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April 2009

Plant-derived polyphenols attenuate lipopolysaccharide-induced nitric oxide and tumour necrosis factor production in murine microglia and macrophages.

Lipopolysaccharides released during bacterial infections induce the expression of pro-inflammatory cytokines and lead to complications such as neuronal damage in the CNS and septic shock in the periphery. While the initial infection is treated by antibiotics, anti-inflammatory agents would be advantageous add-on medications. In order to identify such compounds, we have compared 29 commercially available polyphenol-containing plant extracts and pure compounds for their ability to prevent LPS-induced up-regulation of NO production. Among the botanical extracts, bearberry and grape seed were the most active preparations, exhibiting IC(50) values of around 20 mug/mL. Among the pure compounds, IC(50) values for apigenin, diosmetin and silybin were 15, 19 and 12 muM, in N-11 murine microglia, and 7, 16 and 25 muM, in RAW 264.7 murine macrophages, respectively. In addition, these flavonoids were also able to down-regulate LPS-induced tumour necrosis factor production. Structure-activity relationships of the flavonoids demonstrated three distinct principles: (i) flavonoid-aglycons are more potent than the corresponding glycosides, (ii) flavonoids with a 4’-OH substitution in the B-ring are more potent than those with a 3’-OH-4’-methoxy substitution, (iii) flavonoids of the flavone type (with a C2=C3 double bond) are more potent than those of the flavanone type (with a at C2-C3 single bond).

Mol Nutr Food Res. 2008 Apr;52(4):427-38

Health effects of quercetin: from antioxidant to nutraceutical.

Quercetin, a member of the flavonoids family, is one of the most prominent dietary antioxidants. It is ubiquitously present in foods including vegetables, fruit, tea and wine as well as countless food supplements and is claimed to exert beneficial health effects. This includes protection against various diseases such as osteoporosis, certain forms of cancer, pulmonary and cardiovascular diseases but also against aging. Especially the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical is suggested to be involved in these possible beneficial health effects. Consequently, numerous studies have been performed to gather scientific evidence for these beneficial health claims as well as data regarding the exact mechanism of action and possible toxicological aspects of this flavonoid. The purpose of this review is to evaluate these studies in order to elucidate the possible health-beneficial effects of the antioxidant quercetin. Firstly, the definitions as well as the most important aspects regarding free radicals, antioxidants and oxidative stress will be discussed as background information. Subsequently, the mechanism by which quercetin may operate as an antioxidant (tested in vitro) as well as the potential use of this antioxidant as a nutraceutical (tested both ex vivo and in vivo) will be discussed.

Eur J Pharmacol. 2008 May 13;585(2-3):325-37

Quercetin: potentials in the prevention and therapy of disease.

PURPOSE OF REVIEW: Quercetin is discussed since several decades as a multipotent bioflavonoid with great potential for the prevention and treatment of disease. In the current review, we present the most recent findings on quercetin with regard to the pharmacology, the in-vitro and in-vivo effects in different cell systems and animal models, and the clinical effects in humans. RECENT FINDINGS: Quercetin bioavailability has been underestimated in the past and can be improved by food matrix components or particular delivery forms. Among the biological effects of particular relevance, the antihypertensive effects of quercetin in humans and the improvement of endothelial function should be emphasized. Together with its antithrombotic and anti-inflammatory effects, the latter mainly mediated through the inhibition of cytokines and nitric oxide, quercetin is a candidate for preventing obesity-related diseases. Most exiting are the findings that quercetin enhances physical power by yet unclear mechanisms. The anti-infectious and immunomodulatory activities of quercetin might be related to this effect. SUMMARY: Quercetin is a most promising compound for disease prevention and therapy; however, many of the effects still need confirmation by human intervention trials.

Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):733-40

Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line.

OBJECTIVE AND DESIGN: Mast cell-mediated allergic inflammation is involved in many diseases such as asthma, sinusitis, and rheumatoid arthritis. Mast cells induce production of pro-inflammatory cytokines with immune regulatory properties. We investigated the effect of quercetin on the expression of pro-inflammatory cytokines in human mast cell line, HMC-1. METHODS: HMC-1 cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 (PMACI). RESULTS: Quercetin decreased the gene expression and production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 in PMACI-stimulated HMC-1 cells. Quercetin attenuated PMACI-induced activation of NF-kappaB and p38 mitogen-activated protein kinase. CONCLUSION: Our study provides evidence that quercetin may suitable for the treatment of mast cell-derived allergic inflammatory diseases.

