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Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition.

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Chapter 12Health Benefits of Tea

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12.1. INTRODUCTION

Tea is one of the most popular drinks due to its pleasant taste and perceived health effects. Although health benefits have been attributed to tea consumption since the beginning of its history, scientific investigation of this beverage and its constituents has been under way for about 30 years (McKay and Blumberg 2002; Gardner, Ruxton, and Leeds 2007). Consumption of tea, in particular green tea (GT), has been correlated with low incidence of chronic pathologies in which oxidative stress has been reported to be involved, such as cancer (Chung et al. 2003; Butt and Sultan 2009) and cardiovascular diseases (CVDs; Stangl et al. 2007; Babu and Liu 2008).

The health benefits ascribed to the consumption of teas may be related to the high content of bioactive ingredients such as polyphenols. Polyphenols have been reported to possess antioxidant, antiviral, and anti-inflammatory activities; modulate detoxification enzymes; stimulate immune function and decrease platelet aggregation (Lampe 2003; Frankel and Finley 2008). Among all tea polyphenols, epigallocatechin gallate (EGCG) has been found to be responsible for much of the health-promoting ability of GT (Khan et al. 2006). In general, GT has been found to be superior to black tea (BT) in terms of health effects, owing to the higher content of EGCG, although the role of thearubigins and theaflavins contained in BT have not been properly investigated. In vitro and animal studies provide strong evidence that polyphenols derived from tea possess bioactivity to delay the onset of risk factors associated with disease development (Cabrera, Artacho, and Giménez 2006; Wolfram 2007; Yang et al. 2007; Yang et al. 2009; Yang, Lambert and Sang 2009). Studies conducted on cell cultures and animal models indicate a potentially modulating effect of tea on gene transcription, cell proliferation, and other molecular functions (McKay and Blumberg 2002). Over the last few years, clinical studies have revealed several physiological responses to tea that may be relevant to the promotion of health and the prevention or treatment of some chronic diseases (Crespy and Williamson 2004; Cabrera, Artacho, and Giménez 2006). This chapter covers recent findings on the medicinal properties and health benefits of tea with special reference to antioxidant and anti-inflammatory actions as key mechanisms for cancer and CVD prevention.

12.2. TEA: HISTORY AND ORIGIN

The second emperor of China, Shen Nung, is believed to have discovered tea when the leaf of the plant Camellia sinensis blew into his cup of hot water (2737 BCE). The first European to encounter tea and write about it was the Portuguese Jesuit missionary Father Jasper de Cruz in 1560. Around 1650, the Dutch introduced several teas and tea traditions to New Amsterdam (which later became New York). The first tea sold as a health beverage was in London, England, at Garway’s Coffee House in 1657. In 1826, John Horniman introduced the first retail tea in sealed, lead-lined packages. In 1870, Twinings of England began to blend tea for uniformity. The Englishman Richard Blechynden created iced tea during a heat wave at the St. Louis World Fair in 1904, and the New York tea importer Thomas Sullivan inadvertently invented tea bags in 1908 when he sent tea to clients in small silk bags and they mistakenly steeped the whole bags. Finally, the world’s first instant tea was introduced in 1953. Nowadays, BT is consumed principally in Europe, North America, and North Africa, whereas GT is taken throughout Asia.

12.3. TEA: HOW MANY USE IT, TRADE VOLUME, WAY OF INTAKE, PREPARATION, AND PROCESSING

The four types of tea most commonly found in the market are BT, oolong tea, GT, and white tea. The difference among them lies in the different processing or, in the case of white tea, different harvesting times. White tea leaves are picked and harvested before they fully open; this is done when the buds are still covered by fine white hair. In the case of white tea and GT, the leaves are steamed quickly after harvesting to prevent oxidation of polyphenols and then dried. In the production of BT, the leaves are rolled, disrupting the cellular compartment and bringing phenolic compounds into contact with polyphenol oxidases, and the young C. Sinensis leaves undergo oxidation for 90–120 minutes before drying. During this process, which is referred to as “fermentation,” flavan-3-ols are converted to complex condensation products, such as theaflavins and thearubigins. Oolong tea, which is manufactured mainly in Taiwan and exported to Japan and Germany, is produced with a shorter fermentation period than BT and is said to have a taste and color somewhere between GT and BT (Duthie and Crozier 2003; Del Rio et al. 2004).

12.4. ACTIVE INGREDIENTS AND MECHANISMS OF ACTION

The major active ingredients of tea are catechins, their bioavailability and mechanisms of action are described below.

12.4.1. Catechins in Tea and Their Bioavailability

The major phenolics present in teas are flavan-3-ols (Figure 12.1) and flavonols. The main flavan-3-ols in GT are (–)-epicatechin (EC) and its gallate derivatives. These compounds are present in lower amounts in BT, and are converted by oxidation to theaflavins and thearubigins (Finger, Kuhr, and Engelhardt 1992; Balentine, Wiseman, and Bouwens 1997). Conjugates of quercetin and kaempferol are the main flavonols in tea, with lower levels of myricetin. The conjugating moiety has been reported to vary from mono- to di- and triglycosides (Wang and Sporns 2000; Del Rio et al. 2004). Other related compounds found in tea are gallic acid and quinic esters of gallic, coumaric, and caffeic acids, together with the purine alkaloids theobromine and caffeine, proanthocyanidins, and trace levels of flavones (Crozier, Jaganath, and Clifford 2009).

FIGURE 12.1. Structures of the flavan-3-ols found in tea.

FIGURE 12.1

Structures of the flavan-3-ols found in tea.

