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Dietary Polyphenols and Their Biological Significance

Department of Natural Product Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, P. R. China
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2007, 8(9), 950-988;
Submission received: 12 June 2007 / Revised: 27 August 2007 / Accepted: 27 August 2006 / Published: 12 September 2007


Dietary polyphenols represent a wide variety of compounds that occur in fruits, vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. They are mostly derivatives and/or isomers of flavones, isoflavones, flavonols, catechins and phenolic acids, and possess diverse biological properties such as antioxidant, antiapoptosis, anti-aging, anticarcinogen, anti-inflammation, anti-atherosclerosis, cardiovascular protection, improvement of the endothelial function, as well as inhibition of angiogenesis and cell proliferation activity. Most of these biological actions have been attributed to their intrinsic reducing capabilities. They may also offer indirect protection by activating endogenous defense systems and by modulating cellular signaling processes such as nuclear factor-kappa B (NF-κB) activation, activator protein-1(AP-1) DNA binding, glutathione biosynthesis, phosphoinositide 3 (PI3)-kinase/protein kinase B (Akt) pathway, mitogen-activated protein kinase (MAPK) proteins [extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and P38 ] activation, and the translocation into the nucleus of nuclear factor erythroid 2 related factor 2 (Nrf2). This paper covers the most recent literature on the subject, and describes the biological mechanisms of action and protective effects of dietary polyphenols.

1. Introduction

Oxidative stress results in oxidative alteration of biological macromolecules such as lipids, proteins and nucleic acids. It is considered to play a pivotal role in the pathogenesis of aging and degenerative diseases [13]. In order to cope with an excess of free radicals produced upon oxidative stress, human bodies have developed sophisticated mechanisms for maintaining redox homeostasis. These protective mechanisms include scavenging or detoxification of reactive oxygen species (ROS), blocking ROS production, sequestration of transition metals, as well as enzymatic and nonenzymatic antioxidant defenses produced in the body, that is, endogenous [4,5], and others supplied with the diet, namely, exogenous ones. Among them, dietary polyphenols have been widely studied for their strong antioxidant capacities and other properties by which cell functions are regulated [6,7].
Dietary polyphenols represent a group of secondary metabolites which widely occur in fruits, vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. They are mostly derivatives, and/or isomers of flavones, isoflavones, flavonols, catechins, and phenolic acids. Dietary polyphenols exhibit many biologically significant functions, such as protection against oxidative stress, and degenerative diseases. Experimental data indicate that most of these biological actions can be attributed to their intrinsic antioxidant capabilities. Dietary polyphenols may offer an indirect protection by activating endogenous defense systems and by modulating cellular signaling processes such as NF-κB activation, AP-1 DNA binding, glutathione biosynthesis, PI3-kinase/Akt pathway, MAPK proteins (ERK, JNK and P38) activation, and the translocation into the nucleus of Nrf2 [810].

2. Classification and occurrence of dietary polyphenols

Dietary polyphenols are the most abundant antioxidants in human diets. With over 8,000 structural variants, they are secondary metabolites of plants and denote many substances with aromatic ring(s) bearing one or more hydroxyl moieties. They are subdivided into groups (Figure 1) by the number of phenolic rings and of the structural elements that link these rings [11]: (1) The phenolic acids with the subclasses derived from hydroxybenzoic acids such as gallic acid and from hydroxycinnamic acid, containing caffeic, ferulic, and coumaric acid; (2) the large flavonoid subclass, which includes the flavonols, flavones, isoflavones, flavanones, anthocyanidins, and flavanols; (3) the stilbenes; and (4) the lignans and the polymeric lignins.
The main dietary sources of polyphenols include some common fruits, vegetables and beverages. Phenolic acids account for about one third of the total intake and flavonoids account for the remaining two thirds. The most abundant flavonoids in the diet are flavanols (catechins plus proanthocyanidins), anthocyanins and their oxidation products. The main polyphenol dietary sources are fruit and beverages (fruit juice, wine, tea, coffee, chocolate and beer) and, to a lesser extent vegetables, dry legumes and cereals. Most of dietary polyphenols and their sources in our diets were shown in Table 1.

2.1 Phenolic acids

A major class within the phenolic compounds is the hydroxycinnamic acids, which are widely distributed in plant kingdom. The major hydroxycinnamic acid is caffeic acid, which occurs in foods mainly as an ester with quinic acid called chlorogenic acid (5-caffeoylquinic acid). Chlorogenic acid and caffeic acid are antioxidants in vitro and they might inhibit the formation of mutagenic and carcinogenic N-nitroso compounds for the inhibitory effect on the N-nitrosation reaction in vitro.

2.2 Flavonoids

Flavonoids are the most abundant polyphenols in human diets, and are mainly divided into: (a) anthocyanins, glycosylated derivative of anthocyanidin, present in colorful flowers and fruits; (b) anthoxanthins, a group of colorless compounds further divided in several categories, including flavones, flavans, flavonols, flavanols, isoflavones, and their glycosides. Flavonols are mainly represented by myricetin, fisetin, quercetin and kaempferol.

2.3 Stilbenes

Stibenes are structurally characterized by the presence of a 1,2-diphenylethylene nucleus with hydroxyls substitued on the aromatic rings, and exist in the form of monomers or oligomers. The best known compound is trans-resveratrol, possessing a trihydroxystilbene skelelton.

2.4 Tannins

Tannins are a group of water-soluble polyphenols having molecular weights from 500 to 3,000 which are subdivided into condensed and hydrolisable tannins, and commonly found complexed with alkaloids, polysaccharides and proteins, particularly the latter. On the basis of structural characteristics there are two groups, gallotannins and ellagitannins of hydrolysable tannins.

2.5 Diferuloylmethanes

Diferuloylmethanes are a small group of phenolic compounds with two aromatic rings substitued with hydroxyls, and linked by aliphatic chain containing carbonyl groups. There are also some other polyphenols such as hydroxytyrosol, a simple polyphenol presenting in olive fruits and olive oil [12,13].

3. Bioactivities of dietary polyphenols

Oxidative stress is considered to play a pivotal role in the pathogenesis of aging and several degenerative diseases, such as atherosclerosis, cardiovascular disease, type II diabetes and cancer [13]. In order to cope with an excess of free radicals produced upon oxidative stress, humans have developed endogenous and exogenous mechanisms in order to maintain redox homeostasis. Among these, dietary polyphenols have been largely studied for their strong antioxidant capacities and other properties by which cell activities are regulated (Figures 2 and 3).

