Dietary Flavonoid Quercetin Research Articles

Quercetin Attenuates TNF-Induced Inflammation in Hepatic Cells by Inhibiting the NF-κB Pathway

The dietary flavonoid quercetin is an antioxidant that possesses antiinflammatory and anticarcinogenic properties and may modulate signaling pathways. Inflammation is considered to play a pivotal role in carcinogenesis by triggering activation of transcription factors such as nuclear factor kappa B (NF-κB), functionally dependent on cellular redox status. This study aims to investigate the antiinflammatory effect of quercetin and its role on the NF-κB pathway, and cyclooxygenase-2 (COX-2) and mitogen-activated protein kinases modulation in a human hepatoma cell line (HepG2). Quercetin alone did not modify any of the parameters analyzed but protected cells against activation of the NF-κB route induced by tumor necrosis factor-α. This inhibitory effect of quercetin was mediated, at least in part, by extracellular regulated kinase, c-jun amino-terminal kinase, and reactive oxygen species, and it was accompanied by reduced COX-2 levels. These observations suggest that quercetin may contribute as an antiinflammatory agent in the liver and provide evidences about its role in the prevention of diseases associated with inflammation, including cancer.

Dietary Flavonoid Quercetin Exhibits Uricosuric and Renal Protective Actions in Hyperuricemic Rodents: Renal Organic Ion Transporter Involvement

Dietary Flavonoid Quercetin Exhibits Uricosuric and Renal Protective Actions in Hyperuricemic Rodents: Renal Organic Ion Transporter Involvement

Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38

Dietary flavonoid quercetin has been suggested as a cancer chemopreventive agent, but the mechanisms of action remain unclear. This study investigated the influence of quercetin on p38-MAPK and the potential regulation of the nuclear transcription factor erythroid-2p45-related factor (Nrf2) and the cellular antioxidant/detoxifying defense system related to glutathione (GSH) by p38 in HepG2 cells. Incubation of HepG2 cells with quercetin at a range of concentrations (5–50μM) for 4 or 18h induced a differential effect on the modulation of p38 and Nrf2 in HepG2 cells, 50μM quercetin showed the highest activation of p38 at 4h of treatment and values of p38 similar to those of control cells after 18 h of incubation, together with the inhibition of Nrf2 at both incubation times. Quercetin (50μM) induced a time-dependent activation of p38, which was in concert with a transient stimulation of Nrf2 to provoke its inhibition afterward. Quercetin also increased GSH content, mRNA levels of glutamylcysteine-synthetase (GCS) and expression and/or activity of glutathione-peroxidase, glutathione-reductase and GCS after 4h of incubation, and glutathione-S-transferase after 18h of exposure. Further studies with the p38 specific inhibitor SB203580 showed that the p38 blockage restored the inhibited Nrf2 transcription factor and the enzymatic expression and activity of antioxidant/detoxificant enzymes after 4h exposure. In conclusion, p38-MAPK is involved in the mechanisms of the cell response to quercetin through the modulation of Nrf2 and glutathione-related enzymes in HepG2 cells.

Vascular deconjugation of quercetin glucuronide: The flavonoid paradox revealed?

The dietary flavonoid quercetin exerts protective cardiovascular effects. Because quercetin is rapidly metabolized into less active or inactive glucuronidated metabolites and the plasma concentrations of free quercetin are very low, a huge amount of scientific data generated along decades with the unconjugated compounds in vitro has been questioned. We aimed to determine whether glucuronidated quercetin can deconjugate in situ and whether deconjugation leads to a biological effect. Quercetin and quercetin-3-O-glucuronide (Q3GA) were perfused through the isolated rat mesenteric vascular bed. Quercetin was rapidly metabolized in the mesentery. In contrast, the decay of Q3GA was slower and was accompanied by a progressive increase of quercetin in the perfusate and in the tissue over 6 h, which was prevented by the β-glucuronidase inhibitor saccharolactone. Incubation of mesenteric arterial rings mounted in a wire myograph with Q3GA for ≥1 h resulted in a significant inhibition of the contractile response which was also prevented by saccharolactone. Moreover, the intravenous administration of Q3GA resulted in a slow onset and sustained blood pressure lowering effect, demonstrating for the first time that Q3GA has effects in vivo. We propose that Q3GA behaves as a quercetin carrier in plasma, which deconjugates in situ releasing the aglycone which is the final effector.