Inflamm Res. 2007 May;56(5):210-5

Quercetin regulates

Th1/Th2 balance in a murine model of asthma.

Quercetin is found to be the most active of the flavonoids in studies and many medicinal plants owe much of their activity to their high Quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation. However, its anti-allergic effect in the Th1/Th2 immune response was poorly understood. Recently, it was shown that T-bet and GATA-3 were master Th1 and Th2 regulatory transcription factors. In this study, we have attempted to determine whether Quercetin regulates Th1/Th2 cytokine production, T-bet and GATA-3 gene expression in OVA-induced asthma model mice. Quercetin reduced the increased levels of IL-4, Th2 cytokine production in OVA-sensitized and -challenged mice. The other side, it increased IFN-gamma, Th1 cytokine production in Quercetin administrated mice. We also examined to ascertain whether Quercetin could influence Eosinophil peroxidase (EPO) activity. The administration of Quercetin before the last airway OVA challenge resulted in a significant inhibition of all asthmatic reactions. Accordingly, this study may provide evidence that Quercetin plays a critical role in the amelioration of the pathogenetic process of asthma in mice. These findings provide new insight into the immunopharmacological role of Quercetin in terms of its effects in a murine model of asthma, and also broaden current perspectives in our understanding of the immunopharmacological functions of Quercetin.

Int Immunopharmacol. 2008 Dec 4

Anti-inflammatory activity of quercetin and isoquercitrin in experimental murine allergic asthma.

OBJECTIVE: Eosinophils and cytokines are implicated in the pathogenesis of allergic diseases. In the present study, we investigate the anti-inflammatory effect of quercetin and isoquercitrin in a murine model of asthma. METHODS: BALB/c mice were immunized (ovalbumin/aluminum hydroxide, s. c.), followed by two intranasal ovalbumin challenges. From day 18 to day 22 after the first immunization, the mice received daily gavages of isoquercitrin (15 mg/kg) or quercetin (10 mg/kg). Dexamethasone (1 mg/kg, s. c.) was administered as a positive control. Leucocytes were analyzed in bronchoalveolar lavage fluid (BALF), blood and pulmonary parenchyma at 24 h after the last ovalbumin challenge. Interleukin-5 (IL-5) was analyzed in BALF and lung homogenates. RESULTS: In animals receiving isoquercitrin or quercetin, eosinophil counts were lower in the BALF, blood and lung parenchyma. Neutrophil counts in blood and IL-5 levels in lung homogenate were lower only in isoquercitrin-treated mice. No alterations in mononuclear cell numbers were observed. CONCLUSION: Quercetin and isoquercitrin are effective eosinophilic inflammation suppressors, suggesting a potential for treating allergies.

Inflamm Res. 2007 Oct;56(10):402-8

Quercetin inhalation inhibits the asthmatic responses by exposure to aerosolized-ovalbumin in conscious guinea-pigs.

Effects of quercetin inhalation on immediate (IAR), late-phase (LAR) and late late-phase (LLAR) asthmatic responses by exposure to aerosolized-ovalbumin (AOA) (2w/v% in saline, inhalation for 3 min) were studied in conscious guinea-pigs sensitized with AOA. We measured specific airway resistance (sRaw), and recruitment of leukocytes, histamine and protein contents and phospholipase A2 (PLA2) activity in bronchoalveolar lavage fluid (BALF). Effects of quercetin (10 mg/mL, inhalation for 2 min) compared with cromolyn sodium, salbutamol, and dexamethasone inhalations, respectively. Quercetin inhalation decreased sRaw by 57.15 +/- 3.82% in IAR, 57.72 +/- 7.28% in LAR, and 55.20 +/- 5.69% in LLAR compared with AOA-inhaled control. Salbutamol inhalation (5 mg/mL) significantly inhibited sRaw in IAR, but inhalations of cromolyn sodium (10 mg/mL) and dexamethasone (5 mg/mL) significantly inhibited sRaw in IAR, LAR and LLAR, respectively. Inhibitory activity of quercetin inhalation on sRaw was similar to effect of its oral administration (10 mg/kg) in asthmatic responses. Quercetin (10 mg/mL, inhalation for 2 min) significantly decreased histamine and protein contents, PLA2 activity, and recruitments of leukocytes in BALF and also improved slightly infiltration of eosinophils and neutrophils in histopathological survey. Its anti-asthmatic activity was similar to cromolyn sodium and dexamethasone.