3.1 Antioxidant and free radical scavenging properties

In order to combat and neutralize the deleterious effects of ROS, various antioxidant strategies have evolved either by increasing the endogenous antioxidant enzyme defenses or by enhancing the non-enzymatic defenses through dietary or pharmacological means (Table 2). Dietary polyphenols have been reported to possess potent antioxidant activity by endogenous and exogenous mechanisms.
Dihydrocaffeic acid was able to scavenge free radicals (superoxide anion, hydroxyl and peroxyl radicals) in human EA.hy926 endothelial cells [42]. Curcumin and quercetin increased several antioxidant enzyme activities such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) or glutathione reductase (GR) in vivo and in vitro[8,9,44], and activated endogenous defense systems in vitro[40,45]. Hydroxytyrosol could increase CAT and SOD activities in rats fed a cholesterol-rich diet [35].
The transcription factor Nrf2 regulates the basal and inducible expression of numerous detoxifying and antioxidant genes. The Nrf2–Kelch-like ECH-associated protein 1 (Keap1)-ARE system is now recognized as one of the major cellular defence mechanisms against oxidative and xenobiotic stresses [46]. (−)-Epigallochatechin gallate (EGCG) and (−)-epichatechin gallate (ECG) induced ARE-mediated gene expression through the activation of MAPK proteins (ERK, JNK and p38) in HepG2-ARE-C8 cell [10]. Tanigawa et al. reported that quercetin-induced ARE activity involves upregulation of Nrf2 through the regulation of both transcription and posttranscription sites and repression of Keap1 by affecting the posttranscription site in HepG2 cells [48]. Curcumin could increase the expression of glutathione S-transferase P1 (GSTP1) by activing ARE and Nrf2 in HepG2 cells [40].

3.2. Anti-atherosclerosis and cardioprotection

Studies have shown that some of dietary polyphenols exerted anti-atherosclerosis and cardioprotection (Table 3). Oleuropein inhibited the oxidation of low density lipoprotein (LDL) in vitro[61]. Quercetin decreased lipid peroxidation, upregulated the expression of serum high density lipoprotein (HDL)-associated paraoxonase 1(PON-1) in the HuH7 human hepatoma cell line [66], inhibited oxidized LDL (oxLDL)-triggered apoptosis, and increased intracellular glutathione (GSH) downregulation in COS-1 cells [68].
Proanthocyanidin could significantly reduce cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and c-Jun in Male Sprague Dawley rats [74]. Furthermore, proanthocyanidin could regulate the levels of CD36 mRNA and protein in oxLDL treated peripheral blood mononuclear cells [73]. Resveratrol showed that in vitro it could decrease the expression of vascular cell adhesion molecule-1 (VCAM-1) [64], cyclooxygenase-2 (COX-2) [55], and matrix metalloproteinase-9 (MMP-9) mRNA [56] through suppression of activation of nuclear factor AP-1 [55]. Hydroxytyrosol could not only lower serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), but also slow the lipid peroxidation process in rats fed a cholesterol-rich diet [35].

3.3 Neuroprotective effects on anti-aging and neurodegenerative diseases

Recently, there has been considerable interest in the neuroprotective effects of dietary polyphenols (Table 4), especially in the context of their modes of action as antioxidants [6]. Resveratrol had an impact on cognitive deficits by activating the phosphorylation of protein kinase C (PKC), secreting transthyretin to prevent Aβ aggregation in cultured rat hippocampal cells [77], and stimulating AMP kinase activity in Neuro2a cells and primary neurons [75]. EGCG stimulated the deacetylase activity of recombinant silent information regulator two ortholog 1 (SIRT1) protein in human HT29 cells [80]. Curcumin could disrupt existing plaques and restore distorted neurites in an Alzheimer mouse model [84]. They had been considered as therapeutic agents for altering brain aging processes, and as possible neuroprotective agents in progressive neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases.

3.4 Anti-inflammatory properties

Oxidative stress induced inflammation is mediated by the activation of NF-kB and AP-1. It affects a wide variety of cellular signaling processes leading to generation of inflammatory mediators and chromatin remodeling [95,96]. The latter allows expression of pro-inflammatory genes such as interleukin-1beta (IL-1β), IL-8, tumor necrotic factor alpha (TNF-a), and inducible nitric oxide synthase (iNOS). The undesired effects of oxidative stress have been found to be controlled by the antioxidant and/or anti-inflammatory effects of dietary polyphenols such as curcumin and resveratrol in vivo and in vitro[8890,95,97] (Table 5). Resveratrol inhibited pro-inflammatory gene expression via inhibition of inhibitory κB (IκB), thus inhibiting NF-κB transactivation, as well as restoring transrepressive pathways through the activation of histone deacetylases in RAW 264.7 cells [89].
On the other hand, to counter the effects of oxidative stress, the cells also concomitantly express protective antioxidants such as glutamate cysteine ligase (GCL), manganese superoxide dismutase (MnSOD), and heme oxygenase-1(HO-1). In addition, expression of these antioxidant genes via modulation of MAPK-ARE-Nrf2 pathway is upregulated by EGCG and ECG in HepG2-ARE-C8 cell [10]. Apigenin, luteolin and quercetin had also been reported to inhibit inflammatory responses by downregulating the expression of iNOS and adhesion molecules in NR8383 macrophages and human endothelial cells [9193].

3.5 Antimutagenic/anticarcinogenic properties

Dietary polyphenols could modulate diverse biochemical processes involved in carcinogenesis (Table 6). Curcumin exerted antitumor activities by inhibition of cellular proliferation and angiogenesis, blockade of tumor cell cycle progression, and induction of programmed cell death in vivo and in vitro [109,110]. Cellular signaling cascades mediated by NF-κB or AP-1 acted as a centerplay in regulating many of aforementioned biochemical processes [102,110].
Resveratrol could block the activation of MAPKs and AP-1 in the skin of mice [102]. Consumption of berries and red fruits rich in polyphenols contributed to the reduction of cancer through many mechanisms such as in vitro inhibiting human cytochrome P450-dependent monooxygenases 1A1 (CYP1A1) activities [26], blocking the epidermal growth factor receptor (EGFR) tyrosine kinase activity [107], and decreasing protein kinase CKII activity [103].

3.6 Maintenance of gastrointestinal health and effects on digestive enzymes

It had been reported that digestive enzymes such as lipase, α-amylase, and α-glucosidase, were inhibited by proanthocyanidins and tannins in young chicks, which decreased the digestibility of protein, starch and lipid [119, 120]. Resveratrol could inhibit pancreatic bile salt-dependent lipase (BSDL) activity, expression and secretion in the rat pancreatic AR4-2J cells [121]. Cyanidin-3α-O-rhamnoside and quercetin-3α-O-rhamnoside could inhibit α-glucosidase and advanced glycation end product (AGE) formation in vitro[123]. The inhibition of digestive enzymes by dietary polyphenols may represent an under-reported mechanism for delivering some of the health benefits attributed to a diet rich in fruit and vegetables.

3.7 Modulation of signal transduction pathways

Dietary polyphenols may not merely exert their diverse biological effects as free radical scavengers, but may also modulate cellular signaling processes by affecting signal transduction pathways [122] (Table 7). Studies have been reported that curcumin could in vitro modulate NF-κB activation [124], AP-1 DNA binding [126], signal transducer and activator of transcription-3 (STAT3) phosphorylation [118]. Resveratrol exerted protection in vitro through PI3-kinase/Akt pathway, MAPK proteins (ERK, JNK and P38) activation [58], and the translocation into the nucleus of Nrf2 [132]. Resveratrol could also upregulate the expressions of GCL, MnSOD, and HO-1 against oxidative stress via MAPK-ARE-Nrf2 pathway in PC12 cells [132].