Dietary flavonoid quercetin has no effect on endurance capacity and antioxidant status in long distance runners

Dietary flavonoid quercetin has no effect on endurance capacity and antioxidant status in long distance runners

Dietary Flavonoid Quercetin and Associated Health Benefits—An Overview

Phytochemicals have received a considerable attention in the present day world. Epidemiological studies have established that phytochemicals contribute more qualitatively to the total antioxidant activity of foods than nutrient antioxidants like vitamin C and vitamin E. Among polyphenols, quercetin constitutes the main flavonoid in our daily diet being particularly abundant in onions and apples. Since the realization that many folk medicines in use contain flavonoids, interest in this class of compounds has intensified. Quercetin acts as a strong reducing agent, which together with other dietary reductants such as vitamin C, vitamin E, and carotenoids protect body tissue against oxidative stress. Recent reports suggest that quercetin as antioxidant improves normal cell survival and as pro-oxidant induces apoptosis in cancerous cells whereby prevents tumor proliferation. Among other important properties like modulation of genes related to cell cycle, signal transduction, and xenobiotic metabolism, quercetin has also been attributed with antiviral, anti-inflammatory, antibacterial, and muscle-relaxing properties. In the literature, only a few in vivo studies have been carried out; therefore, before making any authentic health claim about this compound, it is essential to know its nature and its dietary origin. Furthermore, it is important to know the amount present in different diets and its bioavailability, followed by clinical trials and investigations, if researchers are to use it as an chemo-preventive and chemotherapeutic agent against various deleterious degenerative diseases.

Effects of The Dietary Flavonoid Quercetin on Brain Inflammation in Alzheimer'S Disease

Alzheimer's disease (AD) is a neurodegenerative disorder resulting in irreversible loss of neurons, particularly hippocampal neurons, that is clinically characterized by impairment of cognitive functions and changes in behavior. What causes the loss of neurons in AD has not been completely elucidated. However, it is thought that inflammation may play a fundamental role. The dietary flavonoid quercetin has received increased interest due to its multiple biological properties, including anti-inflammatory activity. However, its effects on brain inflammation in AD are not yet known. PURPOSE: To determine the effects of quercetin feedings on neuroinflammation in a mouse model of AD. METHODS: Double transgenic female mice (B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/O) were randomly assigned to either quercetin (QAD) or placebo (PAD) treatments (n=10/group). C57BL/6 mice were used as age matched old (OWT) and young (YWT) controls. Quercetin (1% in mouse chow) (QAD) or placebo (OWT and PAD) was administered from 3 - 13 months. QAD, OWT and PAD were sacrificed at 13 months of age. YWT were sacrificed at 3 months of age. Brain tissue was collected and analyzed for mRNA expression of TNF-alpha, IL-1beta, IL-6 and MCP-1 using RT-PCR. Statistical analysis was done using a One-Way ANOVA with Student-Newman-Keuls post hoc analysis (P<0.05). RESULTS: Whole brain mRNA expressions of TNF-alpha, IL-1beta, IL-6 and MCP-1 were increased in OWT, PAD and QAD versus YWT (P<0.05). Further, PAD had significantly elevated levels of IL-1beta, IL-6, and MCP-1 versus OWT (P<0.05) and quercetin blunted this response for MCP-1 and IL-1b (P<0.05). CONCLUSION: Our data show that brain inflammation is increased in a mouse model of AD and that quercetin can at least partly block the increased brain IL-1beta and MCP-1 expression. These findings may have important implications in AD as well as other neurodegenerative diseases in which inflammation plays a role.

Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels

Considerable epidemiological evidence indicates that dietary consumption of moderate levels of polyphenols decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but can involve changes in rates of nitric oxide (NO) generation by endothelial nitric oxide synthase (eNOS). We examined the vascular responses to quercetin using a combination of biochemical and vessel function criteria. Quercetin treatment for 30 min enhanced relaxation of rat aortic ring segments. Moreover, the addition of L-NAME (100 μM) or charybdotoxin (ChTx) blocked quercetin-mediated vasorelaxation thus demonstrating the effect was partially dependent on NOS and endothelium-derived hyperpolarizing factor (EDHF). Additionally, bovine aortic endothelial cells (BAEC) treated with quercetin showed a rapid increase of intracellular Ca 2+ concentrations as well as a dose- and time-dependent stimulation of eNOS phosphorylation with a concomitant increase in NO production. These results demonstrate that quercetin-mediated stimulation of eNOS phosphorylation increases NO bioavailability in endothelial cells and can thus play a role in the vascular protective effects associated with improved endothelial cell function.