The literature reporting the bioavailability of GT phenolics shows very different and controversial results (Manach et al. 2005). Urinary excretion reported after drinking different doses of tea or tea extracts ranges from unquantifiable concentrations to levels close to 10% of the ingested amount. A very similar pattern of differences could be observed when bioavailability studies were carried out with chocolate, which constitutes the second greatest source of flavan-3-ols (Baba et al. 2000; Mullen et al. 2009), or when single molecules like (–)-EGCG or (+)-catechin were introduced as supplements (Van Amelsvoort et al. 2001; Goldberg, Yan, and Soleas 2003). Analytical limitations have drastically biased the identification and characterization of flavan-3-ol catabolites; also, the unavailability of pure standards for each specific catabolite has significantly limited the quality of bioavailability studies. However, with all the health benefits attributed to GT, it is necessary to define the absorption and catabolism of its bioactive components with greater clarity with the help of more advanced analytical methodologies that are now readily available in most research laboratories. High-performance liquid chromatography (HPLC) with multistage mass spectrometric (MS/MS) detection has been used to analyze flavan-3-ols in biological fluids, which has facilitated the identification of a range of metabolites (Li et al. 2000; Meng et al. 2001). Stalmach et al. (2009) identified a total of 10 metabolites in human plasma, in the form of O-methylated, sulfated, and glucuronide conjugates of EC and EGC, with 29–126 nM peak-plasma concentrations (Cmax) occurring 1.6–2.3 hours after ingestion. Plasma also contained nonmetabolized (–)-EGCG and (–)-EC-3-gallate with respective Cmax values of 55 and 25 nM. In the same study, urine excreted up to 24 hours after consumption of GT contained 15 metabolites of EC and EGC, but (–)-EGCG and (–)-EC-3-gallate were not detected. The overall calculated bioavailability was equivalent to 8% of intake (Stalmach et al. 2009). A similar GT-feeding study was carried out using human volunteers with ileostomy (Stalmach et al. 2009). The 24-hour plasma and urinary profiles were very similar to those obtained with subjects having an intact, functioning colon, confirming that the detected flavan-3-ol metabolites were absorbed principally in the small intestine. More recently, a feeding study with 20 volunteers investigated in detail the catabolism of GT catechins (GTCs) by means of HPLC with tandem mass spectrometry (HPLC-MS/MS; Del Rio et al. 2010). A total of 8 and 39 relevant compounds were identified in plasma and urine, respectively (Table 12.1). In particular, metabolites derived by the action of intestinal or hepatic uridine 5′-diphosho-glucuronyltransferases, sulfotransferases, and catechol-O-methyltransferase were identified with the MS detector through the loss of the conjugating groups (i.e., glucuronic acid and sulfate). In addition to the metabolites reported by Stalmach and colleagues (2009), metabolites derived from colonic bacteria ring fission activity have been identified, as described by Sang et al. (2008). In plasma, EGC-gallate was the only unmetabolized compound in this study and the highest in terms of absolute concentration. The EGC catabolites reached their peak-plasma concentration (Tmax) at 2 hours from ingestion, whereas EC catabolites showed their Tmax at 1 hour. Among conjugates, the main metabolites excreted in urine were EGC-O-glucuronide and its methoxy counterpart methyl-O-EGC-O-glucuronide. The main EC metabolite was methyl-EC-sulfate, whereas the sulfate metabolite of EGC was almost negligible. The main class of colonic catabolites was represented by (–)-5-(3,4-dihydroxyphenyl)-γ-valerolactone (M6′, which can derive from both EC and EGC, and their epimers) and 5-(3′,5′- dihydroxyphenyl)-γ-valerolactone (M6, which can derive solely from EC and catechins). Further, (–)-5-(3,4,5-trihydroxyphenyl)-γ-valerolactone (M4, which can derive solely from EC and catechins) was a relevant colonic product. These molecules, all in their variously conjugated versions, were by far the main excreted metabolites, and their urinary concentration was, on average, 10 times higher than that of flavanol conjugates. Bioavailability of flavan-3-ols, considering for the first time the whole set of catechin-derived catabolites, was 39.5%.

TABLE 12.1. MS/MS Identification and Location of Flavan-3-ols Catabolites.

TABLE 12.1

MS/MS Identification and Location of Flavan-3-ols Catabolites.

The identification of most of the metabolites in these studies was possible thanks to the availability of MS/MS detectors, and this is probably the reason why several older studies failed to pinpoint most flavan-3-ol-derived molecules. Previous research mostly dealt with the treatment of samples with deconjugating enzymes, such as microbial glucuronidases and sulfatases, which allowed the detection of aglycons in biological fluids (Lee et al. 2002; Henning et al. 2005) with non-MS/MS detectors. However, this treatment did not help in understanding the true metabolic processes undergone by dietary catechins and, above all, this kind of detection did not consider the methoxy derivatives, which constitute a notable fraction of the total excreted flavanols. Several studies also failed in identifying and quantifying γ-valerolactones, which alone constitute almost 90% of the excreted flavan-3-ol metabolites. Sang et al. (2008) gave the most complete and detailed description of the human urinary metabolite profile of tea polyphenols using HPLC with electrospray ionization tandem MS/MS with data-dependent acquisition, but they did not set up a bioavailability study. Moreover, contrary to their observations, urinary unconjugated valerolactones were not found by Del Rio et al. (2010), and some molecules with double conjugation were observed in urine for the first time (EGC-sulfate glucuronide, methyl-EGC-sulfate glucuronide, M6-/M6′-sulfate glucuronide, and M6-/M6′-disulfate).

12.4.2. Antioxidant Activity: Human Studies

Oxidative stress, which is the imbalance between free-radical species and antioxidant defense, can originate from an increase in free-radical production either by exogenous processes, such as pollution and cigarette smoking, or by endogenous processes, such as inflammation and respiratory burst (Halliwell and Cross 1994; Serafini and Del Rio 2004; Halliwell 2009). Free radical-initiated auto-oxidation of cellular membrane lipids can lead to cellular necrosis and a variety of pathological conditions such as cancer, CVD, and even aging (Serafini et al. 2006; Halliwell 2009). It has been widely suggested that antioxidant molecules play an important role in the diet-led prevention of oxidative stress-related chronic diseases, and the health benefits associated with tea consumption have been attributed in part to free-radical scavenging and metal-chelating activity (Babu and Liu 2008; Seeram et al. 2008; Sharma and Rao 2009).