3.8 Improvement of endothelium functions

Several studies have indicated that red wine polyphenolic compounds (RWPCs) were able to inhibit proliferation and migration of vascular cells (Table 8). RWPCs induced nitric oxide (NO)-mediated endothelium-dependent relaxations in isolated arteries. The activation of endothelial NO synthase (eNOS) was due to two distinct mechanisms: (a) an increase in [Ca2+] i and (b) a phosphorylation of eNOS by the PI3-kinase/Akt pathway [137]. In addition, RWPCs caused endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations of isolated arteries consecutively to a localized and controlled formation of superoxide anions leading to the activation of the PI3-kinase/Akt pathway [136]. RWPCs also increased endothelial prostacyclin release and inhibited the synthesis and the effects of endothelin-1 in endothelial cell [139,141].
RWPCs could prevent matrix metalloproteinases-2 (MMP-2) activation and vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs) [133,134]. All these mechanisms might contribute to explain the vasodilatory, vasoprotective and anti-hypertensive effects of polyphenols in vivo.
Cyanidin-3-glucoside (Cy3G) and EGCG could enhance vascular eNOS activity and improve vascular endothelial function in bovine vascular endothelial cells [142]. Catechins had anti-angiogenic effects by reducing the vascularization on the chicken chorioallantoic membrane (CAM) [145].

3.9 Protective effect on immune cell functions

Dietary polyphenols appear to have a protective effect on immune cell functions. Alvarez et al. showed that leukocyte functions were improved in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals [149]. They could increase macrophage chemotaxis, phagocytosis, microbicidal activity, and natural killer function, and increase lymphoproliferation and IL-2 release in response to concanavalin A and lipopolysaccharide.
Curcumin could prevent tumor-induced T cell apoptosis by downregulating Bax level and augmenting Bcl-2 expression and restore cytokine-dependent Jak-3/Stat-5a signaling pathway in T cells of tumor bearer [150]. Caffeic acid, ellagic acid, and ferulic acid could inhibit apoptosis through the Bcl-2 independent mechanism in normal human peripheral blood mononuclear cells [116]. Thus, regular intake of these compounds will protect and improve quality of life.

3.10 Antiallergic activity

The incidence of type I allergic disorders have been increasing worldwide, particularly, the hypersensitivity to food. Akiyama and his coworkers reported that the apple condensed tannins intake would inhibit the development of the oral sensitization, and the inhibition could correlate with the rise in the population of TCRγδ-T cells in the intestinal intraepithelial lymphocytes [151]. Moreover, the apple condensed tannins could inhibit the release of histamine from rat basophilic leukemia (RBL-2H3) cells stimulated by the antigen-stimulation and from rat peritoneal mast cells stimulated by compound 48/80. They also inhibited hyaluronidase activity and increase in intracellular free calcium concentration in RBL-2H3 cells stimulated with the antigen [152].

3.11 Antidiabetic effects

Johnston and coworkers demonstrated that glucose uptake into cells under sodium-dependent conditions was inhibited by flavonoid glycosides and non-glycosylated polyphenols in polarised Caco-2 intestinal cells [154]. Under sodium-free conditions, aglycones and non-glycosylated polyphenols inhibited glucose uptake whereas glycosides and phenolic acids were ineffective. These data suggest that aglycones inhibit facilitated glucose uptake whereas glycosides inhibit the active transport of glucose. The non-glycosylated dietary polyphenols appeared to exert their effects via steric hindrance, while EGCG, ECG and (−)-epigallochatechin were effective against both transporters.
More recently, Koboyashi et al. have shown that the green tea polyphenols EGCG and ECG also inhibited glucose transport, possibly by sodium-dependent glucose transporter 1 (SGLT1) inhibition in the rabbit small intestine [155]. Song et al have presented evidence for quercetin-mediated inhibition of the facilitated diffusion glucose transporter 2 (GLUT2) in Chinese hamster ovary cells [156].
Anthocyanins inhibited α-glucosidase activity and reduced blood glucose levels after starch-rich meals. This is a proven clinical therapy for controlling type II diabetes [158] (Table 9).

3.12 Regulation of cell cycle progression

It was demonstrated that resveratrol and proanthocyanidins could regulate cell cycle progression by upregulating p21 expression, G1 phase arrest and downregulating cyclin D1/D2–Cdk6 in vitro [163165, 170] (Table 10).

3.13 Modulation of hormonal effects and contraceptive activity

Some studies showed that dietary polyphenols could modulate the level of hormone. Resveratrol could exert mixed estrogen agonist/antagonist activities in mammary tumor models. It could affect the expression of 17β-estradiol-responsive progesterone receptor (PR) and presnelin 2 proteins in vitro and in vivo [159]. Bhat et al. showed that resveratrol exhibited antiestrogenic properties and inhibited the levels and activity of PR by downregulating α (1)-integrin expression in human endometrial adenocarcinoma cells [160].
Otake and his coworkers demonstrated that quercetin and resveratrol potently reduced estrogen sulfotransferase (EST) activity and inhibited sulfation of 17β-estradiol in normal human mammary epithelial cells [161]. Both of the compounds potently inhibited recombinant human EST. In fact, they could serve as substrates for EST. Gossypol, a polyphenolic compound from cotton seed, had contraceptive activity and could inhibit 11β-hydroxysteroid dehydrogenase and cause hypokalemia in some men [162].

3.14 Effect in the treatment of chronic obstructive pulmonary disease (COPD)

Since a variety of oxidants and free radicals are implicated in the pathogenesis of COPD, it is possible that therapeutic administration of multiple antioxidants will be effective in the treatment of COPD. Various approaches to enhance lung antioxidant capacity and clinical trials of dietary polyphenols in COPD are discussed. Resveratrol, EGCG, and quercetin could inhibit inflammatory gene expression by controling NF-κB activation and regulate GSH biosynthesis and chromatin remodel in human airway epithelial A549 cells [171,172]. Curcumin could decrease protein/mRNA expressions of pulmonary type I collagen (Col-I) and TGF-β1 in rats [173].

3.15 Other bioactive effects

It has been demonstrated that dietary polyphenols have other bioactive effects (Table 11), such as antibacterial activity of Gnemonol B and gnetin E [174], anti-HIV effect of proanthocyanidins [176], hepatoprotective ability of a novel proanthocyanidins IH636 [178], and angiogenesis effect of proanthocyanidins [177].

