.1016/j.jjcc.2008.06.004
PubMed Web of Science® Google Scholar
77Jacob, K., Periago, M. J., Böhm, V., Berruezo, G. R., Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation. Br. J. Nutr. 2008, 99, 137–146.
10.1017/S0007114507791894
CAS PubMed Web of Science® Google Scholar
78Jenkins, D. J., Kendall, C. W., Connelly, P. W., Jackson, C. J. et al., Effects of high- and low-isoflavone (phytoestrogen) soy foods on inflammatory biomarkers and proinflammatory cytokines in middle-aged men and women. Metabolism 2002, 51, 919–924.
10.1053/meta.2002.33352
CAS PubMed Web of Science® Google Scholar
79Johansen, K. M., Skorpe, S., Olsen, J. O., Osterud, B., The effect of red wine on the fibrinolytic system and the cellular activation reactions before and after exercise. Thromb. Res. 1999, 96, 355–363.
10.1016/S0049-3848(99)00120-6
CAS PubMed Web of Science® Google Scholar
80Karlsen, A., Paur, I., Bøhn, S. K., Sakhi, A. K. et al., Bilberry juice modulates plasma concentration of NF-kappaB related inflammatory markers in subjects at increased risk of CVD. Eur. J. Nutr. 2010, 49, 345–355.
10.1007/s00394-010-0092-0
CAS PubMed Web of Science® Google Scholar
81Kempf, K., Herder, C., Erlund, I., Kolb, H. et al., Effects of coffee consumption on subclinical inflammation and other risk factors for type 2 diabetes: a clinical trial. Am. J. Clin. Nutr. 2010, 91, 950–957.
10.3945/ajcn.2009.28548
CAS PubMed Web of Science® Google Scholar
82Kerr, D., Penfold, S., Zouwail, S., Thomas, P. et al., The influence of liberal alcohol consumption on glucose metabolism in patients with type 1 diabetes: a pilot study. QJM 2009, 102, 169–174.
10.1093/qjmed/hcn163
CAS PubMed Web of Science® Google Scholar
83Knab, A. M., Shanely, R. A., Henson, D. A., Jin, F. et al., Influence of quercetin supplementation on disease risk factors in community-dwelling adults. J. Am. Diet. Assoc. 2011, 111, 542–549.
10.1016/j.jada.2011.01.013
CAS PubMed Web of Science® Google Scholar
84Konrad, M., Nieman, D. C., Henson, D. A., Kennerly, K. M. et al., The acute effect of ingesting a quercetin-based supplement on exercise-induced inflammation and immune changes in runners. Int. J. Sport Nutr. Exerc. Metab. 2011, 21, 338–346.
10.1123/ijsnem.21.4.338
CAS PubMed Web of Science® Google Scholar
85Lehtonen, H. M., Suomela, J. P., Tahvonen, R., Yang, B. et al., Different berries and berry fractions have various but slightly positive effects on the associated variables of metabolic diseases on overweight and obese women. Eur. J. Clin. Nutr. 2011, 65, 394–401.
10.1038/ejcn.2010.268
CAS PubMed Web of Science® Google Scholar
86Lenn, J., Uhl, T., Mattacola, C., Boissonneault, G. et al., The effects of fish oil and isoflavones on delayed onset muscle soreness. Med. Sci. Sports Exercise 2002, 34, 1605–1613.
10.1097/00005768-200210000-00012
CAS PubMed Web of Science® Google Scholar
87Llaneza, P., González, C., Fernandez-Iñarrea, J., Alonso, A. et al., Soy isoflavones, diet and physical exercise modify serum cytokines in healthy obese postmenopausal women. Phytomedicine 2011, 18, 245–250.
10.1016/j.phymed.2010.07.011
CAS PubMed Web of Science® Google Scholar
88Mantovani, G., Madeddu, C., Macciò, A., Gramignano, G. et al., Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment. Cancer Epidemiol. Biomarkers Prev. 2004, 13, 1651–1659.