The dietary flavonoid quercetin decreases neuroinflammation in a mouse model of Alzheimer's disease

Inflammation plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The bioactive dietary flavonoid quercetin has received increased interest due to its anti‐inflammatory properties, but its effects on neuroinflammation in AD are not known. The purpose of this study was to determine the effects of dietary flavonoid quercetin on neuroinflammation in AD. Double transgenic female mice (B6C3‐Tg(APPswe, PSEN1dE9) 85Dbo/O) were randomly assigned to either quercetin (QAD) or placebo (PAD) treatments (n=10/group). C57BL/6 mice were used as age matched old (OWT) and young (YWT) controls. Quercetin (1% in mouse chow) (QAD) or placebo (OWT and PAD) was administered from 3–13 months. QAD, OWT and PAD were sacrificed at 13 months of age. YWT were sacrificed at 3 months of age. Brain tissue was collected and analyzed for TNF‐α, IL‐1β, IL‐6 and MCP‐1 mRNA expression using RT‐PCR. YWT showed significantly lower levels of TNF‐α, IL‐1β, IL‐6 and MCP‐1 versus all other groups (P&lt;0.05). Furthermore, PAD showed significantly elevated levels of IL‐1β, IL‐6, and MCP‐1 versus OWT (P&lt;0.05), but quercetin blunted this response for IL‐1β and MCP‐1 (P&lt;0.05). Our data show that quercetin can partly block the increased gene expression of neuroinflammatory factors in AD. These findings may have important implications in AD as well as other neurodegenerative diseases in which inflammation plays a necessary role.

The Dietary Flavonoid Quercetin Increases VO2max and Endurance Capacity

Quercetin, a natural polyphenolic flavonoid substance present in a variety of food plants, has been shown in vitro and in animal studies to have widespread health and performance benefits resulting from a combination of biological properties, including antioxidant and anti-inflammatory activity, as well as the ability to increase mitochondrial biogenesis. Little is known about these effects in humans, however, especially with respect to exercise performance. The authors determined whether quercetin ingestion would enhance maximal aerobic capacity and delay fatigue during prolonged exercise in healthy but untrained participants. Twelve volunteers were randomly assigned to 1 of 2 treatments: (a) 500 mg of quercetin twice daily dissolved in vitamin-enriched Tang or (b) a nondistinguishable placebo (Tang). Baseline VO2max and bike-ride times to fatigue were established. Treatments were administered for a period of 7 days using a randomized, double-blind, placebo-controlled, crossover study design. After treatment both VO2max and ride time to fatigue were determined. Seven days of quercetin feedings were associated with a modest increase in VO2max (3.9% vs. placebo; p < .05) along with a substantial (13.2%) increase in ride time to fatigue (p < .05). These data suggest that as little as 7 days of quercetin supplementation can increase endurance without exercise training in untrained participants. These benefits of quercetin may have important implications for enhancement of athletic and military performance. This apparent increase in fitness without exercise training may have implications beyond that of performance enhancement to health promotion and disease prevention.

Quercetin protects against oxidative stress-related renal dysfunction by cadmium in rats

The aim of this study was to investigate the possible protective role of the dietary flavonoid quercetin on cadmium (Cd)-induced nephrotoxicity using biochemical and histopathological approaches. In experimental rats oral administration of CdCl 2 (5 mg/kg) for 4 weeks significantly induced renal damage which was evident from the increased levels of serum urea, uric acid and creatinine with a significant ( p<0.05) decrease in creatinine clearance. Cd also significantly ( p<0.05) decreased the levels of urea, uric acid and creatinine in urine. Cd-induced oxidative stress in kidney tissue was indicated by the increased levels of renal lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl content with a significant ( p<0.05) decrease in non-enzymatic (total sulphydryl group, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose 6-phosphate dehydrogenase (G6PD)). Moreover the kidneys of Cd-treated rats showed tubular necrosis, degeneration, dilation, desquamation, thickening of basement membrane and luminal cast formation. Quercetin treatment markedly attenuated the Cd-induced biochemical alterations in serum, urine and renal tissue. Quercetin also ameliorated the Cd-induced pathological changes when compared with Cd-alone-treated group. These data indicate that the natural dietary antioxidant quercetin might have protective effect against Cd-induced nephrotoxicity and oxidative stress in rats.