4. Prooxidant activity and cellular effects of the phenoxyl radicals of dietary polyphenols

Dietary polyphenols have beneficial antioxidant, anti-inflammatory and anticancer effects. However, at higher doses or under certain conditions these compounds may exert toxic prooxidant activities [181]. Galati et al.[182] have observed that dietary polyphenols with phenol rings were metabolized by peroxidase to form prooxidant phenoxyl radicals which, in some cases were sufficiently reactive to cooxidize GSH or NADH accompanied by extensive oxygen uptake and reactive oxygen species formation. Polyphenols with catechol rings also cooxidized ascorbate, likely mediated by semiquinone radicals. Incubation of hepatocytes with dietary polyphenols containing phenol rings was found to partially oxidize hepatocyte GSH to GSSG while polyphenols with a catechol ring were found to deplete GSH through formation of GSH conjugates.
Dietary polyphenols with phenol rings also oxidized human erythrocyte oxyhemoglobin and caused erythrocyte hemolysis more readily than polyphenols with catechol rings. It is concluded that polyphenols containing a phenol ring are generally more prooxidant than polyphenols containing a catechol ring. Subsequent studies revealed that [183] B-ring catechol-type flavonoids showed swift formation of their two electron oxidized quinone type metabolites, even upon their one electron oxidation by peroxidases. Enzymatic and/or chemical (auto) oxidation of the flavonoid generates the flavonoid semiquinone radical, which may be scavenged by GSH, thereby regenerating the flavonoid and generating the thiyl radical of glutathione. This thiyl radical may react with GSH to generate a disulfide radical anion which rapidly reduces molecular oxygen to superoxide anion radicals.
Huisman et al. [184] found that wine polyphenols and ethanol do not significantly scavenge superoxide nor affect endothelial nitric oxide production. Studies showed that flavonoids can induce oxidative damage and nick DNA via the production of radicals in the presence of Cu and O (2). Al, Zn, Ca, Mg and Cd have been found to stimulate phenoxyl radical-induced lipid peroxidation [185]. As a result of such enzymatic as well as non-enzymatic antioxidant reactions, phenoxyl radicals are formed as the primary oxidized products. Phenoxyl radicals can initiate lipid peroxidation. It is concluded that the prooxidant cytotoxicity of diet polyphenols is due to formation of ROS [186], role of phenoxyl radical/phenol redox couple [187], and stimulation by metals [185].

5. Bioavailability of dietary polyphenols

Polyphenols are the most abundant antioxidants in the human diet. They show a considerable structural diversity, which largely influences their bioavailability [188]. The biological properties of polyphenols depend on the amount consumed and on their bioavailability. Bioavailability appears to differ greatly between the various polyphenols, and the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues [189]. Both isoflavones and phenolic acids like caffeic acid and gallic acid are the most well absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are large molecular weight polyphenols such as the proanthocyanidins, the galloylated tea catechins, and the anthocyanins [190].
Ellagic acid was detected in human plasma at a maximum concentration (31.9 ng/mL) after 1 h postingestion [191]. Absorption of flavanols such as catechins was enhanced when tea polyphenols were administered as a green tea supplement in capsule form when consumed in the absence of food and led to a small but significant increase in plasma antioxidant activity compared with when tea polyphenols were consumed as black tea or green tea [192,193]. No differences were found in plasma EGCG concentrations and trolox equivalents determined by the trolox equivalent antioxidant capacity assay after administration as a single large dose in the form of either purified EGCG or as green tea extract (Polyphenon E) [194]. Hydroxytyrosol, the major olive oil phenolic compound, is dosedependently absorbed from olive oil [195]. Tuck et al. showed that hydroxytyrosol intravenously and orally administered oil-based dosings resulted in significantly greater elimination of the phenolics in urine within 24 h than the oral, aqueous dosing method. Oral bioavailability estimates of hydroxylInt. tyrosol when administered in an olive oil solution and when dosed as an aqueous solution was 99% and 75%, respectively [13].
Once absorbed, polyphenols are conjugated to glucuronide, sulphate and methyl groups in the gut mucosa and inner tissues. Non-conjugated polyphenols are virtually absent in plasma. Such reactions facilitate their excretion and limit their potential toxicity. EGCG and ECG were present in plasma mostly as the free form, whereas epicatechin and epigallocatechin were mostly present as the glucuronide and sulfate conjugates [192]. Recent data suggest that beta-glucosidases and maybe also lactase phlorizin hydrolase (LPH) in the small intestine are capable of hydrolysing flavonoid glucosides and these compounds are thus taken up as the free aglycon and not as the intact glycosides [196]. It has been reported that around 98% of hydroxytyrosol is present in plasma and urine in conjugated forms, mainly glucuronoconjugates, suggesting an extensive first pass intestinal/hepatic metabolism of the ingested primary forms [197199] and the 3-O-glucuronide of hydroxytyrosol shows stronger activity as a radical scavenger than hydroxytyrosol itself [200]. The major metabolites identified in in vitro and in vivo studies were an Omethylated derivative of hydroxytyrosol, glucuronides of hydroxytyrosol and a novel glutathionyl conjugate of hydroxytyrosol [200,201]. It has been recently reported that hydroxytyrosol and its metabolites are capable of binding human LDL after olive oil ingestion [202].
The polyphenols reaching the colon are extensively metabolised by the microflora into a wide array of low molecular weight phenolic acids. It has been shown that the plasma concentrations of total metabolites ranged from 0 to 4 μmol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol [189]. The biological properties of both conjugated derivatives and microbial metabolites will be essential to better assess the health effects of dietary polyphenols. Alternatively, some health effects of polyphenols may not require their absorption through the gut barrier. Their role as iron chelators in the gut lumen is briefly discussed. Tannic acid and catechin both interact with the gut but only catechin appears able to traverse the gut. In addition, they provide evidence for binding of tannic acid and catechin by endogenous proteins in the intestinal lumen. This may limit their absorption from the small intestine [203].

6. Conclusions

Consumption of polyphenol-rich fruits, vegetables, and beverages derived from plants, such as cocoa, red wine and tea, represents a diet beneficial to human health. Some dietary polyphenols possess antioxidative and anti-inflammatory properties, to some extent, contributing to their cancer chemopreventive potential. These phenolic substances have the ability to abrogate various biochemical processes induced or mediated by the tumor promoters. Some dietary polyphenols also induce apoptosis in premalignant or cancerous cells, and suppress growth and proliferation of various types of tumor cells via induction of apoptosis or arrest of a specific phase of the cell cycle.
However, the specific mechanism(s) by which these compounds affect human health remains unclear, despite extensive research conducted in this area in recent years. Most of that research has focused on the antioxidant properties of dietary polyphenols, which are well characterized and well established in vitro. The in vitro data often conflict with results obtained from in vivo studies on the antioxidant capacity of plasma or the resistance of plasma and lipoproteins to oxidation ex vivo after the consumption of polyphenols-rich foods by human subjects. These inconsistencies between the in vitro and the in vivo data are likely explained by the limited bioavailability of dietary polyphenols and their extensive metabolism in humans. Most of them exert multifacet action, and any clinical applications using these substances should be based on the precise understanding of the physiologically relevant action mechanisms.
Figure 1. Classification of dietary polyphenols.
Figure 1. Classification of dietary polyphenols.
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Figure 2. Bioactivities of dietary polyphenols.
Figure 2. Bioactivities of dietary polyphenols.
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Figure 3. Mechanisms of the biological effects of dietary polyphenols.
Figure 3. Mechanisms of the biological effects of dietary polyphenols.
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Table 1. Classification and sources of dietary polyphenols
Table 1. Classification and sources of dietary polyphenols
Class and subclassDietary polyphenolFoods or beveragesRef

AnthocyanidinsCyanidin 3-galactoside
Cyanidin 3-glucoside
Cyanidin 3-arabinoside
Cyanidin 3-xyloside
Fruits: blackberries,black currant,blueberries, black grape, elderberries,strawberries, cherries, plums, cranberry, pomegranate juice, raspberry
Others: red wine

