Flavonoids in the prevention of chronic diseases

Like carotenoids, polyphenols are among the estimated 60,000 secondary phytochemicals that help plants defend against pests and also serve as coloring, flavoring or fragrance agents. Polyphenols are broadly classified as phenolic acids and flavonoids (pigments), which are mainly found in fruits and drinks derived from plants, such as fruit juices, tea, coffee, cocoa and red wine, but also in vegetables, cereals and chocolate. Since polyphenols are present in large numbers in many foods and are involved in different biological processes, studying them is complex. According to current research, polyphenols may contribute to the prevention of chronic diseases; however, the evidence available to date is not sufficient enough to derive concrete intake recommendations in general or for specific populations with specific disease risks.

Much of the evidence on the efficacy of polyphenols comes from animal studies performed with doses far above the levels to which humans are routinely exposed through their diets. There are also epidemiological and clinical studies on the relationship between the intake of polyphenols – particularly the large class of flavonoids – and the preservation of human health or the prevention of diseases. Many epidemiological studies suggest a possible protective effect of antioxidant polyphenols against cardiovascular diseases (1). Evidence of a potential protective effect against cancer, neurodegenerative diseases and infections has mainly been obtained from experimental studies (2, 3). Here, the functions of polyphenols seem to go beyond the modulation of oxidative stress (4): Of interest are their ability to bind proteins or minerals (5), their ability to attach to bacteria and viruses, and their hormone-like effects (6).

Flavonoids

A particularly large and diverse class of polyphenols are the flavonoids, which are subdivided into a number of other substances: anthocyanins or anthocyanidins, flavanols, flavonols, flavones and isoflavones – which are subdivided into yet other substances (7). Flavonoids (Latin “flavus” = yellow) often produce yellow pigmentation in plants. Anthocyanins (Greek “anthos” = flower and “kyanos” = blue) give fruits such as blueberries, red grapes, currants or blackberries their blue or red color (8). Some examples of particularly flavonoid-rich foods are onions and apples with the flavonol quercetin (9), blue and red berries, especially the blueberry, with anthocyanins (10) and green tea with catechins (11). Certain plants, such as vine plants, also have an enzyme active in flavonoid metabolism that produces stilbene derivatives. Red grapes are an important source of the stilbene derivative resveratrol, a phytoalexin (Greek “phyto” = plant and “alexein” = ward off) that plants produce primarily to stave off infections, such as fungal infections (12). Resveratrol is an antioxidant and seems to have an effect on inflammatory processes. In particular it increases the produc-tion of an enzyme (sirtuin 1) that can prevent the initiation of programmed cell death (apoptosis) and thus have a potentially life-prolonging effect (13, 14). Among the flavonoids the catechins – such as epigallocate-chin-3-gallate (EGCG) – as well as the anthocyanins and among the stilbenes resveratrol count among the most widely scientifically researched polyphenols with potential in the prevention of chronic diseases.     

Cardiovascular disease

According to the WHO, 17.3 million people died worldwide in 2008 from cardiovascular diseases, and by 2030 this number is expected to rise to 23.3 million (15). Of particular interest in the exploration of preventive strategies to curtail this trend are polyphenols – particularly flavonoids and resveratrol. Among other effects, the anti-hypertensive properties of various polyphenols are a focus of research (16).
 
Experimental, epidemiological and clinical studies have provided ample evidence of a possible association between an increased intake of green tea and the promotion of cardiovascular health. As the largest class of polyphenols in green tea, catechins seem to have a protective effect on vascular function through several mechanisms (17). They act as: 1. antioxidants by scavenging free radicals, inhibiting pro-oxidant enzymes and promoting the production of antioxidant enzymes (18); 2. anti-hypertensive agents by regulating vascu-lar tone through, among other things, the activation of nitric oxide in the endothelium (19); 3. lipid-lowering agents by blocking the key enzymes involved in lipid biosynthesis, and by improving the blood lipid profile through the reduction of intestinal fat absorption (20, 21); 4. anti-inflammatory agents by suppressing inflammatory processes of atherosclerotic lesions in the vascular wall (22); 5. anti-proliferative agents by interfering with vascular cell growth factors involved in the onset of arteriosclerosis, thereby hindering the growth and proliferation of smooth muscle cells (24); and 6. anti-thrombotic agents by preventing the clumping of red blood platelets.