In body fluids, total antioxidant capacity (TAC), defined as the moles of oxidants neutralized by 1 L of plasma, assesses the effectiveness of the endogenous nonenzymatic antioxidant network as well as nutritional antioxidant molecules (Serafini and Del Rio 2004). Since the first evidence of how ingestion of GT and BT boosted plasma antioxidant defenses in humans (Serafini, Ghiselli, and Ferro-Luzzi 1994) was obtained, different studies have investigated the ability of diet to modulate plasma TAC following the consumption of tea in human subjects. As presented in Table 12.2, a large majority of the ingestion studies conducted with teas show a clear impact on plasma TAC (Rietveld and Wiseman 2003; Manach et al. 2005; Williamson and Manach 2005; Fernandez-Panchon et al. 2008). A study with three groups of five volunteers drinking water, BT, or GT demonstrated a significant and strong increase in TAC value in the tea groups between 30 and 60 minutes after a single consumption of 300 mL of either GT or BT. The scavenging capacity returned to its initial level after 80 minutes. There was no significant difference between the GT and BT groups (Serafini, Ghiselli, and Ferro-Luzzi 1996). In the same year, Maxwell and Thorpe (1996) measured TAC in 10 healthy subjects following the ingestion of BT and found no significant change. Also, in another tea study conducted by McAnlis et al. (1998), no change in plasma TAC was found. However, in a crossover study with 10 healthy subjects, tea consumption resulted in an increase in TAC 40 minutes after GT ingestion (Benzie et al. 1999). Further, for the same study, a significant increase in TAC value in urine was found. Pietta et al. (1998) found increases in plasma TAC, EGC-gallate, and EC-gallate after ingestion of GT. In agreement with the plasma results, urine samples collected at 6–48 hours contained detectable amounts of final catechin metabolites, including 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3-methoxy-4- hydroxy-hippuric acid, and 3-methoxy-4-hydroxybenzoic acid (vanillic acid). In a crossover study with 24 volunteers, ingestion of GT significantly increased plasma TAC (Leenen et al. 2000). In this study, a single dose ingestion of GT or BT again resulted after 60 minutes in a significant increase of catechins in plasma. As expected on the basis of the higher catechin concentration in GT, the rise in total plasma catechins was significantly higher following the consumption of GT as compared with BT. Consumption of BT and GT also resulted in a significant increase in plasma TAC relative to consumption of water (Leenen et al. 2000). Increases in plasma TAC were found also in a randomized crossover study conducted with BT (Langley-Evans 2000), as well as in 10 young, healthy subjects who received GT on three occasions each separated by 1 week, with the amount of tea increasing stepwise from 150 to 300 and 450 mL (Sung et al. 2000). In the first week, nonsignificant increases compared with baseline values were found. After doubling and tripling the initial amount of GT, a positive dose-response relation was found (Sung et al. 2000). In contrast, no significant effect was found on plasma TAC after ingestion of BT and GT in a randomized crossover study in healthy subjects (Hodgson et al. 2000). A double-blind, placebo-controlled, crossover trial in 60 coronary artery disease subjects was performed by Duffy et al. (2001) to determine the effect of tea consumption on antioxidant status, with no effect on plasma TAC observed. Kimura et al. (2002) showed that after acute ingestion of a tea-polyphenol extract by healthy subjects, plasma TAC did not change although an increase in EGCG concentration was observed. However, the number of subjects enrolled in the acute study (n = 5) might not have been enough to obtain an adequate sample size of statistical significance. When a long-term supplementation was performed on 16 subjects, plasma-free EGCG concentration and TAC did not change. Similarly, Henning et al. (2005), in an acute ingestion study, found no differences in plasma EGCG concentrations and TAC after administration of EGCG either in purified form or as GT extract (GTE). Previously, Henning et al. (2004) in a crossover design studied the effects of GT, BT, and a GTE supplement. Flavanol absorption was enhanced only when tea polyphenols were administered as a GTE supplement in capsules, which led to a small but significant increase in plasma TAC compared to the increase when BT or GT was administered (Henning et al. 2004). In an acute intervention study, Kyle et al. (2007) showed that consumption of BT was associated with significant increases in plasma TAC and concentrations of total phenols, catechins, and the flavonols quercetin and kaempferol within 80 minutes of ingestion. In a chronic intervention study conducted by Van het Hof et al. (1997), healthy subjects consumed 6 cups of GT, BT, or water per day for 4 weeks. A small but significant increase in plasma TAC was observed after 4 weeks with GT but not with BT. Total catechins increased after acute and chronic ingestion of BT, without any effect on plasma TAC and urinary 8-hydroxy-2′-deoxyguanosine and 8-isoprostane levels (Widlansky et al. 2005). Intervention with GTE for 3 weeks increased plasma TAC in a mixed group of smokers and nonsmokers, with a higher excretion of urinary catechins observed at 2 hours (Young et al. 2002).

TABLE 12.2. Antioxidant Effects of Tea in Human Intervention Studies.

TABLE 12.2

Antioxidant Effects of Tea in Human Intervention Studies.

As far as intervention studies evaluating markers of lipid oxidation are considered, the picture is even more complex than with effects on TAC. In a recent study conducted by Bertipaglia de Santana et al. (2008), 100 dyslipidemic individuals were asked to ingest 50 g of soy, 3 g of GT, or 50 g of soy and 3 g of GT daily, whereas the control group ingested a hypocholesterolemic diet. All the groups that used soy or GT or both showed increased plasma TAC, but no statistically significant difference occurred in the plasma levels of lipid hydroperoxides after 45 days of supplementation. Most intervention studies do not show an effect of tea ingestion on markers of lipid oxidation in healthy subjects (McAnlis et al. 1998; Princen et al. 1998; Cherubini, Beal, and Frei 1999; O'Reilly et al. 2001; Hodgson et al. 2002; Mukamal et al. 2007; Bertipaglia de Santana et al. 2008), and only few studies indicate that tea consumption may be effective in reducing lipid peroxidation (Ishikawa et al. 1997; Freese et al. 1999; Inami et al. 2007). Controversial results from intervention studies may be due to wide differences in the target population (i.e., dietary habit and lifestyle) and/or in experimental protocols (i.e., dose and length of treatment); however, a major point to be considered is that the majority of such studies were conducted on healthy subjects for whom oxidative stress markers are at lower levels than in subjects suffering from oxidative stress-related pathologies or chronic inflammation.

12.4.3. Antioxidant Activity: Molecular Aspects

Experimental data indicate that tea polyphenols may offer indirect protection by activating endogenous defense systems (Rahman, Biswas, and Kirkham 2006). Many antioxidant genes are regulated at transcriptional levels by cellular redox status (Liu et al. 2005). Several lines of evidence suggest a tight connection between exogenous and endogenous antioxidants that appear to act in a coordinated fashion. It is reasonable to hypothesize that this link is achieved through antioxidant responsive elements (AREs) present in the promoter regions of many of the genes inducible by oxidative and chemical stresses (Rahman, Biswas, and Kirkham 2006). Studies strongly suggest that tea polyphenols can stimulate antioxidant transcription and detoxify defense systems through ARE (Rahman, Biswas, and Kirkham 2006).

