Antioxidant Flavonoids: Structure, Function and Clinical UsageAlan L. Miller, ND Abstract

Flavonoids occur in most plant species, and account for a significant percentage of the chemical constituents of some; e.g. dried green tea leaves contain approximately 30% flavonoids by weight. Flavonoids have been shown to have antibacterial, anti-inflammatory, antiallergic, antimutagenic, antiviral, antineoplastic, anti-thrombotic, and vasodilatory activity. The potent antioxidant activity of flavonoidstheir ability to scavenge hydroxyl radicals, superoxide anions, and lipid peroxy radicalsmay be the most important function of flavonoids, and underlies many of the above actions in the body. Oxidative damage is implicated in most disease processes, and epidemiological, clinical, and laboratory research on flavonoids and other antioxidants suggest their use in the prevention and treatment of a number of these. Catechin and its derivatives, oligomeric proanthocyanidins, quercetin and quercetin chalcone, Ginkgo flavone glycosides, silymarin, and others can be utilized in preventative and treatment protocols for cardiovascular disease, cancer, inflammatory conditions, asthma, periodontal disease, liver disease, cataracts and macular degeneration.Source: Alternative Medicine Review 1996 (Jul); 1 (2): 103111 http://www.chiro.org/nutrition/ABSTRACTS/Antioxidant_Flavonoids.shtml

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Pure dietary flavonoids quercetin and ()epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy menWai Mun Loke, Jonathan M Hodgson, Julie M Proudfoot, Allan J McKinley, Ian B Puddey and Kevin D Croft Dietary flavonoids may improve endothelial function and ultimately lead to beneficial cardiovascular effects. The objective was to assess whether pure dietary flavonoids can modulate nitric oxide and endothelin-1 production and thereby improve endothelial function. 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 Snitrosothiols 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. Relative to water (control), quercetin and ()-epicatechin resulted in a significant increase in plasma Snitrosothiols, 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. Dietary flavonoids, such as quercetin and ()-epicatechin, can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function.

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Flavonoids From Argentine Tagetes (Asteraceae) With Antimicrobial ActivityMara L. Tereschuk, Mario D. Baigor, Lucia I. C. de Figueroa, Lidia R. AbdalaABSTRACT The flavonoids, constituting one of the most numerous and widespread groups of natural plant constituents, are important to humans not only because they contribute to plant colors but also because many members are physiologically active. These lowmolecular-weight substances, found in all vascular plants, are phenylbenzopyrones. Over 4000 structures have been identified in plant sources, and they are categorized into several groups Primarily recognized as pigments responsible for the autumnal burst of hues and the many shades of yellow, orange, and red in flowers and food, the flavonoids are found in fruits, vegetables, nuts, seeds, stems, flowers, and leaves as well as tea and wine and are important constituents of the human diet . They are prominent components of citrus fruits and other food sources. Flavonols (quercetin, myricetin, and kaempferol) and flavones (apigenin and luteolin) are the most common phenolics in plantbased foods. Quercetin is also a predominant component of onions, apples, and berries. Such flavanones as naringin are typically present in citrus fruit, and flavanols, particularly catechin, are present as catechin gallate in such beverages as green or black tea and wine. Some major sources of flavonoids are outlined in Table 1 (2). The daily intake of flavonoids in humans has been estimated to be approx 25 mg/d, a quantity that could provide pharmacologically significant concentrations in body fluids and tissues, assuming good absorption from the gastrointestinal tract (3).

Book Title: Public Health Microbiology: Methods and Protocols Series: Methods in Molecular Biology | Volume: 268 | Pub. Date: May-20-2004 | Page Range: 317-330 | DOI: 10.1385/1-59259-766-1:317