Quercetin blocks caveolae-dependent pro-inflammatory responses induced by co-planar PCBs

Polychlorinated biphenyls (PCBs) are widespread environmental contaminants, and co-planar PCBs can induce oxidative stress and activation of pro-inflammatory signaling cascades which are associated with atherosclerosis. The majority of the toxicological effects elicited by the co-planar PCB exposure are associated to the activation of the aryl hydrocarbon receptor (AHR) and subsequent induction of responsive genes. Previous studies from our group have shown that quercetin, a nutritionally relevant flavonoid can significantly reduce PCB77 induction of oxidative stress and expression of the AHR responsive gene cytochrome P450 1A1 (CYP1A1). We also have evidence that membrane domains called caveolae may regulate PCB-induced inflammatory parameters. Thus, we hypothesized that quercetin can modulate PCB-induced endothelial inflammation associated with caveolae. To test this hypothesis, endothelial cells were exposed to co-planar PCBs in combination with quercetin, and the expression of pro-inflammatory genes was analyzed by real-time PCR. Quercetin co-treatment significantly blocked both PCB77 and PCB126 induction of CYP1A1, vascular cell adhesion molecule 1 (VCAM-1), E-selectin and P-selectin. Exposure to PCB77 also induced caveolin-1 protein expression, which was reduced by co-treatment with quercetin. Our results suggest that inflammatory pathways induced by co-planar PCBs can be down-regulated by the dietary flavonoid quercetin through mechanisms associated with functional caveolae.

Effects of the Dietary Flavonoid Quercetin Upon Performance and Health

There is increased interest among such diverse groups as the military, athletes, and the aged for novel plant-derived dietary supplements to enhance performance and maintain/improve health. Quercetin, a flavonoid found in fruits and vegetables, has unique biological properties that are likely to improve mental/physical performance and reduce infection risk during intense exercise. These properties include antiinflammatory, antioxidant, and psychostimulant activity, as well as the ability to stimulate mitochondrial biogenesis, and they form the basis for potential benefits to overall health and disease resistance. However, most information regarding quercetin is based upon in vitro and animal studies. Therefore, there is a pressing need for well-designed clinical trials to evaluate this novel dietary supplement further. This article will examine the recent scientific literature concerning the role of quercetin in mental and physical performance and health.

Flavonoid intake and ovarian cancer risk in a population‐based case‐control study

Several recent studies have evaluated the association between dietary flavonoid intake and ovarian cancer risk, and all reported significant or suggestive inverse associations with certain flavonoids or flavonoid subclasses; however, most of these studies were small to moderate in size. We, therefore, examined this association in a large, population-based case-control study. We calculated intake of 5 common dietary flavonoids (myricetin, kaempferol, quercetin, luteolin, and apigenin), as well as total intake of these flavonoids, for 1,141 cases and 1,183 frequency-matched controls. We used unconditional logistic regression to estimate the relative risk (RR) of ovarian cancer for each quintile of flavonoid intake when compared with the lowest quintile. We did not observe an association between total flavonoid intake and ovarian cancer risk. The multivariable-adjusted RR for the highest versus lowest quintile of total flavonoid intake was 1.06 (95% confidence interval [CI] = 0.78-1.45). In analyses of each individual flavonoid, only intake of apigenin was associated with a borderline significant decrease in risk (RR, highest vs. lowest quintile = 0.79, 95% CI = 0.59-1.06; p-trend = 0.26), and this association was significant after adjustment for intake of the other 4 individual flavonoids (comparable RR = 0.72, 95% CI = 0.53-0.98; p-trend = 0.09). These results provide limited support for an association between flavonoid intake and ovarian cancer risk. However, given the findings of previous studies and the biologic plausibility of this association, additional studies are warranted.