An ARE, also referred to as the “electrophile response element,” is a cis-acting transcriptional regulatory element involved in the activation of coding of genes for a number of antioxidant proteins and phase II detoxifying enzymes, including glutathione peroxidase (GPx), heme oxygenase 1 (HO-1), γ-glutamylcysteine synthetase (γ-GCS), superoxide dismutase (SOD), and glutathione reductase (GR; Lee and Johnson 2004; Chen et al. 2006; Mann, Niehueser-Saran et al. 2007; Mann, Rowlands et al. 2007; Gopalakrishnan and Kong 2008). Nuclear factor-erythroid 2-related factor 2 (Nfr2) is the transcription factor that is responsible for both constitutive and inducible expression of ARE-regulated genes (Chen et al. 2006; Gopalakrishnan and Kong 2008). Under normal physiological conditions, Nfr2 is bound to kelch-like ECH-associated protein-1 (Keap1; Figure 12.2) and thereby sequestered in the cytoplasm in association with the actin cytoskeleton (Mann, Niehueser-Saran et al. 2007; Gopalakrishnan and Kong 2008). Under conditions of increased oxidative or xenobiotic stress, Nfr2 dissociates from Keap1, translocates to the nucleus, and binds to ARE sequences in association with other members of the basic leucine zinc zipper transcription factor family, such as Maf, resulting in the transcriptional activation of phase II detoxifying enzymes and antioxidant genes (Na and Surh 2008).

FIGURE 12.2. Interaction of EGCG with lipid rafts, inactivating mitogen-activated protein kinase and consequently downregulating nuclear factor κB, activating protein 1, and Nfr2 pathways.

FIGURE 12.2

Interaction of EGCG with lipid rafts, inactivating mitogen-activated protein kinase and consequently downregulating nuclear factor κB, activating protein 1, and Nfr2 pathways. A laminin receptor in lipid rafts mediates EGCG transport to cytosol, (more...)

Nuclear translocation and export of Nfr2 have been reported to be modulated by phosphorylation via mitogen-activated protein kinases (e.g., extracellular regulated kinase [ERK]1/2, p38 MAPK) and/or protein kinase C (PKC; Mann, Niehueser-Saran et al. 2007). It was found that PKC was inhibited in vitro by tea flavonoids (Middleton, Kandaswami, and Theoharides 2000). Phenolic compounds have been found to modulate the MAPK pathway by acting on several steps of the activation cascade (Park and Dong 2003; Santangelo et al. 2007). Recent proteomic investigations have identified a large number of proteins interacting with EGCG; nearly all of them are hypothesized to mediate GTCs action (Patra et al. 2008). Membrane lipid rafts and sphingolipid- and cholesterol-enriched membrane microdomains assemble important signaling proteins into complexes prone to be activated by molecular triggers (Brown 2006; Sengupta, Baird, and Holowka 2007). It has been demonstrated that the lipid raft is used as a platform by a 67-kDa laminin receptor (LamR). The LamR may systematically reshape the rafts and affect the uptake of EGCG (Patra et al. 2008; Tachibana 2009). The EGCG is first incorporated into the plasma membrane, and then reloaded into the rafts where LamRs are present (Figure 12.2). In the rafts, EGCG interacts with many receptors, and the nonspecific binding of EGCG in membrane lipid rafts destabilizes the rafts, structure and inactivates MAPK signaling. The structure-activity relationship analysis of major GTCs (and their epimers) on cell-surface binding suggests that the binding activities of pyrogallol-type catechins (EGCG and GCG) are higher than those of catechol-type catechins (ECG and CG). The mechanism of endocytosis of EGCG has not yet been experimentally dissected. However, it is reasonable to believe that LamR, in association with rafts, transports EGCG to the cytosol (Patra et al. 2008). It was previously known that expression of 67 LamR confers EGCG responsiveness to tumor cells and that LamR is usually upregulated in cancer cells (Patra et al. 2008). This may explain observations about the markedly different mechanisms of EGCG action in normal and transformed cells (Balasubramanian, Efimova, and Eckert 2002). Despite the inhibitory effects of EGCG on the MAPK pathway, the GT polyphenol extract, and EGCG in particular, stimulates the transcription of phase II detoxifying enzymes through the ARE (Yu et al. 1997; McKay and Blumberg 2002). Low and high concentrations of EGCG lead to different effects. Higher concentrations of EGCG result in the sustained activation of MAPK, especially JNKs, that ultimately leads to apoptosis (Bode and Dong 2003). Depending on the concentration, EGCG is auto-oxidized under cell-culture conditions (Hou et al. 2005; Surh, Kundu, and Na 2008; Yang et al. 2008), exerting pro-oxidant activity and decreasing the glutathione (GSH) concentration in some cell types (Saeki et al. 2002). It is not clear whether EGCG auto-oxidation induces the occurrence of effects inside animal tissues, because these tissues are endowed with antioxidative enzymes and are usually under lower oxygen partial pressure than the cell-culture medium. However, the polyphenol-related ARE-mediated upregulation of MnSOD expression seems to be mediated by nitric oxide (NO) and/or reactive oxygen species (ROS) generation (Mann, Niehueser-Saran et al. 2007; Mann, Rowlands et al. 2007). It has been suggested that some quinone derivatives of polyphenols can oxidize two highly reactive cysteine thiol groups of Keap1, resulting in disulfide bond formation and Nfr2 release (Surh, Kundu, and Na 2008). It is paradoxical, but the activation of Nfr2/ARE signaling by antioxidant polyphenols to induce cytoprotective enzymes is attributed to their pro-oxidant activity. The versatility of EGCG, which makes it able to interact with so many targets, also makes the proposition of a unified mechanism of action very difficult.