CAS PubMed Web of Science® Google Scholar
89Marfella, R., Cacciapuoti, F., Siniscalchi, M., Sasso, F. C. et al., Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus. Diabet. Med. 2006, 23, 974–981.
10.1111/j.1464-5491.2006.01886.x
CAS PubMed Web of Science® Google Scholar
90Marotta, F., Yoshida, C., Barreto, R., Naito, Y. et al., Oxidative-inflammatory damage in cirrhosis: effect of vitamin E and a fermented papaya preparation. J. Gastroenterol. Hepatol. 2007, 22, 697–703.
10.1111/j.1440-1746.2007.04937.x
CAS PubMed Web of Science® Google Scholar
91Maskarinec, G., Oum, R., Chaptman, A. K., Ognjanovic, S., Inflammatory markers in a randomised soya intervention among men. Br. J. Nutr. 2009b, 101, 1740–1744.
10.1017/S0007114508147389
CAS PubMed Web of Science® Google Scholar
92Maskarinec, G., Steude, J. S., Franke, A. A., Cooney, R. V., Inflammatory markers in a 2-year soy intervention among premenopausal women. J. Inflamm. (Lond) 2009a, 6, 9. doi:10.1016/j.amjcard.2012.03.03.
10.1186/1476-9255-6-9
PubMed Web of Science® Google Scholar
93Mathur, S., Devaraj, S., Grundy, S. M., Jialal, I., Cocoa products decrease low density lipoprotein oxidative susceptibility but do not affect biomarkers of inflammation in humans. J. Nutr. 2002, 132, 3663–3667.
10.1093/jn/132.12.3663
CAS PubMed Web of Science® Google Scholar
94McBrier, N. M., Vairo, G. L., Bagshaw, D., Lekan, J. M. et al., Cocoa-based protein and carbohydrate drink decreases perceived soreness after exhaustive aerobic exercise: a pragmatic preliminary analysis. J. Strength Cond. Res. 2010, 24, 2203–2210.
10.1519/JSC.0b013e3181e4f7f9
PubMed Web of Science® Google Scholar
95Mena, M. P., Sacanella, E., Vazquez-Agell, M., Morales, M., et al., Inhibition of circulating immune cell activation: a molecular antiinflammatory effect of the Mediterranean diet. Am. J. Clin. Nutr. 2009, 89, 248–256.
10.3945/ajcn.2008.26094
CAS PubMed Web of Science® Google Scholar
96Miraghajani-Sadat, M., Esmaillzadeh, A., Najafabadi, M. M., Mirlohi, M. et al., Soy milk consumption, inflammation, coagulation, and oxidative stress among type 2 diabetic patients with nephropathy. Diabetes Care 2012, doi:10.1016/j.amjcard.2012.03.030.
10.1016/j.amjcard.2012.03.030
Web of Science® Google Scholar
97Monagas, M., Khan, N., Andres-Lacueva, C., Casas, R. et al., Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease. Am. J. Clin. Nutr. 2009, 90, 1144–1150.
10.3945/ajcn.2009.27716
CAS PubMed Web of Science® Google Scholar
98Mukamal, K. J., MacDermott, K., Vinson, J. A., Oyama, N. et al., A 6-month randomized pilot study of black tea and cardiovascular risk factors. Am. Heart J. 2007, 154, 724. e1–6.
10.1016/j.ahj.2007.07.008
CAS PubMed Web of Science® Google Scholar
99Nantz, M. P., Rowe, C. A., Nieves, C. Jr, Percival, S. S., Immunity and antioxidant capacity in humans is enhanced by consumption of a dried, encapsulated fruit and vegetable juice concentrate. J. Nutr. 2006, 136, 2606–2610.
10.1093/jn/136.10.2606
CAS PubMed Web of Science® Google Scholar
100Naruszewicz, M., Laniewska, I., Millo, B., Dłuzniewski, M., Combination therapy of statin with flavonoids rich extract from chokeberry fruits enhanced reduction in cardiovascular risk markers in patients after myocardial infraction (MI). Atherosclerosis 2007, 194, e179–e184.