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Flavonoid-Rich Dark Chocolate Improves Endothelial Function and Increases Plasma Epicatechin Concentrations in Healthy AdultsMary B. Engler, PhD, Marguerite M. Engler, PhD, Chung Y. Chen, PhD, Mary J. Malloy, MD, Amanda Browne, BS, Elisa Y. Chiu, BS, MS, Ho-Kyung Kwak, PhD, Paul Milbury, MS, Steven M. Paul, PhD, Jeffrey Blumberg, PhD, FACN and Michele L. Mietus-Snyder, MD Dark chocolate derived from the plant (Theobroma cacao) is a rich source of flavonoids. Cardioprotective effects including antioxidant properties, inhibition of platelet activity, and activation of endothelial nitric oxide synthase have been ascribed to the cocoa flavonoids. To investigate the effects of flavonoid-rich dark chocolate on endothelial function, measures of oxidative stress, blood lipids, and blood pressure in healthy adult subjects. The study was a randomized, double-blind, placebo-controlled design conducted over a 2 week period in 21 healthy adult subjects. Subjects were randomly assigned to daily intake of high-flavonoid (213 mg procyanidins, 46 mg epicatechin) or low-flavonoid dark chocolate bars (46 g, 1.6 oz). High-flavonoid chocolate consumption improved endothelium-dependent flow-mediated dilation (FMD) of the brachial artery (mean change = 1.3 0.7%) as compared to low-flavonoid chocolate consumption (mean change = 0.96 0.5%) (p = 0.024). No significant differences were noted in the resistance to LDL oxidation, total antioxidant capacity, 8-isoprostanes, blood pressure, lipid parameters, body weight or body mass index (BMI) between the two groups. Plasma epicatechin concentrations were markedly increased at 2 weeks in the highflavonoid group (204.4 18.5 nmol/L, p 0.001) but not in the low-flavonoid group (17.5 9 nmol/L, p = 0.99). Flavonoid-rich dark chocolate improves endothelial function and is associated with an increase in plasma epicatechin concentrations in healthy adults. No changes in oxidative stress measures, lipid profiles, blood pressure, body weight or BMI were seen.

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Flavonoids activate pregnane X receptor-mediated CYP3A4 gene expression by inhibiting cyclindependent kinases in HepG2 liver carcinoma cellsHanqing Dong, Wenwei Lin, Jing Wu, Taosheng Chen

The expression of the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is regulated by the pregnane X receptor (PXR), which is modulated by numerous signaling pathways, including the cyclin-dependent kinase (Cdk) pathway. Flavonoids, commonly consumed by humans as dietary constituents, have been shown to modulate various signaling pathways (e.g., inhibiting Cdks). Flavonoids have also been shown to induce CYPs expression, but the underlying mechanism of action is unknown. Here, we report the mechanism responsible for flavonoid-mediated PXR activation and CYP expression. In a cell-based screen designed to identify compounds that activate PXR-mediated CYP3A4 gene expression in HepG2 human carcinoma cells, we identified several flavonoids, such as luteolin and apigenin, as PXR activators. The flavonoids did not directly bind to PXR, suggesting that an alternative mechanism may be responsible for flavonoid-mediated PXR activation. Consistent with the Cdk5-inhibitory effect of flavonoids, Cdk5 and p35 (a non-cyclin regulatory subunit required to activate Cdk5) were expressed in HepG2. The activation of Cdk5 attenuated PXR-mediated CYP3A4 expression whereas its downregulation enhanced it. The Cdk5-mediated downregulation of CYP3A4 promoter activity was restored by flavonoids, suggesting that flavonoids activate PXR by inactivating Cdk5. In vitro kinase assays showed that Cdk5 directly phosphorylates PXR. The Cdk kinase profiling assay showed that apigenin inhibits multiple Cdks, suggesting that several Cdks may be involved in activation of PXR by flavonoids. Our results for the first time link the stimulatory effect of flavonoids on CYP expression to their inhibitory effect on Cdks, through a PXR-mediated mechanism. These results may have important implications on the pharmacokinetics of drugs coadministered with herbal remedy and herbal-drug interactions. BMC Biochemistry 2010, 11:23doi:10.1186/1471-2091-11-23 Published: 16 June 2010