Vegetables: capers, celery, chives, onions, red onions, dock leaves, fennel, hot peppers,cherry tomatoes, spinach, sweet potato leaves, lettuce, celery, broccoli, Hartwort leaves, kale
Cereal: buckwheat, beans(green/yellow)
Fruits: apples, apricots, grapes, plums, bilberries, blackberries, blueberries, cranberries, olive elderberries, currants, cherries, black currant juice, apple juice, ginkgo biloba
Spices and herbs: dill weed
Others: red wine, tea (green, black), tea (black beverage), cocoa powder, turnip (green), endive, leek

Citrus fruits and juices: lemon, lemon juice, lime juice, orange, orange juice, grapefruit, tangerine juice
Spices and herbs: peppermint

Fruits: celery, olives
Vegetables: hot peppers, celery hearts, fresh parsley
Spices and herbs: oregano, rosemary, dry parsley, thyme
Flavanols (Flavan-3-ols)(+)-Catechin
(−)-Epicatechin 3-gallate Morin
Fruits: apples, apricots, grapes, peaches, nectarines, pears,plums, raisins, raspberries, cherries, blackberries, blueberries, cranberries
Others: red wine, tea (green, black), chocolate (dark, milk), white wine, cocoa

Isoflavones (Flavans)Genistein
Fruits: grape seed/skin
Others: soybean, soy nuts, soy flour/bread, tofu, miso, soy milk, tofu yogurt, soy cheese/sauce/hot dog

Flavonoid glycosideRutin
Fruits: lemon, orange, orange juice, grapefruit, tangerine juice26

Phenolic acids27
Hydroxycinnamic acidsCaffeic acid
Chlorogenic acid
Ferulic acid
Neochlorogenic acid
P-coumaric acid
Sinapic acid
Caftaric acids
Fruits: bluberry, cranberry, pear, cherry(sweet), apple, orange, grapefruit, cherry juice,apple juice, lemon, peach,
Vegetables: potato, lettuce, spinach
Others: coffee beans, tea, coffee, cider

Hydroxybenzoic acidsEllagic acid
Gallic acid
Fruits: strawberry, raspberry grape juice( black/green), longan seed, pomegranate juice28

Fruits: grapes, peanuts,
Others: red wine

TanninsCatechin polymers
Epicatechin polymers
Sanguin H6
Tannic acids
Fruits: grape (dark/light) seed/skin, apple juice, strawberries, longan, raspberries, pomegranate, walnuts, muscadine grape, muscadine grape, peach, blackberry (juices/jams/jellies), olive, plum,
Vegetables: chick pea, black-eyed peas, lentils,
Cereal: haricot bean,
Others: red wine, white wine, cocoa, chocolate, oak-aged red wine, tea, cider, tea, coffee, immature fruits