Arch Pharm Res. 2008 Jun;31(6):771-8

Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans.

BACKGROUND: Quercetin, a flavonoid present in the human diet, which is found in high levels in onions, apples, tea and wine, has been shown previously to inhibit platelet aggregation and signaling in vitro. Consequently, it has been proposed that quercetin may contribute to the protective effects against cardiovascular disease of a diet rich in fruit and vegetables. OBJECTIVES: A pilot human dietary intervention study was designed to investigate the relationship between the ingestion of dietary quercetin and platelet function. METHODS: Human subjects ingested either 150 mg or 300 mg quercetin-4’-O-beta-D-glucoside supplement to determine the systemic availability of quercetin. Platelets were isolated from subjects to analyse collagen-stimulated cell signaling and aggregation. RESULTS: Plasma quercetin concentrations peaked at 4.66 microm (+/- 0.77) and 9.72 microm (+/- 1.38) 30 min after ingestion of 150-mg and 300-mg doses of quercetin-4’-O-beta-D-glucoside, respectively, demonstrating that quercetin was bioavailable, with plasma concentrations attained in the range known to affect platelet function in vitro. Platelet aggregation was inhibited 30 and 120 min after ingestion of both doses of quercetin-4’-O-beta-D-glucoside. Correspondingly, collagen-stimulated tyrosine phosphorylation of total platelet proteins was inhibited. This was accompanied by reduced tyrosine phosphorylation of the tyrosine kinase Syk and phospholipase Cgamma2, components of the platelet glycoprotein VI collagen receptor signaling pathway. CONCLUSIONS: This study provides new evidence of the relatively high systemic availability of quercetin in the form of quercetin-4’-O-beta-D-glucoside by supplementation, and implicates quercetin as a dietary inhibitor of platelet cell signaling and thrombus formation.

J Thromb Haemost. 2004 Dec;2(12):2138-45

Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease.

BACKGROUND: It has been shown that acute intake of red wine improves endothelial-dependent vasodilatation. It is not clear, however, which constituents of red wine are responsible for this effect. We examined whether acute intake of a red grape polyphenol extract has a positive effect on brachial artery flow-mediated dilatation. METHODS: We recruited 30 male patients with coronary heart disease. They were randomly assigned either to a red grape polyphenol extract (600 mg) dissolved in 20 ml of water (n = 15) or 20 ml of water (placebo) (n = 15). The extract of grapes contained 4.32 mg epicatechin, 2.72 mg catechin, 2.07 mg gallic acid, 0.9 mg trans-resveratrol, 0.47 mg rutin, 0.42 mg epsilon-viniferin, 0.28 mg, p-coumaric acid, 0.14 mg ferulic acid and 0.04 mg quercetin per gram. Flow-mediated dilatation of the brachial artery was evaluated after reactive hyperemia induced by cuff obstruction of the forearm, using high-resolution ultasonography. Particularly, flow-mediated dilatation was measured after fasting and 30, 60 and 120 min after the intake of the grape extract or placebo. RESULTS: Intake of the red grape polyphenol extract caused an increase in flow-mediated dilatation, peaking at 60 min, which was significantly higher than the baseline values (4.52+/-1.34 versus 2.6+/-1.5%; P < 0.001) and the corresponding values at 60 min after the intake of placebo (4.52+/-1.34 versus 2.64+/-1.8%, P < 0.001). There was no change in FMD values after the intake of placebo throughout the whole duration of the study. CONCLUSION: Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. These results could probably, at least partly, explain the favorable effects of red wine on the cardiovascular system.

Eur J Cardiovasc Prev Rehabil. 2005 Dec;12(6):596-600

Quercetin reduces blood pressure in hypertensive subjects.