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Antioxidant activity of dietary fruits, vegetables, and commercial frozen fruit pulps.Hassimotto NM, Genovese MI, Lajolo FM. ABSTRACT Fruits, vegetables, and commercial frozen pulps (FP) consumed in the Brazilian diet were analyzed for antioxidant activities using two different methods, one that determines the inhibition of copper-induced peroxidation of liposome and another based on the inhibition of the co-oxidation of linoleic acid and beta-carotene. The anthocyanin-rich samples showed the highest, concentration-dependent, antioxidant activities in both systems. In the liposome system, at both 10 and 50 microM gallic acid equivalent (GAE) addition levels, the neutral and acidic flavonoids of red cabbage, red lettuce, black bean, mulberry, Gala apple peel, jambolao, acai FP, mulberry FP, and the acidic flavonoids of acerola FP showed the highest antioxidant activities (>85% inhibition). In the beta-carotene bleaching system, the samples cited above plus red guava gave inhibition values >70%. On the other hand, some samples showed prooxidant activity in the liposome system coincident with a low antioxidant activity in the beta-carotene system. There was no relationship between total phenolics content, vitamin C, and antioxidant activity, suggesting that the antioxidant activity is a result of a combination of different compounds having synergic and antagonistic effects. PMID: 15826041 PubMed

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Mammalian Cells: Implications for Inflammation, Heart Disease, and CancerElliott Middleton, Jr., Chithan Kandaswami and Theoharis C. Theoharides ABSTRACT Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

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Flavonoid intake and coronary mortality in Finland: a cohort studyPaul Knekt, Ritva Jarvinen, Antti Reunanen, , Jouni Maatela ABSTRACT

Objective: To study the association between dietary intake of flavonoids and subsequent coronary mortality. Design: A cohort study based on data collected at the Finnish mobile clinic health examination survey from 1967-72 and followed up until 1992. Settings: 30 communities from different parts of Finland. Subjects: 5133 Finnish men and women aged 30-69 years and free from heart disease at baseline. Main outcome measure: Dietary intake of flavonoids, total mortality, and coronary mortality. Results: In women a significant inverse gradient was observed between dietary intake of flavonoids and total and coronary mortality. The relative risks between highest and lowest quarters of flavonoid intake adjusted for age, smoking, serum cholesterol concentration, blood pressure, and body mass index were 0.69 (95% confidence interval 0.53 to 0.90) and 0.54 (0.33 to 0.87) for total and coronary mortality, respectively. The corresponding values for men were 0.76 (0.63 to 0.93) and 0.78 (0.56 to 1.08), respectively. Adjustment for intake of antioxidant vitamins and fatty acids weakened the associations for women; the relative risks for coronary heart disease were 0.73 (0.41 to 1.32) and 0.67 (0.44 to 1.00) in women and men, respectively. Intakes of onions and apples, the main dietary sources of flavonoids, presented similar associations. The relative risks for coronary mortality between highest and lowest quarters of apple intake were 0.57 (0.36 to 0.91) and 0.81 (0.61 to 1.09) for women and men, respectively. The corresponding values for onions were 0.50 (0.30 to 0.82) and 0.74 (0.53 to 1.02), respectively. Conclusion: The results suggest that people with very low intakes of flavonoids have higher risks of coronary disease.

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Sirving O. Keli, MD, PhD; Michael G. L. Hertog, PhD; Edith J. M. Feskens, PhD; Daan Kromhout, PhD, MPH Background Epidemiological studies suggested that consumption of fruit and vegetables may protect against stroke. The hypothesis that dietary antioxidant vitamins and flavonoids account for this observation is investigated in a prospective study. Methods A cohort of 552 men aged 50 to 69 years was examined in 1970 and followed up for 15 years. Mean nutrient and food intake was calculated from crosscheck dietary histories taken in 1960, 1965, and 1970. The association between antioxidants, selected foods, and stroke incidence was assessed by Cox proportional hazards regression analysis. Adjustment was made for confounding by age, systolic blood pressure, serum cholesterol, cigarette smoking, energy intake, and consumption of fish and alcohol. Results Forty-two cases of first fatal or nonfatal stroke were documented. Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk (RR) of the highest vs the lowest quartile of flavonoid intake ( 28.6 mg/d vs 0.05). The associations for the individual flavonoid intakes were similar to those for the total intake. There was also no significant association between intake of flavonoid-rich foods and the incidence of total and site-specific cancers. Conclusion: Our results do not support a major role of 5 common flavonols and flavones or selected flavonoid-rich foods in cancer prevention.American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26913 Vol. 89, No. 3, 905-912, March 2009 2009 American Society for Clinical Nutrition