12.4.4. Anti-Inflammatory Activity: Molecular Aspects

Inflammation is a normal host defense mechanism that protects the host from infection and other insults. Where an inflammatory response does occur, it is normally well regulated so that it does not cause excessive damage to the host, is self-limiting, and resolves rapidly (Calder et al. 2009). This self-regulation involves the activation of negative feedback mechanisms such as the secretion of anti-inflammatory cytokines, inhibition of proinflammatory signaling cascades, shedding of receptors for inflammatory mediators, and activation of regulatory cells. Pathological inflammation involves a loss of tolerance and/or a loss of regulatory processes. Where inflammation is excessive, irreparable damage to host tissues and disease can occur. Inflammation is considered a critical factor in many human diseases and conditions, including obesity, CVDs, neurodegenerative diseases, diabetes, aging, and cancer.

Although inflammation-induced tissue damage occurs in an organ-specific manner in different diseases or conditions, there is some commonality among the responses seen in the different organs. There are many mediators, such as adhesion molecules (AMs) including intercellular AM 1 (ICAM 1) and vascular AM 1 (VCAM-1); lipid-derived eicosanoids, including prostaglandin (PG) E2 (PGE2), PGI2, leukotriene (LT) B4, and LTC4; cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, and IL-10; and chemokines, including IL-8, monocyte-chemoattractant protein-1 (MCP-1), and macrophage inflammatory molecule 1α (MIP1α). These mediators coordinate the events of acute inflammation, regulate vascular changes, and perform inflammatory cell recruitment (Santangelo et al. 2007). The anti-inflammatory activities of catechins may be due to their suppression of leukocyte adhesion to endothelium and subsequent transmigration through inhibition of transcriptional factors-mediated production of cytokines and AMs in both endothelial and inflammatory cells (Surh et al. 2005; Biesalski 2007; Babu and Liu 2008). It has also been suggested that the molecular mechanisms involved in the anti-inflammatory activities of tea polyphenols include the inhibition of proinflammatory enzymes, such as cyclooxygenase 2 (COX-2), lipoxygenase (LOX), and inducible NO synthase (iNOS), and the modulation of signal transduction and transcription factors, including nuclear factor κB (NF-κB), activating protein 1 (AP-1), Nfr2, MAPK, and PKC (Frei and Higdon 2003; Santangelo et al. 2007). Among inflammatory cells, polymorphonuclear leukocytes are particularly adept at generating and releasing ROS and reactive nitrogen species (RNS). Among the proinflammatory enzymes, iNOS and COX are responsible for increasing the levels of NO and PGE2. A number of studies have found that flavonoids inhibit production of NO and expression of iNOS messenger ribonucleic acid (mRNA) by macrophages, and it is implied that they therefore might have anti-inflammatory properties (Crouvezier et al. 2001). It has also been observed that several flavonoids are able to decrease the expression of different proinflammatory cytokines/ chemokins, which include TNF-α, IL-1β, IL-6, IL-8, and MCP-1, in many cell types (Santangelo et al. 2007). The ECG, EGC, and EGCG enhanced the production of the anti-inflammatory cytokine, IL-10, whereas EC and theaflavins had no effect. (Santangelo et al. 2007). Molecular mechanisms, including catechin-mediated inhibition of transcription factors NFκB and AP-1 and reduction of MAPK activity, have been suggested as relevant anti-inflammatory pathways for tea (Figure 12.2; Sueoka et al. 2001; Lambert and Yang 2003; Park and Dong 2003; Tipoe et al. 2007).

The NFκB is a dimer that classically consists of a p50 subunit and a transactivating subunit p65 (or relA; Santangelo et al. 2007; Gopalakrishnan and Kong 2008). In unstimulated cells, NFκB is sequestered in the cytoplasm as an inactive non-DNA-binding form, associated with inhibitor κB proteins (IκBs). On cell stimulation with various NFκB inducers, IκB proteins are rapidly phosphorylated by IκB kinase (IKK) complex and subsequently degraded by the ubiquitin proteasome pathway. The released NFκB dimer can then move into the nucleus, where it induces the expression of various genes (Santangelo et al. 2007; Gopalakrishnan and Kong 2008). The influence of EGCG on the NFκB pathway has been extensively studied, and studies demonstrate its inhibitory effects on NFκB obtained by counteracting the activation of IKK and the phosphorylation and degradation of IKBa (Sueoka et al. 2001; Lambert and Yang 2003; Park and Dong 2003; Wheeler et al. 2004, Santangelo et al. 2007; Tipoe et al. 2007). Importantly, the gallate group is functionally necessary for the inhibition of IKK activity, and the presence of the catechin structure dramatically enhances this effect (Santangelo et al. 2007). The EGCG inhibits phosphorylation of p65, thus providing an additional mechanism for the inhibition of NFκB activation; this effect could be the result of IKK inhibition, because IKK can phosphorylate the p65 subunit in vitro (Wheeler et al. 2004). In addition, theaflavins block phosphorylation and/or degradation of IκB (Bode and Dong 2003). Despite the central role of NFκB in inflammation-associated genes expression, this transcription factor requires assistance from MAPK (Santangelo et al. 2007). The EGCG prevents IL-12 production and the expression of COX-2 by inhibiting phosphorylation of p38 MAPK, augmenting phosphorylation of ERK and nuclear-protein binding to NFκB site (Yoon and Baek 2005; Santangelo et al. 2007).

The AP-1 transcription factors and the AP-1 factor-associated signal transduction, implicated in inflammatory response, are important targets of EGCG action (Sueoka et al. 2001; Balasubramanian, Efimova, and Eckert 2002; Lambert and Yang 2003; Park and Dong 2003; Tipoe et al. 2007). The AP-1 proteins consist of homodimers of Jun proteins and heterodimers of Jun and Fos factors (Gopalakrishnan and Kong 2008). The exact subunit composition is influenced by the nature of the extracellular stimulus and the MAPK signaling pathway that is activated (JNK, ERK, etc.). On stimulation, regulation of AP-1 activity occurs through activating transcription of these genes as well as through phosphorylation of existing Jun and Fos proteins at specific serine and threonine sites (Sueoka et al. 2001; Lambert and Yang 2003; Park and Dong 2003; Tipoe et al. 2007). Similar to the mechanism described for antioxidant enzyme regulation, EGCG produces a reduction in MAPK activity and reduces AP-1 factor level and activity in immortalized and transformed keratinocytes; however, it increases AP-1 factor levels in normal keratinocytes (Balasubramanian, Efimova, and Eckert 2002). Both EGCG and theaflavin-3,3′-digallate were found to inhibit phosphorylation of ERKs, and theaflavin-3,3′-digallate inhibited p38 kinase phosphorylation (Bode and Dong 2003). Both ERKs and p38 kinase phosphorylation are implicated in AP-1 activation. In addition, induction of Nfr2 and overexpression of HO-1 (ARE-mediated) suppressed MCP-1 and VCAM-1 expression, suppressed monocyte adhesion to endothelial cells and transmigration, suppressed activation of p38 MAP kinase, and inhibited atherosclerotic lesion formation (Chen et al. 2006). Induction of other antioxidant genes such as MnSOD may involve rapid phosphorylation of ERK1/2 and IκB, translocation of the p50 subunit of NFκB to the nucleus, and transactivation of MnSOD expression (Mann, Niehueser-Saran et al. 2007; Mann, Rowlands et al. 2007), indicating an interplay between red-ox and inflammatory transcription factors. In addition, interaction with lipid rafts may account for flavonoid anti-inflammatory activity, because in T lymphocytes lipid rafts are implicated in signaling from the T-cell antigen receptor (TCR; Kabouridis and Jury 2008).