10.1016/j.atherosclerosis.2006.12.032
CAS PubMed Web of Science® Google Scholar
101Nasca, M. M., Zhou, J. R., Welty, F. K., Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women. Am. J. Cardiol. 2008, 102, 84–86.
10.1016/j.amjcard.2008.02.100
CAS PubMed Web of Science® Google Scholar
102Nieman, D. C., Henson, D. A., Davis, J. M., Dumke, C. L. et al., Quercetin ingestion does not alter cytokine changes in athletes competing in the Western States Endurance Run. J. Interferon Cytokine Res. 2007, 27, 1003–1011.
10.1089/jir.2007.0050
CAS PubMed Web of Science® Google Scholar
103Nieman, D. C., Henson, D. A., Davis, J. M., Angela Murphy, E. et al., Quercetin's influence on exercise-induced changes in plasma cytokines and muscle and leukocyte cytokine mRNA. J. Appl. Physiol. 2007, 103, 1728–1735.
10.1152/japplphysiol.00707.2007
CAS PubMed Web of Science® Google Scholar
104Nieman, D. C., Henson, D. A., Maxwell, K. R., Williams, A. S. et al., Effects of quercetin and EGCG on mitochondrial biogenesis and immunity. Med. Sci. Sports Exerc. 2009, 41, 1467–1475.
10.1249/MSS.0b013e318199491f
CAS PubMed Web of Science® Google Scholar
105Panagiotakos, D. B., Dimakopoulou, K., Katsouyanni, K., Bellander, T. et al., Mediterranean diet and inflammatory response in myocardial infarction survivors. Int. J. Epidemiol. 2009, 38, 856–866.
10.1093/ije/dyp142
PubMed Web of Science® Google Scholar
106Papageorgiou, N., Tousoulis, D., Psaltopoulou, T., Giolis, A. et al., Divergent anti-inflammatory effects of different oil acute consumption on healthy individuals. Eur. J. Clin. Nutr. 2011, 65, 514–519.
10.1038/ejcn.2011.8
CAS PubMed Web of Science® Google Scholar
107Peluso, I., Raguzzini, A., Villano, D. V., Cesqui, E. et al., High fat meal increase of IL-17 is prevented by ingestion of fruit juice drink in healthy overweight subjects. Curr. Pharm. Des. 2012, 18, 85–90.
10.2174/138161212798919020
CAS PubMed Web of Science® Google Scholar
108Phillips, T., Childs, A. C., Dreon, D. M., Phinney, S. et al., A dietary supplement attenuates IL-6 and CRP after eccentric exercise in untrained males. Med. Sci. Sports Exerc. 2003, 35, 2032–2037.
10.1249/01.MSS.0000099112.32342.10
CAS PubMed Web of Science® Google Scholar
109Rajaram, S., Connell, K. M., Sabaté, J., Effect of almond-enriched high-monounsaturated fat diet on selected markers of inflammation: a randomised, controlled, crossover study. Br. J. Nutr. 2010, 103, 907–912.
10.1017/S0007114509992480
CAS PubMed Web of Science® Google Scholar
110Rankin, J. W., Andreae, M. C., Oliver Chen, C. Y., O'Keefe, S. F., Effect of raisin consumption on oxidative stress and inflammation in obesity. Diabetes Obes. Metab. 2008, 10, 1086–1096.
10.1111/j.1463-1326.2008.00867.x
CAS PubMed Web of Science® Google Scholar
111Rinelli, S., Spadafranca, A., Fiorillo, G., Cocucci, M. et al., Circulating salicylic acid and metabolic and inflammatory responses after fruit ingestion. Plant Foods Hum. Nutr. 2012, 67, 100–104.
10.1007/s11130-012-0282-4
CAS PubMed Web of Science® Google Scholar
112Riso, P., Visioli, F., Grande, S., Guarnieri, S. et al., Effect of a tomato-based drink on markers of inflammation, immunomodulation, and oxidative stress. J. Agric. Food Chem. 2006, 54, 2563–2566.
