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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jada.2009.11.024 Byline: Raul Zamora-Ros, Cristina Andres-Lacueva, Rosa M. Lamuela-Raventos, Toni Berenguer, Paula Jakszyn, Aurelio Barricarte, Eva Ardanaz, Pilar Amiano, Miren Dorronsoro, Nerea LarraA[+ or -]aga, Carmen Martinez, Maria J. Sanchez, Carmen Navarro, Maria D. Chirlaque, Maria J. Tormo, J. Ramon Quiros, Carlos A. Gonzalez Abstract: Epidemiologic studies have suggested associations between flavonoid intake and health benefits. Traditional Mediterranean diets consist of a high consumption of plant products rich in flavonoids. Article History: Accepted 8 September 2009

This article provides an overview of current research on flavonoids as presented during a workshop entitled, 'Flavonoids and Heart Health,' held by the ILSI North America Project Committee on Flavonoids in Washington, DC, May 31 and June 1, 2005. Because a thorough knowledge and understanding about the science of flavonoids and their effects on health will aid in establishing dietary recommendations for bioactive components such as flavonoids, a systematic review of the science of select flavonoid classes (i.e., flavonols, flavones, flavanones, isoflavones, flavan-3-ols, anthocyanins, and proanthocyanidins) was presented. The objectives of the workshop were to 1) present and discuss current research on flavonoid intake and the relation between flavonoids and heart health; 2) develop information that could lead to expert consensus on the state-of-the-science of dietary intake of flavonoids on heart health; and 3) summarize and prioritize the research needed to establish the relations between specific flavonoids and heart health. Presentations included the basics of the biology of flavonoids, including the types and distribution in foods, analytical methodologies used to determine the amounts in foods, the bioavailability, the consumption patterns and potential biomarkers of intake, risk assessment and safety evaluation, structure/ function claims, and the proposed mechanism(s) of the relation between certain flavonoids and heart health endpoints. Data presented support the concept that certain flavonoids in the diet can be associated with significant health benefits, including heart health. Research gaps were identified to help advance the science.

Luteolin is 3',4',5,7-tetrahydroxyflavone found in celery, green pepper, and perilla leaf that inhibits tumorigenesis in animal models. We examined luteolin-mediated regulation of cell cycle progression and apoptosis in the HT-29 human colon cancer cell line. Luteolin decreased DNA synthesis and viable HT-29 cell numbers in a concentration-dependent manner. It inhibited cyclin-dependent kinase (CDK)4 and CDK2 activity, resulting in [G.sub.1] arrest with a concomitant decrease of phosphorylation of retinoblastoma protein. Activities of CDK4 and CDK2 decreased within 2 h after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 [micro]mol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2. Cyclin [D.sub.1] levels decreased after luteolin treatment, although no changes in expression of cyclin A, cyclin E, CDK4, or CDK2 were detected. Luteolin also promoted [G.sub.2]/M arrest at 24 h posttreatment by downregulating cyclin [B.sub.1] expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of [p21.sup.CIP1/WAF1], survivin, Mcl-1, Bcl-[x.sub.L], and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. We demonstrate that luteolin promotes both cell cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its antitumorigenic activities. cyclin-dependent kinase; cyclin; [G.sub.1] phase arrest; [G.sub.2]/M phase arrest; cell division cycle 2

Inflammation and oxidative stress are associated with cancer, atherosclerosis, and other chronic diseases. Dietary flavonoids have been reported to possess antiinflammatory and antioxidant properties, but their mechanisms of action and structure-activity relations have not been fully investigated. We hypothesized that differences in antioxidant activity between the structurally similar flavones, luteolin and chrysin (differing only in B-ring hydroxylation patterns), would differentially affect inflammation-associated Cox-2 expression and PG[E.sub.2] formation. Pretreatment of RAW 264.7 macrophage-like cells with 25, 50, or 100 [micro]mol/L concentrations of luteolin inhibited lipopolysaccharide (LPS)-induced Cox-2 protein expression (P < 0.0001). Chrysin pretreatment did not reduce LPS-induced Cox-2 protein expression at any level tested. Conversely, both luteolin and chrysin completely suppressed LPS-induced PG[E.sub.2] formation (P < 0.001). Luteolin, but not chrysin, inhibited xanthine/xanthine oxidase-generated superoxide formation at 100 [micro]mol/L in a cell-free system (P < 0.001). Although both luteolin and chrysin reduced LPS-induced hydroxyl radical formation relative to the positive control (P < 0.001), luteolin was superior to chrysin (P = 0.003). In summary, luteolin and chrysin suppressed PG[E.sub.2] formation equally well, despite differential effects on Cox-2 protein expression and on superoxide and hydroxyl radical scavenging. These data indicate that flavones may display similar antiinflammatory activity via different mechanisms. KEY WORDS: * luteolin * chrysin * cyclooxygenase-2 * prostaglandin [E.sub.2] * reactive oxygen species

In light of the continuing need for effective anticancer agents, and the association of fruit and vegetable consumption with reduced cancer risk, edible plants are increasingly being considered as sources of anticancer drugs. Cranberry presscake (the material remaining after squeezing juice from the berries), when fed to mice bearing human breast tumor MDA-MB-435 cells, was shown previously to decrease the growth and metastasis of tumors. Therefore, further studies were undertaken to isolate the components of cranberry that contributed to this anticancer activity, and determine the mechanisms by which they inhibited proliferation. Using standard chromatographic techniques, a warm-water extract of cranberry presscake was fractionated, and an acidified methanol eluate (Fraction 6, or Fr6) containing flavonoids demonstrated antiproliferative activity. The extract inhibited proliferation of 8 human tumor cell lines of multiple origins. The androgen-dependent prostate cell line LNCaP was the most sensitive of those tested (10 mg/L Fr6 inhibited its growth by 50%), and the estrogen-independent breast line MDA-MB-435 and the androgen-independent prostate line DU145 were the least sensitive (250 mg/L Fr6 inhibited their growth by 50%). Other human tumor lines originating from breast (MCF-7), skin (SK-MEL-5), colon (HT-29), lung (DMS114), and brain (U87) had intermediate sensitivity to Fr6. Using flow cytometric analyses of DNA distribution (cell cycle) and annexin V-positivity (apoptosis), Fr6 was shown in MDA-MB-435 cells to block cell cycle progression (P < 0.05) and induce cells to undergo apoptosis (P < 0.05) in a dose-dependent manner. Fr6 is potentially a source of a novel anticancer agent. KEY WORDS: * anticancer agent * flavonoids * cranberry * breast cancer