Dietary flavonoid intake and non-Hodgkin lymphoma riskCara L Frankenfeld, James R Cerhan, Wendy Cozen, Scott Davis, Maryjean Schenk, Lindsay M Morton, Patricia Hartge and Mary H Ward ABSTRACT Background: The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects. Objective: We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.[Type text] Page 24

Design: During 19982000, we identified incident NHL cases aged 2074 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequencymatched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake. Results: Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypesdiffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146). Conclusion: A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.American Journal of Clinical Nutrition, Vol. 87, No. 5, 1439-1445, May 2008 2008 American Society for Nutrition

Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not?Barry Halliwell, Joseph Rafter and Andrew Jenner

ABSTRACTFoods and beverages rich in phenolic compounds, especially flavonoids, have often been associated with decreased risk of developing several diseases. However, it remains unclear whether this protective effect is attributable to the phenols or to other agents in the diet. Alleged health-promoting effects of flavonoids are usually attributed to their powerful antioxidant activities, but evidence for in vivo antioxidant effects of flavonoids is confusing and equivocal. This may be because maximal plasma concentrations, even after extensive flavonoid intake, may be low (insufficient to exert significant systemic[Type text] Page 25

antioxidant effects) and because flavonoid metabolites tend to have decreased antioxidant activity. Reports of substantial increases in plasma total antioxidant activity after flavonoid intake must be interpreted with caution; findings may be attributable to changes in urate concentrations. However, phenols might exert direct effects within the gastrointestinal tract, because of the high concentrations present. These effects could include binding of prooxidant iron, scavenging of reactive nitrogen, chlorine, and oxygen species, and perhaps inhibition of cyclooxygenases and lipoxygenases. Our measurements of flavonoids and other phenols in human fecal water are consistent with this concept. We argue that tocopherols and tocotrienols may also exert direct beneficial effects in the gastrointestinal tract and that their return to the gastrointestinal tract by the liver through the bile may be physiologically advantageous. American Journal of Clinical Nutrition, Vol. 81, No. 1, 268S-276S, January 2005 2005 American Society for Clinical Nutrition

Consumption of flavonoids in onions and black tea: lack of effect on F2-isoprostanes and autoantibodies to oxidized LDL in healthy humansJames D O'Reilly, Anthony I Mallet, Gareth T McAnlis, Ian S Young, Barry Halliwell, Tom AB Sanders and Helen Wiseman Abstact Background: Oxidative damage to lipids in vivo may be involved in the development of atherosclerosis and cancer. Onions and black tea are foods rich in flavonoids, predominantly the flavonoid quercetin, which is a potent in vitro inhibitor of membrane lipid peroxidation and LDL oxidation. Objective: Our objective was to investigate the effects of consuming a high-flavonoid (HF) diet enriched with onions and black tea on indexes of oxidative damage in vivo compared with a low-flavonoid (LF) diet.

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Design: Thirty-two healthy humans were studied in a randomized crossover design. Indexes of oxidative damage used were plasma F2-isoprostanes (a biomarker of lipid peroxidation in vivo) and the titer of antibodies to malondialdehyde (MDA)-modified LDL. Results: There were no significant differences in the intake of macronutrients or assessed micronutrients, plasma F2-isoprostane concentrations, and MDA-LDL autoantibody titer between the HF and LF dietary treatments. In the men, however, plasma concentrations of the F2-isoprostane 8-epi-prostaglandin F2 were slightly higher after the HF treatment phase than after the LF treatment [0.31 0.029 nmol/L (111 10.4 ng/L) compared with 0.26 0.022 nmol/L (92 7.8 ng/L); P = 0.041]. In all subjects, plasma quercetin concentrations were significantly higher after the HF treatment phase than after the LF treatment: 221.6 37.4 nmol/L compared with less than the limit of detection of 66.2 nmol/L. Conclusion: Flavonoid consumption in onions and tea had no significant effect on plasma F2-isoprostane concentrations and MDA-LDL autoantibody titer in this study and thus does not seem to inhibit lipid peroxidation in humans. American Journal of Clinical Nutrition, Vol. 73, No. 6, 1040-1044, June 2001 2001 American Society for Clinical Nutrition

Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytesM Noroozi, WJ Angerson and ME Lean This study assessed the antioxidant potencies of several widespread dietary flavonoids across a range of concentrations and compared with vitamin C as a positive control. The antioxidant effects of pretreatment with flavonoids and vitamin C, at standardized concentrations (7.6, 23.2, 93, and 279.4 micromol/L), on oxygen radical- generated DNA damage from hydrogen peroxide (100 micromol/L) in human lymphocytes were examined by using the single-cell gel electrophoresis assay (comet assay). Pretreatment with all flavonoids and vitamin C produced dose-dependent reductions in oxidative DNA damage. At a concentration of 279 micromol/L, they were ranked in decreasing order of potency as follows: luteolin (9% of damage from unopposed hydrogen peroxide), myricetin (10%), quercetin (22%), kaempferol (32%), quercitrin (quercetin-3-Lrhamnoside) (45%), apigenin (59%), quercetin- 3-glucoside (62%), rutin (quercetin-3beta-D-rutinoside) (82%), and vitamin C (78%). The protective effect of vitamin C against DNA damage at this concentration was significantly less than that of all the flavonoids except apigenin, quercetin-3-glucoside, and rutin. The ranking was similar[Type text] Page 27

with estimated ED50 (concentration to produce 50% protection) values. The protective effect of quercetin and vitamin C at a concentration of 23.2 micromol/L was found to be additive (quercetin: 71% of maximal DNA damage from unopposed hydrogen peroxide; vitamin C: 83%; both in combination: 62%). These data suggest that the free flavonoids are more protective than the conjugated flavonoids (eg, quercetin compared with its conjugate quercetin-3-glucoside, P < 0.001). Data are also consistent with the hypothesis that antioxidant activity of free flavonoids is related to the number and position of hydroxyl groups. American Journal of Clinical Nutrition, Vol 67, 1210-1218, Copyright 1998 by The American Society for Clinical Nutrition, Inc

Cocoa polyphenols and inflammatory mediatorsHelmut Sies, Tankred Schewe, Christian Heiss and Malte Kelm

ABSTRACTCocoa products are sources of flavan-3-ols, which have attracted interest regarding cardiovascular health. This review provides a survey of our research on the effects of cocoa polyphenols on leukotriene and nitric oxide (NO) metabolism and on myeloperoxidase-induced modification of LDL. Because intake of flavonoid-rich chocolate by human subjects was reported to decrease the plasma concentrations of proinflammatory cysteinyl leukotrienes, we assessed whether cocoa polyphenols inhibited human 5-lipoxygenase, the key enzyme of leukotriene synthesis. ()Epicatechin and other cocoa flavan-3-ols proved to be inhibitory at the enzyme level. This action may confer antileukotriene action in vivo. In a double-blind crossover study, 20 individuals at risk for cardiovascular diseases received cocoa beverages with high or low contents of flavan-3-ols. NO-dependent, flow-mediated dilation of the brachial artery and concentrations of nitroso compounds in plasma were measured, and it was shown that ingestion of the high-flavanol coca drink but not the low-flavanol cocoa drink[Type text] Page 28

significantly increased plasma concentrations of nitroso compounds and flow-mediated dilation of the brachial artery. Therefore, ingested flavonoids may reverse endothelial dysfunction through enhancement of NO bioactivity. Oxidative modification of LDL appears to be crucial for atherogenesis, and one of the mediators is the proinflammatory proatherogenic enzyme myeloperoxidase. Micromolar concentrations of ()-epicatechin or other flavonoids were found to suppress lipid peroxidation in LDL induced by myeloperoxidase in the presence of physiologically relevant concentrations of nitrite, an NO metabolite. Adverse effects of NO metabolites, such as nitrite and peroxynitrite, were thus attenuated.American Journal of Clinical Nutrition, Vol. 81, No. 1, 304S-312S, January 2005 2005 American Society for Clinical Nutrition

The transparent testa4 Mutation Prevents Flavonoid Synthesis and Alters Auxin Transport and the Response of Arabidopsis Roots to Gravity and LightCharles S. Buer and Gloria K. Muday