10.1021/jf053033c
CAS PubMed Web of Science® Google Scholar
113Ryan-Borchers, T. A., Park, J. S., Chew, B. P., McGuire, M. K. et al., Soy isoflavones modulate immune function in healthy postmenopausal women. Am. J. Clin. Nutr. 2006, 83, 1118–1125.
10.1093/ajcn/83.5.1118
CAS PubMed Web of Science® Google Scholar
114Rytter, E., Vessby, B., Asgård, R., Ersson, C. et al., Supplementation with a combination of antioxidants does not affect glycaemic control, oxidative stress or inflammation in type 2 diabetes subjects. Free Radic. Res. 2010, 44, 1445–1453.
10.3109/10715762.2010.515219
CAS PubMed Web of Science® Google Scholar
115Ryu, O. H., Lee, J., Lee, K. W., Kim, H. Y. et al., Effects of green tea consumption on inflammation, insulin resistance and pulse wave velocity in type 2 diabetes patients. Diabetes Res. Clin. Pract. 2006, 71, 356–358.
10.1016/j.diabres.2005.08.001
CAS PubMed Web of Science® Google Scholar
116Sánchez-Moreno, C., Cano, M. P., de Ancos, B., Plaza, L. et al., Consumption of high-pressurized vegetable soup increases plasma vitamin C and decreases oxidative stress and inflammatory biomarkers in healthy humans. J. Nutr. 2004, 134, 3021–3025.
10.1093/jn/134.11.3021
CAS PubMed Web of Science® Google Scholar
117Sánchez-Moreno, C., Cano, M. P., de Ancos, B., Plaza, L. et al., Mediterranean vegetable soup consumption increases plasma vitamin C and decreases F2-isoprostanes, prostaglandin E2 and monocyte chemotactic protein-1 in healthy humans. J. Nutr. Biochem. 2006, 17, 183–189.
10.1016/j.jnutbio.2005.07.001
CAS PubMed Web of Science® Google Scholar
118Sierksma, A., Patel, H., Ouchi, N., Kihara, S. et al., Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-alpha, and insulin sensitivity. Diabetes Care 2004, 27, 184–189.
10.2337/diacare.27.1.184
CAS PubMed Web of Science® Google Scholar
119Tomé-Carneiro, J., Gonzálvez, M., Larrosa, M., Yáñez-Gascón, M. J. et al., One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 2012 [Epub ahead of print]. doi:10.1016/j.amjcard.2012.03.030.
10.1016/j.amjcard.2012.03.030
PubMed Web of Science® Google Scholar
120Tousoulis, D., Ntarladimas, I., Antoniades, C., Vasiliadou, C. et al., Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system. Clin. Nutr. 2008, 27, 594–600.
10.1016/j.clnu.2008.01.002
CAS PubMed Web of Science® Google Scholar
121Trombold, J. R., Barnes, J. N., Critchley, L., Coyle, E. F., Ellagitannin consumption improves strength recovery 2–3 d after eccentric exercise. Med. Sci. Sports Exerc. 2010, 42, 493–498.
10.1249/MSS.0b013e3181b64edd
CAS PubMed Web of Science® Google Scholar
122Urpi-Sarda, M., Casas, R., Chiva-Blanch, G., Romero-Mamani, E. S. et al., Virgin olive oil and nuts as key foods of the Mediterranean diet effects on inflammatory biomakers related to atherosclerosis. Pharmacol. Res. 2012, 65, 577–583.
10.1016/j.phrs.2012.03.006
CAS PubMed Web of Science® Google Scholar
123van Doorn, M. B., Espirito Santo, S. M., Meijer, P., Kamerling, I. M. et al., Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects. Am. J. Clin. Nutr. 2006, 84, 1324–1329.