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 F2-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 F2-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.

Quercetin inhibits vascular superoxide production induced by endothelin-1: Role of NADPH oxidase, uncoupled eNOS and PKC

Chronic administration of the most abundant dietary flavonoid quercetin exerts antihypertensive effects and improves endothelial function. We have investigated the effects of quercetin and its methylated metabolite isorhamnetin (1–10 μM) on endothelial dysfunction and superoxide (O 2 −) production induced by endothelin-1 (ET-1, 10 nM). ET-1 increased the contractile response induced by phenylephrine and reduced the relaxant responses to acetylcholine in phenylephrine contracted intact aorta, and these effects were prevented by co-incubation with quercetin, isorhamnetin or chelerythrine (protein kinase C (PKC) inhibitor). This endothelial dysfunction was also improved by superoxide dismutase (SOD), apocynin (NADPH oxidase inhibitor) and sepiapterin (tetrahydrobiopterin synthesis substrate). Furthermore, ET-1 increased intracellular O 2 − production in all layers of the vessel, protein expression of NADPH oxidase subunit p47 phox without affecting p22 phox expression and lucigenin-enhanced chemiluminescence signal stimulated by calcium ionophore A23187. All these changes were prevented by both quercetin and isorhamnetin. Moreover, apocynin, endothelium denudation and N G-nitro- l-arginine methylester ( l-NAME, nitric oxide synthase inhibitor) suppressed the ET-1-induced increase in A23187-stimulated O 2 − generation. Moreover, quercetin but not isorhamnetin, inhibited the increased PKC activity induced by ET-1. Taken together these results indicate that ET-1-induced NADPH oxidase up-regulation and eNOS uncoupling via PKC leading to endothelial dysfunction and these effects were prevented by quercetin and isorhamnetin.

Dietary flavonoids induce MLL translocations in primary human CD34+ cells

Genetic abnormalities leading to infant leukemias already occur during fetal development and often involve rearrangements of the mixed-lineage leukemia (MLL) gene. These rearrangements resemble the aberrations observed in therapy-related leukemias following treatment with topoisomerase II (topoII)-inhibiting agents such as etoposide. Since flavonoids are potent topoII inhibitors, we examined the role of three widely consumed dietary flavonoids (quercetin, genistein and kaempferol) on the development of MLL rearrangements in primary human CD34(+) cells. Using the neutral Comet assay, we demonstrated a dose-dependent double-strand break (DSB) formation after exposure to flavonoids. An incorrect repair of these DSBs resulted in chromosomal translocations that co-localized with those identified in infant leukemias. Most of these translocations were formed by microhomology-mediated end joining. Moreover, in all but one translocation, SINE/Alu or LINE/L1 repetitive elements were present in at least one side of the breakpoint junction. Beside MLL translocations, fluorescence in situ hybridization analysis demonstrated monosomy or trisomy of MLL in 8-10% of the quercetin-exposed CD34(+) cells. Our study demonstrates that biologically relevant concentrations of flavonoids can induce MLL abnormalities in primary hematopoietic progenitor cells. This is particularly alarming knowing that the differences in metabolism and excretion rate between mother and fetus can lead to a higher flavonoid concentration on the fetal side. Therefore, it is important to raise public awareness and set guidelines for marketing flavonoid supplements to reduce the risk of infant leukemias.

Quercetin and Isorhamnetin Prevent Endothelial Dysfunction, Superoxide Production, and Overexpression of p47phox Induced by Angiotensin II in Rat Aorta

The dietary flavonoid quercetin reduces blood pressure and improves endothelial function in several rat models of hypertension. We analyzed the effects of quercetin and its methylated metabolite isorhamnetin on the aortic endothelial dysfunction induced by incubation with angiotensin II (AngII) in vitro for 6 h. AngII diminished the relaxant responses to acetylcholine in phenylephrine-contracted aorta. Coincubation with quercetin or isorhamnetin, or addition of superoxide (O2−) dismutase or apocynin to the assay medium, prevented these inhibitory effects. At 6 h, AngII induced a marked increase in O2− production as measured by dihydroethidium fluorescence, which was prevented by quercetin and isorhamnetin. AngII also increased the expression of p47phox, a regulatory subunit of the membrane NADPH oxidase. Immunohistochemical analysis revealed that overexpression of p47phox occurred mainly in the medial layer. p47phox overexpression was also prevented by quercetin and isorhamnetin. Taken together, these results show for the first time, to our knowledge, that quercetin and isorhamnetin prevent AngII-induced endothelial dysfunction by inhibiting the overexpression of p47phox and the subsequent increased O2− production, resulting in increased nitric oxide bioavailability.