ABSTRACTWe examined whether flavonoids act as endogenous auxin transport regulators during gravity vector and light intensity changes in Arabidopsis thaliana roots. Flavonoid deficient transparent testa4 [tt4(2YY6)] seedlings had elevated root basipetal auxin transport compared with the wild type, consistent with the absence of a negative auxin transport regulator. The tt4(2YY6) roots had delayed gravitropism that was chemically complemented with a flavonoid intermediate. Flavonoid accumulation was found in wild-type columella cells, the site of gravity perception, and in epidermal and cortical cells, the site of differential growth, but flavonoid accumulation was absent in tt4(2YY6) roots. Flavonoid accumulation was higher in gravity-stimulated root tips as compared with vertical controls, with maximum differences coinciding with the timing of gravitropic bending, and was located in epidermal cells. Exogenous indole-3-acetic acid (IAA) also elevated flavonoid accumulation, suggesting that flavonoid changes in response to gravity might be partly as a result of changing IAA distribution. Acropetal[Type text] Page 29

IAA transport was also elevated in roots of tt4(2YY6). Flavonoid synthesis was repressed in the dark, as were differences in root acropetal transport in tt4(2YY6). These results are consistent with light- and gravity-induced flavonoid stimulation that alters auxin transport in roots and dependent physiological processes, including gravitropic bending and root development. The Plant Cell 16:1191-1205 (2004) 2004 American Society of Plant Biologists

Dietary intake of flavonoids and asthma in adultsV. Garcia, I. C. W. Arts, J. A. C. Sterne, R. L. Thompson and S. O. Shaheen

ABSTRACTEpidemiological studies have suggested that a high consumption of apples may protect against asthma and chronic obstructive pulmonary disease. This effect has been attributed to their high flavonoid content, but few studies have investigated the relationship between flavonoid intake and obstructive lung disease directly. In a population-based, case-control study of 1,471 adults aged 1650 yrs in London (UK), the present study examined whether dietary intake of catechins, flavonols and flavones was negatively associated with asthma, asthma severity and chronic sputum production. Asthma was defined by positive responses to a standard screening questionnaire in 1996 and information about usual diet was obtained by a food frequency questionnaire in 1997. After controlling for potential confounders, dietary intake of these three flavonoid subclasses was not significantly associated with asthma, (odds ratio per quintile (95% confidence interval) = 0.94 (0.861.02); 1.00 (0.921.09); 0.98 (0.88 1.08) for flavones, flavonols and total catechins, respectively) nor was it associated with asthma severity, or chronic sputum production.[Type text] Page 30

In conclusion, no evidence was found for a protective effect of three major subclasses of dietary flavonoids on asthma. It is possible that other flavonoids or polyphenols present in apples may explain the protective effect of apples on obstructive lung disease. Eur Respir J 2005; 26:449-452 Copyright ERS Journals Ltd 2005 doi: 10.1183/09031936.05.00142104

Select Flavonoids and Whole Juice From Purple Grapes Inhibit Platelet Function and Enhance Nitric Oxide ReleaseJane E. Freedman, MD; Crawford Parker, III, MD; Liqing Li, MS; Jacob A. Perlman; Balz Frei, PhD; Vadim Ivanov, PhD; Leslie R. Deak, BS; Mark D. Iafrati, MD; John D. Folts, PhD

ABSTRACTBackgroundModerate red wine consumption is inversely associated with coronary ischemia, and both red wine and purple grape juice (PGJ) contain flavonoids with antioxidant and antiplatelet properties believed to be protective against cardiovascular events. Acute cardiac events are also associated with decreased platelet-derived nitric oxide (NO) release. In this study, the effects of PGJ and PGJ-derived flavonoids on platelet function and platelet NO production were determined. Methods and ResultsIncubation of platelets with dilute PGJ led to inhibition of aggregation, enhanced release of platelet-derived NO, and decreased superoxide production. To confirm the in vivo relevance of these findings, 20 healthy subjects consumed 7 mL kg-1 d-1 of PGJ for 14 days. Platelet aggregation was inhibited after PGJ supplementation, platelet-derived NO production increased from 3.51.2 to 6.01.5 pmol/108 platelets, and superoxide release decreased from 29.55.0 to 19.23.1 arbitrary units (P