Epidemiological studies report that quercetin, an antioxidant flavonol found in apples, berries, and onions, is associated with reduced risk of coronary heart disease and stroke. Quercetin supplementation also reduces blood pressure in hypertensive rodents. The efficacy of quercetin supplementation to lower blood pressure in hypertensive humans has never been evaluated. We tested the hypothesis that quercetin supplementation reduces blood pressure in hypertensive patients. We then determined whether the antihypertensive effect of quercetin is associated with reductions in systemic oxidant stress. Men and women with prehypertension (n = 19) and stage 1 hypertension (n = 22) were enrolled in a randomized, double-blind, placebo-controlled, crossover study to test the efficacy of 730 mg quercetin/d for 28 d vs. placebo. Blood pressure (mm Hg, systolic/diastolic) at enrollment was 137 +/- 2/86 +/- 1 in prehypertensives and 148 +/- 2/96 +/- 1 in stage 1 hypertensive subjects. Blood pressure was not altered in prehypertensive patients after quercetin supplementation. In contrast, reductions in (P < 0.01) systolic (-7 +/- 2 mm Hg), diastolic (-5 +/- 2 mm Hg), and mean arterial pressures (-5 +/- 2 mm Hg) were observed in stage 1 hypertensive patients after quercetin treatment. However, indices of oxidant stress measured in the plasma and urine were not affected by quercetin. These data are the first to our knowledge to show that quercetin supplementation reduces blood pressure in hypertensive subjects. Contrary to animal-based studies, there was no quercetin-evoked reduction in systemic markers of oxidative stress.

J Nutr. 2007 Nov;137(11):2405-11

Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men.

BACKGROUND: Dietary flavonoids may improve endothelial function and ultimately lead to beneficial cardiovascular effects. OBJECTIVE: The objective was to assess whether pure dietary flavonoids can modulate nitric oxide and endothelin-1 production and thereby improve endothelial function. DESIGN: A randomized, placebo-controlled, crossover trial in 12 healthy men was conducted to compare the acute effects of the oral administration of 200 mg quercetin, (-)-epicatechin, or epigallocatechin gallate on nitric oxide, endothelin-1, and oxidative stress after nitric oxide production was assessed via the measurement of plasma S-nitrosothiols and plasma and urinary nitrite and nitrate concentrations. The effects on oxidative stress were assessed by measuring plasma and urinary F(2)-isoprostanes. Plasma and urinary concentrations of quercetin, (-)-epicatechin, and epigallocatechin gallate were measured to establish the absorption of these flavonoids. RESULTS: Relative to water (control), quercetin and (-)-epicatechin resulted in a significant increase in plasma S-nitrosothiols, plasma nitrite, and urinary nitrate concentrations (P < 0.05), but not in plasma nitrate or urinary nitrite. Epigallocatechin gallate did not alter any of the measures of nitric oxide production. Quercetin and (-)-epicatechin resulted in a significant reduction in plasma endothelin-1 concentration (P < 0.05), but only quercetin significantly decreased the urinary endothelin-1 concentration. None of the 3 treatments significantly changed plasma or urinary F(2)-isoprostane concentrations. Significant increases in the circulating concentrations of the 3 flavonoids were observed (P < 0.05) after the corresponding treatment. CONCLUSIONS: Dietary flavonoids, such as quercetin and (-)-epicatechin, can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function.

Am J Clin Nutr. 2008 Oct;88(4):1018-25

Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats.

The aim of this study was to analyze the effects of chronic administration of high doses of quercetin on metabolic syndrome abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance. For this purpose, obese Zucker rats and their lean littermates were used. The rats received a daily dose of quercetin (2 or 10 mg/kg of body weight) or vehicle for 10 weeks. Body weight and systolic blood pressure (SBP) were recorded weekly. At the end of the treatment, plasma concentrations of triglycerides, total cholesterol, free-fatty acids (FFAs), glucose, insulin, adiponectin, and nitrate plus nitrite (NOx) were determined. Tumor necrosis factor-alpha (TNF-alpha) production, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) protein expression were analyzed in visceral adipose tissue (VAT). The raised SBP and high plasma concentrations of triglycerides, total cholesterol, FFA, and insulin found in obese Zucker rats were reduced in obese rats that received either of the doses of quercetin assayed. The higher dose also improved the inflammatory status peculiar to this model, as it increased the plasma concentration of adiponectin, reduced NOx levels in plasma, and lowered VAT TNF-alpha production in obese Zucker rats. Furthermore, chronic intake of the higher dose of quercetin enhanced VAT eNOS expression among obese Zucker rats, whereas it downregulated VAT iNOS expression. In conclusion, both doses of quercetin improved dyslipidemia, hypertension, and hyperinsulinemia in obese Zucker rats, but only the high dose produced antiinflammatory effects in VAT together with a reduction in body weight gain.

Obesity (Silver Spring). 2008 Sep;16(9):2081-7