DiferuloylmethaneCurcuminherbal remedy, dietary spice turmeric33
Table 2. Antioxidant and free radical scavenging properties of dietary polyphenols.
Table 2. Antioxidant and free radical scavenging properties of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
Epigallocatechin, EGCG, ECGInhibiting lipoxygenase and cyclooxygenaseIn human colon mucosa and colon tumor tissuesIn vitro34
Inducing ARE-mediated gene expression through the activation of MAPK proteins (ERK, JNK and p38)In HepG2-ARE-C8 cellIn vitro10
HydroxytyrosolIncreasing CAT and SOD activitiesIn rats fed a cholesterol-rich dietIn vivo35
Inhibiting the activities of 12-lipoxygenase and 5-lipoxygenase
Reducing leukotriene B4 production
In rat platelets and rat polymorphonuclear leukocytes (PMNL)In vitro36
Proanthocyanidin B4
Increasing CAT, glutathione S-transferase (GST) and SOD activities
Elevating cellular GSH content
In cardiac H9C2 cellsIn vitro37
CurcuminInhibiting CYP1A2, CYP3A4, CYP2B6, CYP2D6, and CYP2C9The plasmids with human cytochrome P450 NADPH reductaseIn vitro38
Inhibiting mitochondrial proton F0F1-ATPase/ATP synthaseRat brain F0F1-ATPaseIn vitro39
Increasing the expression of GSTP1 by activing ARE and Nrf2In HepG2 cellsIn vivo40
Increasing CAT, SOD activity and heat shock proteins 70 expression
Decreasing the activity of iNOS
Decreasing malondialdehyde (MDA), NO(2)(−) + NO(3)(−) and myeloperoxidase (MPO) level and serum transaminase concentration
In rat modelIn vivo8
Kaempferol-3-OgalactosideInhibiting human recombinant synovial phospholipase A2 (PLA2)In miceIn vivo41
EGCG, Quercetin, Kaempferol Morin, Apigenin, Daidzein, ECGInhibiting mitochondrial proton F0F1-ATPase/ATP synthaseRat brain F0F1-ATPaseIn vitro39
Ellagic acid Gallic acid CorilaginInhibiting tyrosinase, xanthine oxidase, and the formation of superoxide radicalIn substrate of L-tyrosineIn vitro29
Dihydrocaffeic acidEnhancing eNOS activity and protein expression Scavenging intracellular ROSIn human EA.hy926 endothelial cellsIn vitro42
Caffeic acid (+)-catechinInhibiting peroxynitrite-mediated oxidation of dopamineIn dopamineIn vitro43
QuercetinPreventing lactate dehydrogenase (LDH ) leakage
Increasing SOD, CAT, GSH, GPx, and GR activity
In mouse liverIn vivo9
Decreasing MDA and lipoperoxidation
Increasing Cu/Zn SOD and GPx mRNA
In HepG2 cellsIn vitro44
Increasing the expression and activity of NADPH:quinone oxidoreductase-1( NQO1)In the MCF-7 human breast carcinoma cellseIn vitro45
Enhancing γ-glutamylcysteine synthetase (γ-GCS)In HepG2 cellsIn vitro47
Enhancing the ARE binding activity and Nrf2-mediated transcription activity
Upregulating and stabilizing Nrf2
Reducing the level of Keap1 protein
In HepG2 cellsIn vitro48
ResveratrolInhibiting O-acetyltransferase and sulfotransferase activities
Preventing the oxidative DNA damage
In male Wistar rats treated with potassium bromateIn vivo49
Inhibiting the production of H2O2 and MPO activity
Increasing GSH levels and SOD activities
Decreasing the levels of MPO and oxidized GR
In mouse skinEx vivo50
Reducing PhIP-DNA-adduct formation by O-acetyltransferase and sulfotransferase catalysisIn primary cultures of human mammary epithelial cellsIn vitro51
Inhibiting the expression and activity of CYP 1A1/1A2In microsomes and intact HepG2 cellsIn vitro52
Inhibiting mitochondrial proton F0F1-ATPase/ATP synthaseRat brain and liver F0F1-ATPaseIn vitro39
Suppressing CYP1A1 and IL-1 β transcription by blocking aryl hydrocarbon receptorEx vivo
In vivo
(−)-Epicatechin Procyanidin EGCG, ECGInhibiting recombinant human platelet 12-lipoxygenase and 15-lipoxygenaseIn rabbit smooth muscle cells and in J774A.1 cellsIn vitro54
Table 3. Anti-atherosclerosis and cardioprotection of dietary polyphenols.
Table 3. Anti-atherosclerosis and cardioprotection of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
ResveratrolSuppresing the expression and activity of COX-2
Suppresing activation of AP-1
In human mammary epithelial cellsIn vitro55
Inhibiting the activity and expression of MMP-9In U937 cellsIn vitro56
Enhancing myocardial angiogenesis by induction of VEGF, thioredoxin-1 (Trx-1), and HO-1In male Sprague Dawley ratsIn vivo57
Inhibiting the expression and binding activity of the monocyte chemotactic protein-1 (MCP-1) receptor, CC-chemokine receptor-2 (CCR2)on THP-1 monocytesIn vitro58
Increasing NO and NOS levels
Increasing intracellular cyclc GMP (cGMP) level and decreasing atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels
In cultured rat cardiac fibroblastsIn vitro59
(−)-EpicatechinInhibiting 7β-OH-cholesterol formationIn endothelial cellsIn vitro60
HydroxytyrosolPreventing platelet aggregation and eicosanoid formation
Inhibiting thromboxane B2 production
In platelet rich plasmaIn vitro61
Inhibit thromboxane B2 productionIn patients with uncomplicated type I diabetesIn vivo62
Caffeic acid
Inhibiting leukotriene B4 generation
Inhibiting 5-lipoxygenase
In rat peritoneal leukocytesIn vitro63
Reducing monocytoid cell adhesion to stimulated endothelium
Decreasing VCAM-1 mRNA and protein
In human umbilical vein endothelial cells (HUVECs)In vitro64
OleuropeinDecreasing creatine kinase and GSH releaseIn the isolated rat heartEx vivo65
Upregulating the expression of serum HDL-associated PON-1In the HuH7 human hepatoma cell lineIn vitro66
Inducing interferon-gamma (IFN-γ) gene expression
Downregulating IL-4 gene expression
In peripheral blood mononuclear cellsIn vitro67
Increasing the intracellular GSH and activating γ-GCS heavy subunit (GCS(h)) promoterIn COS-1 cellsIn vitro68
EGCG and ECGInhibiting rat VSMCs adhesion on collagen and laminin
Interference with VSMC’s integrin β1 receptor and binding to extracellular matrix (ECM) proteins
In rat VSMCsIn vitro69
GenisteinDecreasing hydroxyproline concentrations
Suppressing the progression of myocardial fibrosis
In Long-Evans Tokushima Otsuka non-diabetic ratsIn vivo70
Incorporating into LDLs, increasing their oxidation resistance and antiproliferative efficacyIn cultured U937 cellsEx vivo71
ProcyanidinsDecreasing leukotriene-prostacyclin ratio in plasmaIn humans and human aortic endothelial cellsIn vivo
In vitro
ProanthocyanidinInhibiting CD36 mRNA expressionIn peripheral blood mononuclear cellIn vitro73
ProanthocyanidinReducing cardiomyocyte apoptosis by inhibiting ischemia–reperfusion-induced activation of JNK-1 and c-JunIn Male Sprague Dawley ratsIn vivo74
HydroxytyrosolLowering serum TC and LDL-C
Slowing the lipid peroxidation process
In rats fed a cholesterol-rich dietIn vivo35
Table 4. Neuroprotective effects of dietary polyphenols.
Table 4. Neuroprotective effects of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
HydroxytyrosolAttenuating Fe2+-and NO-induced cytotoxicity
Increasing cellular ATP
Reducing lipid peroxidation
Hyperpolarizing basal mitochondrial membrane potential
In murine-dissociated brain cells and miceIn vitro
Ex vivo
ResveratrolStimulating AMP kinase activityIn Neuro2a cells and primary neuronsIn vitro75
Preventing fibrosis, NF-κB activation and TGF-β increases induced by chronic CCl(4) treatmentIn ratsIn vivo76
Activating the phosphorylation of PKC
Secreting transthyretin to prevent Aβ aggregation
In cultured rat hippocampal cellsIn vitro77
Protecting dopaminergic neurons
Activating sirtuin family of NAD-dependent histone deacetylases
In organotypic midbrain slice cultureIn vitro78
Inhibiting IL-6, IL-8, VEGF and prostaglandin E2 (PGE2) production
Attenuating the expression of COX-2 and activation of NF-κB
Inducing the expression of MAPK phosphatase-1
Suppressing the phosphorylation of MAPK (p38 and JNK)
In human astrocytoma U373MG cellsIn vitro79