However, the large body of in vitro and cellular evidence can be influenced somehow by the concentrations utilized, which range from 2 to 100 μM, in contrast to physiological levels in plasma that are not higher than 1 μM, following the ingestion of flavonoid-rich food (Manach et al. 2004). Moreover, in vivo, catechins are extensively metabolized and transformed into molecules having different chemical structures and activities compared to those originally present in the food. A large majority of in vitro and cellular experiments have not been performed with the metabolites present in body fluids, which further increases the chance of misinterpretation of results.

12.4.5. Anti-Inflammatory Activity: Human Study

In spite of a large amount of in vitro evidence, consumption of BT and GT in humans had only slight effects on inflammation markers such as IL-6, IL-1β, TNF-α, and C-reactive protein (CRP; de Maat et al. 2000; Widlansky et al. 2005; Ryu et al. 2006; Mukamal et al. 2007), as summarized in Table 12.3. Administration of BT, GT, and GTE for 4 weeks had no effect on the inflammatory markers IL-6, IL-1β, TNF-α, CRP, and fibrinogen (de Maat et al. 2000); however, BT lowered P-selectin levels concomitantly with an increase of 4-O-methyl gallic acid (Hodgson et al. 2001). Contrary to these findings, Wildansky et al. (2005) observed in patients with coronary artery disease an increase in plasma catechins after 4 weeks of 900 mL of BT per day; however, this was not accompanied by a reduction in CRP. Further, CRP, as well as IL-6, was unaffected by GT administration in diabetic patients (Ryu et al. 2006), and fibrinogen, CRP, IL-6, TNF-α, ICAM, and VCAM were all unaffected by 6 months of BT consumption in diabetic subjects (Mukamal et al. 2007). However, Steptoe et al. (2007) revealed a reduction in CRP levels after 6 weeks of BT consumption.

TABLE 12.3. Overview of Human Intervention Studies on the Anti-Inflammatory Effects of Tea.

TABLE 12.3

Overview of Human Intervention Studies on the Anti-Inflammatory Effects of Tea.

The assumption that tea flavonoids are responsible for anti-inflammatory action cannot be fully justified on the basis of current in vivo evidence. Studies investigating the effect of catechins on the markers of inflammation are scarce and do not focus on pure molecules. Moreover, most of the studies do not assess flavonoid absorption, or they fail to associate the anti-inflammatory effect following tea ingestion with changes in the circulating levels of tea constituents or their metabolites.

12.4.6. Antiviral Activity of Green Tea Catechins (Veregen)

External genital warts are very common and represent a significant health problem, particularly for young adults. One review revealed that the efficacy of all treatments is less than optimal and multiple therapies may be necessary for complete resolution of the condition (Mayeaux and Dunton 2008). Recently, the Food and Drug Administration (FDA) approved the marketing of sinecatechins (Veregen, Bradley/MediGene, AG, D-82152 Planegg/Martinsried, Germany), a botanical drug product, for the treatment of external genital and perianal warts. Sinecatechins is a water extract of GT leaves from C. sinensis. This is the first case of an herbal extract being approved as a drug for clinical therapy. The novel drug, produced from GT, now represents a real alternative to conventional therapy and demonstrates how well-designed clinical trials for the investigation of the therapeutic features of GT and catechins may lead to important formulations beneficial to health (Stockfleth et al. 2008; Tatti et al. 2009).

12.5. HEALTH EFFECTS: THE SCIENTIFIC EVIDENCE

Tea polyphenols found in black and green tea may have a protective effect against heart disease and some cancers, as described below.

12.5.1. Anticancer Activity of Green Tea

Cancer is not one disease but a plethora of different diseases with important differences in terms of lethality, which have much to do with individual response. In many cases, the efficacy of the weapons we have against cancer is limited. Some cancers may turn very aggressive, and when this happens only palliative therapy is available for the patient. Important examples are aggressive lung, breast, pancreatic, and prostate cancers. Lifestyle has always been considered a fundamental risk factor for cancers; the diseases do not have a prevalent genetic imprinting. Therefore, although unfortunately it was recognized only quite recently, the prevention or inhibition of progression of subclinical cancer toward more aggressive stages is considered in many cases to be the most effective therapy. The definition of chemoprevention is as follows: a strategy for pharmacological intervention with natural or synthetic compounds that may prevent, inhibit, delay, or reverse carcinogenesis (Sporn et al. 1976; William et al. 2009).