10.1093/ajcn/84.6.1324
PubMed Web of Science® Google Scholar
124van Meijl, L. E., Mensink, R. P., Effects of low-fat dairy consumption on markers of low-grade systemic inflammation and endothelial function in overweight and obese subjects: an intervention study. Br. J. Nutr. 2010, 104, 1523–1527.
10.1017/S0007114510002515
CAS PubMed Web of Science® Google Scholar
125Vázquez-Agell, M., Sacanella, E., Tobias, E., Monagas, M. et al., Inflammatory markers of atherosclerosis are decreased after moderate consumption of cava (sparkling wine) in men with low cardiovascular risk. J. Nutr. 2007, 137, 2279–2284.
10.1093/jn/137.10.2279
CAS PubMed Web of Science® Google Scholar
126Watson, J., Byars, M. L., McGill, P., Kelman, A. W., Cytokine and prostaglandin production by monocytes of volunteers and rheumatoid arthritis patients treated with dietary supplements of blackcurrant seed oil. Br. J. Rheumatol. 1993, 32, 1055–1058.
10.1093/rheumatology/32.12.1055
CAS PubMed Web of Science® Google Scholar
127Watzl, B., Bub, A., Blockhaus, M., Herbert, B. M. et al., Prolonged tomato juice consumption has no effect on cell-mediated immunity of well-nourished elderly men and women. J. Nutr. 2000, 130, 1719–1723.
10.1093/jn/130.7.1719
CAS PubMed Web of Science® Google Scholar
128Watzl, B., Bub, A., Briviba, K., Rechkemmer, G., Supplementation of a low-carotenoid diet with tomato or carrot juice modulates immune functions in healthy men. Ann. Nutr. Metab. 2003, 47, 255–261.
10.1159/000072397
CAS PubMed Web of Science® Google Scholar
129Watzl, B., Bub, A., Pretzer, G., Roser, S. et al., Daily moderate amounts of red wine or alcohol have no effect on the immune system of healthy men. Eur. J. Clin. Nutr. 2002, 58, 40–45.
10.1038/sj.ejcn.1601742
CAS Web of Science® Google Scholar
130Watzl, B., Bub, A., Pretzer, G., Roser, S. et al., Daily moderate amounts of red wine or alcohol have no effect on the immune system of healthy men. Eur. J. Clin. Nutr. 2004, 58, 40–45.
10.1038/sj.ejcn.1601742
CAS PubMed Web of Science® Google Scholar
131Watzl, B., Kulling, S. E., Möseneder, J., Barth, S. W. et al., A 4-wk intervention with high intake of carotenoid-rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. Am. J. Clin. Nutr. 2005, 82, 1052–1058.
10.1093/ajcn/82.5.1052
CAS PubMed Web of Science® Google Scholar
132Williams, M. J., Sutherland, W. H., Whelan, A. P., McCormick, M. P. et al., Acute effect of drinking red and white wines on circulating levels of inflammation-sensitive molecules in men with coronary artery disease. Metabolism 2004, 53, 318–323.
10.1016/j.metabol.2003.10.012
CAS PubMed Web of Science® Google Scholar
133Zemel, M. B., Sun, X., Sobhani, T., Wilson, B., Effects of dairy compared with soy on oxidative and inflammatory stress in overweight and obese subjects. Am. J. Clin. Nutr. 2010, 91, 16–22.
10.3945/ajcn.2009.28468
CAS PubMed Web of Science® Google Scholar
134Zern, T. L., Wood, R. J., Greene, C., West, K. L. et al., Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. J. Nutr. 2005, 135, 1911–1917.
10.1093/jn/135.8.1911
CAS PubMed Web of Science® Google Scholar
135Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009, 6, e1000097.
10.1371/journal.pmed.1000097
PubMed Web of Science® Google Scholar
136Sun, C. H., Li, Y., Zhang, Y. B., Wang, F. et al., The effect of vitamin-mineral supplementation on CRP and IL-6: a systemic review and meta-analysis of randomised controlled trials. Nutr. Metab. Cardiovasc. Dis. 2011, 21, 576–583.