Attenuating disruption of mitochondrial membrane potential and release of cytochrome c
Decreasing the activities of caspase-9 and caspase-3 and increase in the Bax to Bcl-2 ratio
In rat PC12 cellsIn vitro115
Stimulating the deacetylase activity of recombinant SIRT1 proteinIn human HT29 cellsIn vitro80
Increasing the activities of PKC and ERK1/2
Decreasing the expression of Bax, Bad, and Mdm2
Increasing the expression of Bcl-2, Bcl-w, and Bcl-xL
In human neuroblastoma
SH-SY5Y cell
In vitro81
Quercetin Genestein
Attenuating the apoptotic injury induced N-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium hydrochloride (MPP+)In mesencephalic dopamine neuronesIn vivo82
Protecting neurons from oxLDL-induced apoptosis by inhibiting the activation of JNK, c-Jun and caspase-3In cultured primary neuronsIn vitro83
CurcuminDisrupting existing plaques and restoring distorted neurites
Crossing the blood-brain barrier and labels senile plaques and cerebrovascular amyloid angiopathy
In an Alzheimer mouse model
In APPswe/PS1dE9 mice
In vivo84
Table 5. Anti-inflammatory effects of dietary polyphenols.
Table 5. Anti-inflammatory effects of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
ProcyanidinsInhibiting transcription and secretion of IL-1βIn peripheral blood mononuclear cellsIn vitro85
Inducing apoptosis by activating caspases 3, 8, and 9In Isolated peripheral blood monocytesIn vitro86
Downregulating CD11b expression
Attenuating adhesion and migration of peripheral blood CD8+T cells
In peripheral blood CD8+ T cellsIn vitro87
ResveratrolInhibiting stimulation of caspase-3 and cleavage of PARP induced by IL-1βIn human articular chondrocytesIn vitro88
Suppressing the expression of iNOS mRNA and protein by inhibiting the activation of NF-κB
Inhibiting NO generation
In RAW 264.7 cellsIn vitro89
Upregulating MAP kinase phosphatase-5In prostate cellsIn vitro90
Blocking the expression of intercellular adhesion molecule-1 (ICAM-1), VCAM-1, and E-selectin
Inhibiting prostaglandin synthesis and IL-6, 8 production
In human endothelial cellsIn vitro91
Inhibiting the upregulation of THP-1 adhesion and VCAM-1 expression
Inhibiting the activity of the NF-κB
In HUVECsIn vitro92
Inhibiting NO production and iNOS protein expressionIn NR8383 macrophagesIn vitro93
Hydroxy-cinnamic acids
Localizing into endothelial cells
Reducing the upregulation of IL-8, MCP-1, and ICAM-1
In human microvascular endothelial cellsIn vitro94
CurcuminDecreasing MPO activity and TNF-α on chronic colitis
Reducing nitrites levels and the activation of p38 MAPK
Downregulating COX-2 and iNOS expression
In ratsIn vivo95
Upregulating MAP kinase phosphatase-5In prostate cellsIn vitro90
Suppressing the induction of COX-2 and iNOS
Inhibiting the expression of ICAM-1 and MCP-1
Suppressing the Janus kinase (JAK)-STAT via activation of Src homology 2 domain-containing protein tyrosine phosphatases (SHP-2 )
In both rat primary microglia and murine BV2 microglial cellsIn vitro97
Table 6. Antimutagenic/anticarcinogenic properties of dietary polyphenols.
Table 6. Antimutagenic/anticarcinogenic properties of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
HydroxytyrosolInhibiting cell proliferation
Inducing apoptosis by arresting the cells in the G0/G1 phase with a concomitant decrease in the cell percentage in the S and G2/M phases
In human promyelocytic leukaemia cells HL60In vitro98
ResveratrolInhibiting cell proliferation and downregulating telomerase activityIn human colon tumor cellsIn vitro99
Inducing apoptosis mediated by p53-dependent pathwayIn HepG2 cellsIn vitro100
Inhibiting cell proliferation by interfering with an estrogen receptor-α (ERα)-associated PI3K pathwayIn estrogen-responsive MCF-7 human breast cancer cellsIn vitro101
Suppressing COX-2 expression by blocking the activation of MAPKs and AP-1In dorsal skin of female ICR miceIn vitro102
Decreasing the expression of COX-1, COX-2, c-myc, c-fos, c-jun, transforming growth factor-beta1 (TGF-β1) and TNF-αIn mouse skinEx vivo50
Inhibiting oncogenic disease through the inhibition of protein kinase CKII activityIn HeLa cell lysatesIn vitro103
Inhibiting the Ca(2+)-dependent activities of PKCα and PKCβIOn the activities of PKC isozymesIn vitro104
Inhibiting nitrobenzene(NB)-DNA adducts and NB–Hb adductsIn male Kunming miceIn vivo105
Chlorogenic acidInhibiting the formation of DNA single strand breaksIn supercoiled pBR322 DNAIn vitro106
Blocking EGFR tyrosine kinase activityIn MiaPaCa-2 cancer cellsIn vitro107
Inhibiting human CYP1A1 activities
Inhibiting the formation of diolepoxide 2(DE2) and B[a]P activation
On 7-ethoxyresorufin O-deethylationIn vitro26
Interacting with P-glycoprotein and modulating the activity of ATP-binding cassette transporter, breast cancer resistance protein (BCRP/ABCG2)In two separate BCRP-overexpressing cell linesIn vitro108
EGCGInhibiting telomeraseIn human cancer cells
In nude mice models
In vitro
In vivo
CurcuminSuppressing proliferation and angiogenesis
Inhibiting NF-κB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, COX-2, MMP, and VEGF)
In various pancreatic cancer cell lines and nude miceIn vitro
In vivo
Inducing apoptosis by sustained phosphorylation of JNK and p38 MAPK
Inhibitiing NF-κB transcriptional activity
Inducing phosphorylation of c-jun and stimulation of AP-1 transcriptional activity
In HCT116 cellsIn vitro110
Inducing apoptosis through activation of caspase-8, BID cleavage and cytochrome c release
Suppressing ectopic expression of Bcl-2 and Bcl-xl
In human acute myelogenous leukemia HL-60 cellsIn vitro111
Inhibiting the Akt/mTOR/p70S6K pathway and activating the ERK1/2 pathway
Inhibiting tumor growth and inducing autophagy
In U87-MG and U373-MG malignant glioma cells
In the subcutaneous xenograft model of U87-MG cells
In vitro
In vivo
Table 7. Effects of dietary polyphenols on signal transduction pathways.
Table 7. Effects of dietary polyphenols on signal transduction pathways.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
CurcuminInhibiting both myeloid differential factor 88 (MyD88)-and TIR domain-containing adapter inducing IFN-β (TRIF)-dependent pathways
Inhibiting homodimerization of Toll-like receptor 4(TLR4)
Suppressing the activation of NF-κB by inhibiting IκB kinase β activity in MyD88-dependent pathway
Inhibiting IFN-regulatory factor 3 (IRF3) activation
In 293T cellsIn vitro124
Inhibiting the level of NOS mRNA and protein
Suppressing NF-κB activation through inhibitory of IκB kinase activity
In macrophagesIn vitro125
Suppressing COX-2 expression by inhibiting AP-1 and NF-κBIn BV2 microglial cellsIn vitro126
Inhibiting IL-6-inducible STAT3 phosphorylation and nuclear translocationIn human multiple myeloma cellsIn vitro118
Upregulating CYP3A4 via pregnane X receptor (PXR) activation
Activating the electrophile responsive element (EpRE) of HO-1 and enhancing the gastrointestinal (GI)-GPx activity
In HepG2 cellsIn vitro127
Suppressing JAK-STAT inflammatory signaling through activation of SHP-2In both rat primary microglia and murine BV2 microglial cellsIn vitro97
ProanthocyanidinsPromoting apoptosis through alterations in Cdki-Cdk-cyclin cascade, and caspase-3 activation via loss of mitochondrial membrane potentialIn human epidermoid carcinoma A431 cellsIn vitro128
ProanthocyanidinsInhibiting the phosphorylation of ERK1/2, JNK and p38
Inhibiting the activation of NF-κB/p65 through inhibition of degradation of IκBα and activation of IκB kinase α
In SKH-1 hairless miceIn vivo129
Caffeic acidModulating ceramide-induced signal transduction pathway and NF-κB activation
Inhibiting protein tyrosine kinase activity
In U937 cellsIn vitro113