Epidemiological studies suggest that increased consumption of anthocyanins may reduce the risk of cardiovascular diseases. Studies have shown the consumption of red berries, such as strawberries or blueberries to provide a source of anthocyanins. The Iowa Women’s Health Study in the US reported that over 16 years, a daily intake of 0.2 mg of anthocyanins was associated with a lower risk of cardiovascular disease in postmenopausal women (25). In the WHO’s MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) study project, subjects from France who regularly consumed alcohol (red wine) were found to live longer than participants from 17 other Western countries, including the US and the UK (26–28), although the cholesterol levels of the French population were similar to those of other groups. A possible cause for this “French paradox” is thought to be a cardio-protective effect of anthocyanins in red wine. A Norwegian randomized controlled trial of men and women aged 47–74 years reported a signifi-cant improvement in risk factors for cardiovascular diseases following supplementation with anthocyanins (29). At present, the possible mechanisms of anthocyanins – for example, as antioxidants protecting against DNA damage and lipid peroxidation and as factors that can positively influence the immune response through the production of cytokine – are being intensively researched. To get meaningful results, detailed aspects still need to be investigated in further intervention studies (30).

Resveratrol has been studied intensively in recent years for potential cardio-protective effects. Population-based studies have shown that Mediterranean diets rich in resveratrol can lower the risk for the development of cardiovascular disease in humans (31,32). Studies with animals have shown evidence of a slowing of the aging process by the stilbene derivative (13, 14, 33). In addition, supplements containing resveratrol have shown anti-inflammatory and antioxidant effects in animal experiments, an indication of potential preventive effects on numerous degenerative diseases (34, 35). Further studies aimed at a deeper understanding of several possible mechanisms by which resveratrol might contribute to the health of the heart and circulatory system are in progress (36, 37).  

Cancer

According to the WHO, 7.6 million people died worldwide in 2008 from cancer, and it is estimated that this number will increase to 13.1 million by 2030 (38). To counter this trend, polyphenols are also being looked at in the exploration and establishment of cancer-defense strategies. The focus here is on catechins from green tea due to their possible supportive effect in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most studied catechin due to its potential cancer-preventive properties, which seem to act on cell signaling pathways (39). Functioning signaling pathways are critical for the maintenance of cellular equilibrium and the mediation of biological processes. Thus, the disruption of such signaling pathways is associated with different types of diseases, such as cancer. A cancer-preventive effect of catechins may be due to the regulation of diverse signaling pathways, whereby processes, such as cell growth, division and death, may be positively influenced through the control of gene expression. Among other things, catechins inhibit the transmission of the insulin-like growth factor (IGF-1) and the formation of metastases. EGCG has, for example, been able to induce the death of leukemic B-cells in vitro. The functional mechanism of cate-chins in cell signal transduction is very complex and has not yet been fully explored (40).

Several epidemiological studies from China have provided evidence of an association between an increased consumption of green tea and the prevention of gastrointestinal cancers, such as gastric and esophageal cancer (41–43). However, equivalent studies with Chinese and Asian-American women with regard to breast cancer prevention did not yield consistent results, since the risk of breast cancer is certainly influenced by genetic predisposition (45, 46). In a clinical study from China, women with ovarian cancer who drank at least one cup of green tea a day lived longer than patients without this dietary habit (46, 47). In Japan, the effect of green tea and coffee consumption on the very aggressive and rarely curable pancreatic cancer was inves-tigated in a population-based study, with the result that a preventive effect could not be clearly attributed to green tea (48). A risk-reducing effect of green tea in the development of prostate cancer could be observed in some but not all epidemiological studies from China and Japan (49–51). While catechins have inhibited the growth of lung cancer cells in vitro (52), until now only a slight indication of a preventive effect of green tea against cancer could be demonstrated in cohort studies (53).

That anthocyanins may protect against cancer has been suggested by a series of in vitro and in vivo studies (animal models with various tumor types). Beyond their cytoprotective function as an antioxidant, they seem, for example, to activate “detoxifying”enzymes that inhibit the proliferation of cancer cells and induce their death. Their anti-inflammatory effect could also play a role in this context. In animal models, anthocyanins have shown preventive potential against cancer cells in tumors of the esophagus and colon, as well as in the development of skin and lung cancer (54).

Resveratrol has also been shown not only to act as an antioxidant but also to inhibit the division of cancer cells and initiate their death. Evidence of resveratrol’s cancer-protective potential is based on results from in vitro and in vivo studies and have yet to be confirmed in human studies (55).

Neurodegenerative and infectious diseases

Studies have associated the catechin epigallocatechin-3-gallate (EGCG) with a possible preventive effect against neurodegenerative diseases, although the underlying molecular mechanisms remain to be explored. The catechin seems to be redox-sensitive and possibly acts on amyloid protein deposits in the brain that are likely involved in the development of diseases, such as Alzheimer’s disease (56). The state of research for anthocyanins is similar: Their presumed preventive potential is inferred mainly from their antioxidant mode of action (57). With resveratrol, factors providing a basis for neurodegenerative protection in addition to its antioxidant and anti-inflammatory properties include the activation of the regulatory enzyme sirtuin 1 (58). Flavonoids, such as catechins and anthocyanins and the stilbene resveratrol, have been shown in numerous experimental studies to have anti-inflammatory and antibacterial effects (58–60), which suggests a potential against inflammation and infections. Epidemiological and clinical studies demonstrating this effect in humans, however, are still pending.