10.1016/j.numecd.2009.12.014
CAS PubMed Web of Science® Google Scholar
137Ramsay, C., How do you include trials with more than two groups into a single meta-analysis? EPOC 2003, 14, 2. http://epoc.cochrane.org/sites/epoc.cochrane.org/files/uploads/2003%20Mar%20EPOC%20Newsletter.pdf
Google Scholar
138Bax, L., Yu, L. M., Ikeda, N., Tsuruta, H. et al., Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med. Res. Methodol. 2006, 6, 50, doi:10.1186/1471-2288-6-50.
10.1186/1471‐2288‐6‐50
PubMed Google Scholar
139Wallace, B. C., Schmid, C. H., Lau, J., Trikalinos, T. A., Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med. Res. Methodol. 2009, 9, 80. doi:10.1186/1471-2288-9-80.
10.1186/1471‐2288‐9‐80
PubMed Web of Science® Google Scholar
140Del Rio, D., Rodriguez-Mateos, A., Spencer, J. P., Tognolini, M. et al., Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal. 2012, 17, 1–76.
PubMed Google Scholar
141Liptrott, N. J., Penny, M., Bray, P. G., Sathish, J. et al., The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br. J. Pharmacol. 2009, 156, 497–508.
10.1111/j.1476-5381.2008.00050.x
CAS PubMed Web of Science® Google Scholar
142Kimura, A., Ishida, Y., Hayashi, T., Wada, T. et al., Interferon-gamma plays protective roles in sodium arsenite-induced renal injury by up-regulating intrarenal multidrug resistance-associated protein 1 expression. Am. J. Pathol. 2006, 169, 1118–1128.
10.2353/ajpath.2006.060024
CAS PubMed Web of Science® Google Scholar
143Egert, S., Rimbach, G., Which sources of flavonoids: complex diets or dietary supplements? Adv. Nutr. 2011, 2, 8–14.
10.3945/an.110.000026
CAS PubMed Web of Science® Google Scholar
144Vischini, G., Niscola, P., Stefoni, A., Farneti, F., Increased plasma levels of tacrolimus after ingestion of green tea. Am. J. Kidney Dis. 2011 58, 329. doi:10.1053/j.ajkd.2011.05.013.
10.1053/j.ajkd.2011.05.013
PubMed Web of Science® Google Scholar
145Vaquero, M. P., Sánchez Muniz, F. J., Jiménez Redondo, S., Prats Oliván, P. et al., Major diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins. Nutr. Hosp. 2010, 25, 193–206.
CAS PubMed Web of Science® Google Scholar
146Bailey, D. G., Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br. J. Clin. Pharmacol. 2010, 70, 645–655.
10.1111/j.1365-2125.2010.03722.x
CAS PubMed Web of Science® Google Scholar
147Hanley, M. J., Cancalon, P., Widmer, W. W., Greenblatt, D. J., The effect of grapefruit juice on drug disposition. Exp. Opin. Drug Metab. Toxicol. 2011, 7, 267–286.
10.1517/17425255.2011.553189
CAS PubMed Web of Science® Google Scholar
148Murray, M., Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis. Curr. Drug Metab. 2006, 7, 67–81.
10.2174/138920006774832569
CAS PubMed Web of Science® Google Scholar
149Holbrook, A. M., Pereira, J. A., Labiris, R., McDonald, H. et al., Systematic overview of warfarin and its drug and food interactions. Arch. Intern. Med. 2005, 165, 1095–1106.
10.1001/archinte.165.10.1095
CAS PubMed Web of Science® Google Scholar
150Bailey, D. G., Dresser, G. K., Interactions between grapefruit juice and cardiovascular drugs. Am. J. Cardiovasc. Drugs 2004, 4, 281–297.
10.2165/00129784-200404050-00002
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume57, Issue5

May 2013

Pages 784-801

Effect of flavonoids on circulating levels of TNF-α and IL-6 in humans: A systematic review and meta-analysis