The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation

Large conductance Ca(2+)-activated K(+) channels (BKCa) regulate coronary artery tone in vivo, play a key role in blood pressure regulation, and have been suggested as novel potential drug targets in hypertension. Quercetin exerts systemic and coronary vasodilator effects in vitro and reduces blood pressure in several rat models of hypertension, and its consumption is associated with a lower mortality rate from coronary heart disease in epidemiological studies. We hypothesized that quercetin might activate BKCa channel in isolated myocytes from rat coronary arteries and that this mechanism might be involved in its coronary artery relaxant effects. Membrane currents were measured using the whole-cell configuration of the patch-clamp technique. Contractile tension was recorded in rat coronary artery rings mounted in a myograph. Quercetin (>0.1 muM) increased the outward currents in the whole range of test potentials, hyperpolarized cell membranes, and increased the frequency of spontaneous transient outward currents (STOCs) carried by BKCa channels. These effects were abolished by the selective BKCa blocker iberiotoxin and by catalase. Quercetin increased dichlorofluorescein fluorescence in coronary arteries in a polyethylenglycol-catalase-sensitive manner, indicating that it increased cytosolic H(2)O(2). The membrane-permeable analogue of H(2)O(2)t-butylhydroperoxide mimicked the effects of quercetin on outward currents. The vasodilator effect of quercetin in isolated rat coronary arteries was partially inhibited by iberiotoxin. Quercetin increased BKCa currents via production of intracellular H(2)O(2). This effect is involved, at least partly, in the coronary vasodilator effects of quercetin.

Flavonoids Protect Human Retinal Pigment Epithelial Cells from Oxidative-Stress–Induced Death

To determine whether specific dietary and synthetic flavonoids can protect human retinal pigment epithelial (RPE) cells from oxidative-stress-induced death. The efficacy and potency were determined of a variety of dietary and synthetic flavonoids on the survival of human ARPE-19 cells and primary human RPE cells treated with either hydrogen peroxide (H2O2) or t-butyl hydroperoxide (t-BOOH). We determined the effective concentrations (EC50s) and the toxicities (LD50s) of the flavonoids after 24 hours, by using the MTT assay. The efficacy of vitamins E and C on RPE cell survival were compared under identical conditions. The ability of specific flavonoids to protect RPE cells from cell death was determined at various time intervals after the cells were exposed to oxidative stress. The ability of flavonoids to block the accumulation of intracellular reactive oxygen species was examined with dichlorofluorescein (DCF) fluorescence. Finally, the ability of flavonoids to induce phase-2 detoxifying enzymes was tested by immunoblot analysis for the transcription factor Nrf2 and the phase-2 gene product heme-oxygenase 1. Specific flavonoids protected human RPE cells from oxidative-stress-induced death with efficacies between 80% and 100% and potencies in the high-nanomolar and low-micromolar range. The toxicities of most of the effective flavonoids were low. The effective flavonoids included the dietary flavonoids fisetin, luteolin, quercetin, eriodictyol, baicalein, galangin and EGCG, and the synthetic flavonoids, 3,6-dihydroxy flavonol and 3,7 dihydroxy flavonol. Several flavonoids can protect RPE cells even when they are added after the cells have been exposed to oxidative stress. The flavonoids acted through an intracellular route to block the accumulation of reactive oxygen species. Many of these flavonoids induced the expression of Nrf2 and the phase-2 gene product heme-oxygenase 1 in human RPE cells. The results identify a select group of flavonoids that protect RPE cells from oxidative-stress-induced death with a high degree of potency and low toxicity. Many of these flavonoids also induce the expression of phase-2 detoxification proteins which could function to provide additional protection against oxidative stress. This select group of flavonoids and the foods that contain high levels of these compounds may have some clinical benefit for patients with retinal diseases associated with oxidative stress.