Hypotheses and studies on the possible anticancer activity of GT go back a long time and have been extensively reviewed (Bode and Dong 2009; Boehm et al. 2009; Yang et al. 2009; Butt and Sultan 2009). There are three main streams of information leading to the final conclusion that active compounds such as catechins, found in high quantities in GT, may be beneficial in this regard. The first is epidemiological evidence; the second is preclinical data; and the third stream, still in its infancy, is based on clinical trials. In all these branches, although discussion is still rather open, epidemiology supports the increasing consensus that GT consumption decreases cancer risk (Yoshizawa et al. 1987; Dreosti, Wargovich, and Yang 1997; Katiyar and Mukhtar 1996. Bode and Dong 2009; Boehm et al. 2009; Yang et al. 2009; Butt and Sultan 2009). Studies involving many in vitro and in vivo experimental systems provide convincing evidence that supports epidemiological findings (Yang and Wang 1993; Yang 1997; Yang, Maliakal, and Meng 2002). Anticancer activity of GT has been demonstrated in many cancer models, including lung, mammary gland, skin, esophagus, stomach, liver, pancreas, intestine, and colon (Wang et al. 1989; Huang et al. 1992; Yang and Wang 1993; Gensler et al. 1996; Dreosti, Wargovich, and Yang 1997; Huang et al. 1997; Yang 1997; Chung et al. 1998). These studies raise considerable interest in this issue, although the precise mechanism of action of GTCs and EGCG, which seems to be the most powerful biologically active catechin, is still unclear. At the moment, several hypotheses have been made and experimental data suggest that catechins may interact directly with several molecular targets (Tachibana 2009) and affect gene expression and signaling by epigenetic mechanisms (Patra et al. 2008). However, the most relevant issue faced as of now is how to collect clinical evidence of the anticancer activity of catechins by performing pilot or definitive clinical trials targeting specific preneoplastic or cancer lesions. Section 12.5.2 addresses this issue by providing a paradigmatic example of chemoprevention by means of catechins in an important cancer model: prostate cancer.

12.5.2. Green Tea Catechins Extract against Human Prostate Cancer

Prostate cancer is the second leading cause of cancer-related death among men in Western countries, representing at the moment a major health problem that is slowly but constantly growing as the population ages (Haas and Sakr 1997). The threat is particularly growing in Italy, where it was recently announced that prostate cancer is now the most lethal cancer prevalent among the male population. This finding can certainly be correlated with the fact that Italians are now the oldest population in Europe.

Prostate cancer represents an ideal candidate for chemoprevention because of its high incidence and long latency period before the development of clinically evident disease. Several potential chemopreventive agents have already been tested, including COX-2 inhibitors (Basler and Piazza 2004), 5-α-reductase inhibitors (Thompson et al. 2003), and vitamin D analogs (Packianathan et al. 2004). Among natural compounds, GTEs very rich in catechins (GTCs) have been recently used because results from epidemiological and case control studies support the idea of a chemopreventive effect of bioactive compounds extracted from GT, such as catechins (Jian et al. 2004). The possible mechanism of anticancer activity of GTCs has been extensively reviewed (Khan et al. 2006). Although the molecular mechanisms of GTC action are still unclear, supporting evidence suggests that GTCs induce apoptosis in cancer cells by a mechanism that is not related to altered activity of the members of the B cell lymphoma 2 (BCL-2) family.

The most biologically active of the catechins, EGCG, has been found to inhibit angiogenesis, causing nutritional deficiency in tumor cells. The GTCs have also been found to induce the synthesis of some hepatic phase II enzymes involved in the detoxification of xenobiotics and chemical carcinogens (Khan et al. 2006). In addition, GTCs were found to possess antimetastatic potential by inhibiting urokinase, metalloproteinase 2 (MMP-2), and MMP-9. The EGCG has been found to downregulate the androgen receptor in human prostate cancer cells in culture. Therefore, a plethora of scientific papers have created the rationale for a strong potential antiproliferative effect of GTCs in cultured human prostate cancer cells. The antiproliferative effect was demonstrated specifically against cancer cells in vitro (Caporali et al. 2004). In this work, a gene named clusterin (CLU), recently proposed as a novel tumor suppressor for prostate cancer (Bettuzzi et al. 2009), was found to mediate GTC activity (Caporali et al. 2004). This result is remarkable because catechins often inhibit protein activity and gene expression; CLU seems to be one of the rare genes upregulated by GTCs. In the same work, it was demonstrated that oral administration of a 0.3% solution of GTCs in drinking water was effective in vivo in inhibiting prostate cancer progression in a well-known animal model of this disease, that is, the transgenic adenocarcinoma of mouse prostate (TRAMP). All male TRAMP mice spontaneously develop prostate cancer as a function of age, but only 20% of the animals developed prostate cancer when the GTC solution was given right after weaning as the sole source of drinking water. The possibility that GTC action is mediated by CLU was also confirmed in vivo because mice responding to GTCs showed recovery of CLU expression (which is downregulated during prostate cancer progression) immediately followed by reactivation of caspase-9 expression. Mice refractory to GTC treatment did not express either CLU or caspase-9 (Caporali et al. 2004; Scaltriti et al. 2006).

On the basis of these findings, a pilot clinical trial was recently conducted to assess the efficacy of GTCs in real clinical settings. In this study (Bettuzzi et al. 2006), 60 patients bearing pure HGPIN, the most likely preinvasive stage of prostate cancer, were randomly divided into two groups, one taking 600 mg/day of GTCs and the other taking placebo for a duration of 1 year. The primary aim of the study was to determine the impact of administration of GTCs on prevalence/progression of prostate cancer. At the end of the study, only 3% of the patients who received GTCs were diagnosed with cancer by repeated needle biopsy, as compared to 30% of the placebo arm. More data were gathered later in the same cohort of patients. In a follow-up study (Brausi, Rizzi, and Bettuzzi 2008), it was found that the clinical conditions of patients were stable even 2 years after suspension of chemoprevention with GTCs. This result suggests the hypothesis that the clinical benefit consisting of a powerful inhibition of prostate cancer progression achieved in subjects after 1 year of GTC administration is a stable condition. In this paradigmatic example, natural compounds extracted from GT were found to be very effective, representing a new hope of curing prostate cancer at least in its early phases.

12.5.3. Tea and Cardiovascular Diseases

Half of the mortality in Western populations over 40 years of age is due to diseases of the cardiovascular system, of which the main pathophysiological factor is atherosclerosis. Atherogenesis is a chronic inflammatory process that involves a complex interplay between circulating cellular and blood elements within the cells of the artery wall (Steinberg and Witzum 1990). This process occurs at a young age in the arteries as accumulation of lipids in the subintimal area, known as “fatty streaks.” Fatty streaks, consisting of subendothelial aggregates of lipid-laden foam cells, predominantly macrophages, may progress to fibrous plaques, which represent the characteristic lesions of advancing atherosclerosis. The fibrous plaque comprises mainly smooth muscle cells and is the product of GTC action cytokines and growth factors. Fibrous plaques may undergo calcification, necrosis, hemorrhages, ulceration, or thrombosis to form a complex lesion that is most commonly associated with clinical atherosclerosis (Steinberg and Witzum 1990).