QuercetinInhibiting phosphorylation of JNK and p38 MAPK on ROS-mediated signalingIn HUVECsIn vitro117
Modulating Akt/PKB and ERK1/2 signalling cascades on neuronal viabilityIn primary cortical neuronsIn vitro
In vivo
EquolMediating rapid vascular relaxation by Ca2+-independent activation of eNOS/Hsp90 involving ERK1/2 and Akt phosphorylationIn human endothelial cellsIn vitro131
ResveratrolInhibiting monocyte CCR2 binding activity in an NO-, MAPK- and PI3K-dependent manner
Inhibiting CCR2 mRNA in an NO- and MAPK-independent, PI3K-dependent manner
on THP-1 monocytesIn vitro58
Inhibiting proliferation of cardiac fibroblasts by NO-cGMP signaling pathwayIn cultured rat cardiac fibroblastsIn vitro59
Inducing phase II genes by regulating ARE/EpRE activation
Modifying the capability of Keap1 in sequestering Nrf2
In PC12 cellsIn vitro132
Table 8. Protective effects of dietary polyphenols on endothelial cells and blood vessels
Table 8. Protective effects of dietary polyphenols on endothelial cells and blood vessels
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
Inhibiting apoptosis through modulation of Bcl-2 and Bax
Inhibiting nuclear transactivation of p53
Decreasing the activity of caspase-3
Blocking JNK- and p38 MAPK-related signaling
In HUVECsIn vitro117
RWPCsInhibiting the expression of VEGF mRNA and protein
Preventing the activation of the p38 MAPK pathway
In VSMCsIn vitro133
Inhibiting the invasion and migration of VSMCs
Inhibiting pro-MMP-2 expression and its activation via inhibition of membrane type 1-MMP (MT1-MMP) activity
In VSMCsIn vitro134
Inhibiting VSMCs migration through inhibiting the PI3K activity and p38 MAPK phosphorylation
Inhibiting the phosphorylation of MKK3/6
In cultured VSMCsIn vitro135
Inducing EDHF-mediated relaxations through activation of the PI3-kinase/Akt pathwayIn porcine coronary arteriesIn vivo136
Increasing intracellular Ca2+ and activate tyrosine kinases
Increasing NO production
In bovine aortic endothelial cellsIn vitro137
Inhibiting NADPH oxidase activity and/or reducing endothelin-1(ET-1) releaseIn Twelve-week-old
male Wistar rats
In vivo138
Inhibiting the synthesis of ET-1In cultured bovine aortic endothelial cellsIn vitro139
Elevating NO and prostacyclin (PGI2)In ratsIn vivo140
Ehancing PGI2 releaseIn endothelial cellIn vitro141
Cy3GEnhancing eNOS activity and expression
Inducing NO production
Regulating phosphorylation of eNOS and Akt Increasing cGMP production
In bovine vascular endothelial cellsIn vitro142
EGCGHaving endothelial-dependent vasodilator actions
Activatiing phosphatidylinositol 3-kinase, Akt, and eNOS
In bovine aortic endothelial cellsIn vitro143
Increasing eNOS activity
Inducing a sustained activation of Akt, ERK1/2, and eNOS Ser1179 phosphorylation
In bovine aortic endothelial cellsIn vitro144
CatechinsReducing the vascularization induced by the angiogenin-like protein on chicken CAMIn chichenIn vitro145
ActivinReducing ICAM-1, VCAM-1 and E-selectinIn systemic sclerosisIn vivo146
ProanthocyanidinDownregulating VCAM-1 expression;
Decreasing TNFα-induced adherence of T-cells to HUVECs
In primary HUVECsIn vitro147
Procyanidins Flavan-3-olsInhibiting angiotensin I converting enzyme (ACE) activityIn two substratesIn vitro148
Table 9. Antidiabetic activity of dietary polyphenols.
Table 9. Antidiabetic activity of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
CurcuminInhibiting diabetes-induced elevation in the levels of IL-1β, VEGF, and NF-κB
Decreasing oxidatively modified DNA and nitrotyrosine
In streptozotocin-induced diabetic ratsIn vivo153
EGCG, ECG, ()-epigallochatechinInhibiting SGLT1 and sodium-free GLUTIn polarised Caco-2 intestinal cellsIn vitro154
Inhibiting SGLT1 and glucose uptakeIn the rabbit small intestineIn vivo155
QuercetinReducing blood glucose levels
Inhibiting sodium-dependent vitamin C transporter 1 (SVCT1) and GLUT2
In Chinese hamster ovary cellsIn vitro156
MangiferinInhibiting sucrase, isomaltase, and aldose reductaseIn ratsIn vivo157
Tannins AnthocyaninInhibiting α-amylase and α-glucosidaseIn the substrate of 2-chloro-4-nitro-phenyl-4-O-b-D-galactopyranosyl-maltosideIn vitro158
Table 10. Regulate cell cycle progression of dietary polyphenols.
Table 10. Regulate cell cycle progression of dietary polyphenols.
Dietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
ResveratrolUpregulating p21 expression and cause G1 phase arrestIn HepG2 cellsIn vitro163
Inhibiting cyclin D1/D2-cdk6, cyclin D1/D2-cdk4, and cyclin E-cdk2 complexesIn human epidermoid carcinoma A431 cellsIn vitro164
Downregulatiing cyclin D1/Cdk4 complex and upregulating cyclin E and A expressionIn the human colonic adenocarcinoma cell line Caco-2In vitro165
Decreasing in the hyperphosphorylated form of pRb and increasing in hypophosphorylated pRb
Downregulating the protein expression of E2F (1–5) family members of transcription factors and their heterodimeric partners DP1 and DP2
Leading to a G0/G1 arrest
In human epidermoid carcinoma A431 cellsIn vitro166
Inhibiting the expression of cyclin B1, D1, A1 and β-cateninIn six human cancer cell lines (MCF7, SW480, HCE7, Seg-1, Bic-1, and HL60)In vitro167
Arresting cell cycle in the G1-S phaseIn VSMCsIn vitro168
Upregulating the expression of cyclins A, E, and B1In human SK-Mel-28 melanoma cellsIn vitro169
ProanthocyanidinsIncreasing G1-phase arrest
Inhibiting cyclin-dependent kinases (Cdk) Cdk2, Cdk4, Cdk6 and cyclins D1, D2 and E
Increasing the protein expression of cyclin-dependent kinase inhibitors (Cdki), Cip1/p21 and Kip1/p27
Enhancing the binding of Cdki-Cdk
In human epidermoid carcinoma A431 cellsIn vitro170
Table 11. Other bioactive effects of dietary polyphenols.
Table 11. Other bioactive effects of dietary polyphenols.
Type of ActivityDietary polyphenolsProtective effects and mechanismsConditionsLevelsRef
Antibacterial activityGnemonol B and gnetin EExhibiting strong antibacterial activities against vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA)In Enterococci and Staphylococcus aureusIn vitro174
HydroxytyrosolAntimycoplasmal activity against M. pneumoniae, M. hominis, and M. fermentansIn MycoplasmaIn vitro175
Anti-HIV effectsProanthocyanidinsDownregulating the expression of the HIV-1 entry co-receptors, CCR2b, CCR3 and CCR5In normal peripheral blood mononuclear cellsIn vitro176
Angiogenesis effectProanthocyanidins
Upregulating VEGF expressionIn cultured keratinocytesIn vitro177
Hepato-protective abilityA novel Proanthocyanidins IH636Increasing the expression of Bcl-xL
Attenuating acetaminophen-induced hepatic DNA damage, apoptotic and necrotic cell death of liver cells
In male ICR miceIn vivo178
DaidzeinAmeliorating the d-galactosamine-induced increase in malondialdehyde-protein adducts and cytosolic SOD activitiesIn the rat liverIn vivo179
GenisteinReducing experimental liver damage caused by CCl(4) by preventing lipid peroxidation and strengthening antioxidant systemsIn ratsIn vitro180


This project was supported by a grant from the National Natural Science Foundation of P.R.China (No. 30472072)


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Han, X.; Shen, T.; Lou, H. Dietary Polyphenols and Their Biological Significance. Int. J. Mol. Sci. 2007, 8, 950-988.

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Han X, Shen T, Lou H. Dietary Polyphenols and Their Biological Significance. International Journal of Molecular Sciences. 2007; 8(9):950-988.

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Han, Xiuzhen, Tao Shen, and Hongxiang Lou. 2007. "Dietary Polyphenols and Their Biological Significance" International Journal of Molecular Sciences 8, no. 9: 950-988.

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