Lipid metabolism is usually impaired (Briel et al. 2009) in CVD, and increased oxidative stress (Molavi and Mehta 2004) has also been reported to be involved in CVD development. Other disturbances associated with CVD include inflammation (Fearon and Fearon 2008), platelet aggregation (Caslake and Packard 2003), and impaired endothelial function (Constans and Conri 2006). Tea flavan-3-ols have been reported to affect these disturbances. Besides being antioxidant molecules, flavan-3-ols can modulate the lipid profile (Richard et al. 2009) and blood coagulation (Vita 2005). In humans, significant decreases (approximately 10 mg/dL [0.25 mmol/L]) in total and low-density lipoprotein cholesterol were reported after consumption of a GTE (Nantz et al. 2009). A similar decrease was achieved by a capsule containing theaflavin-enriched GTE (375 mg) taken daily (Maron et al. 2003) and with 2 cups of GT, containing approximately 250 mg of total catechins (Erba et al. 2005).

Endothelial function is being increasingly recognized as a biomarker of cardiovascular health, and dysfunction of the endothelial layer is recognized as an early etiological factor in atherogenesis (Hunt 2000). There is accumulating evidence to indicate that GTCs can positively impact endothelial and vascular functions in animals and humans (Ihm et al. 2009; Park et al. 2009), and a number of plausible molecular mechanisms have been proposed (Moore, Jackson, and Minihane 2009). However, the literature on the topic is not entirely consistent, and there is also a strong concern regarding the physiological relevance of in vitro and cellular findings that utilized GTC at far higher concentrations than those achieved through diet.

Different studies have investigated the association between GT consumption and CVD mortality with contrasting results (Sato et al. 1989; Nakachi et al. 2000; Iwai et al. 2002). An inverse association between tea intake and mortality from CVD was observed in a large epidemiological study (Kuriyama 2008) and was found to be more pronounced in women, with a multivariate hazard ratio (95% confidence intervals) of CVD mortality in the highest quartile of intake equal to 0.69 (0.53–0.90; p < 0.05). In a cohort of 76,979 individuals aged 40–79 years who were free of stroke, coronary heart disease, and cancer at entry, it was shown that the multivariable hazard ratios for those drinking 1–6 cups/week, 1–2 cups/day, 3–5 cups/day, and 6 cups/day were, respectively, 0.34 (0.06–1.75), 0.28 (0.07–1.11), 0.39 (0.18–0.85; p < 0.05), and 0.42 (0.17–0.88; p < 0.05) for CVD among women compared to nondrinkers of tea (Mineharu et al. 2009). It must be pointed out that most of the published epidemiological studies were conducted in Asian countries, where consumption of GT is far higher compared to the rest of the world.

12.6. ADVERSE EFFECTS OF GREEN TEA CATECHINS EXTRACT ADMINISTRATION

In the literature, more than 30 cases of hepatitis caused by GTE (GTCs) supplementation have been reported (Adachi et al. 2003; Garcia-Moran et al. 2004; Abu el Wafa et al. 2005; Gloro et al. 2005; Bonkovsky 2006). In all cases, symptoms were similar, and occurred about 30 days after the beginning of treatment. Abdominal pain, elevated transaminase levels, and jaundice were the main symptoms observed. In most cases, suspension of GTC administration and hospitalization was followed by slow recovery, and enzyme levels returned to normal within 3 months; however, two cases had complete liver failure leading to transplantation, which was successful (Gow et al. 2004). The fact that in at least three cases the symptoms returned in patients who resumed the supplement following recovery from the first attack is proof that GTE was the cause of the liver failure (Molinari et al. 2006). The first reports were from people in France taking an extract known as Exolise from Arkopharma (BP 28–06511 CARROS Cedex - FRANCE), which was sold as an aid for weight loss (Seddik et al. 2001; Sgro et al. 2002; Vial et al. 2003). Exolise was removed from the market by the French authorities.

The connection between GTE consumption and idiopathic hepatitis is hard to explain. It seems more likely that instead of toxic exposure, the condition may rather be a triggered reaction similar to other cases of idiopathic hepatitis. The paradox is that there is no hint in the literature that indicates whole GT causes liver toxicity. Therefore, adverse effects may be specifically related only to the extracts. Although the total risk is considered to be quite low, these extracts have to be taken with caution, and automedication is not always a good idea. Liver function has to be checked soon after beginning the treatment. As in the case of all medications, the risk-benefit calculation must be favorable.

12.7. RESEARCH NEEDS

Future research on the health effects of tea in humans should focus on the biological significance of its in vivo catabolism. As stated in Section 12.4.1, most polyphenols present in tea, with probably the only exception of EGCG, undergo drastic modification as a result of reaction with human and microbial enzymes. The molecules generated by this interaction are concentrated in biological fluids and should be studied for their long-terms effects in human intervention studies. Moreover, gut microflora differ greatly among subjects, and this feature could mean different microbial catabolism and, consequently, different biological effects. Therefore, future intervention studies should consider the colonic microflora profile of each volunteer to check for possible interactions. The observed antioxidant effect of tea ingestion in vivo requires more evidence about the mechanism of action through which this effect is delivered.

Possible mechanisms of antioxidant action such as induction of endogenous redox-controlled pathways or direct effect of polyphenols metabolites should be unraveled, providing clear-cut evidence in long-term intervention studies to isolate the molecules responsible for the effect. The experimental evidence in humans suggests a potential role for GT in modulating inflammatory response in vivo. However, the limited number of studies and the contrasting results obtained suggest a strong need for increasing the body of evidence in tailored human intervention studies before drawing final conclusions about the anti-inflammatory role of tea polyphenols.

12.8. CONCLUSIONS

In conclusion, scientific evidence of the health effects of tea ingestion on CVD and cancer is mounting. However, no clear-cut conclusion has been reached on the mechanism of action of the molecules involved in this effect, although anti-inflammatory, antioxidant, and endothelial function effects seem to play a key role. Despite the lack of convincing evidence in long-term intervention studies, tea catechins are still the major player in the biological activity of teas. However, tailored human trials with proper placebo or pure molecules are needed to clarify whether catechins represent ancillary ingredients or key molecules involved in the biological properties of GT. In the meantime, an increase in the consumption of tea, with a negligible calorie load, should be encouraged.

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