The nutraceutical benefit, part I: green tea☆

G reen tea has been consumed as a beverage for thousands of years in China and in Japan; it also has been used for its medicinal purposes. Because of the lack of specific scientific methods, scientists have dismissed the notion of green tea for its healing properties. However, in recent years, much attention has focused on the role of green tea for its antimicrobial, immunostimulatory, anticarcinogenic, and antiinflammatory capacities and for its protective effect against cardiovascular diseases. Green tea comes from the plant Camilla sinesis, which contains polyphenols such as epigallocatechin gallate (EGCG), epicatechin gallate, epigallocatechin, and epicatechin, which have antioxidant properties.1–3 The antimicrobial capacity of green tea is effective against various bacteria that cause diarrhea (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Vibrio cholerae O1)4 and dental caries (e.g., Escherichia coli, Streptococcus salivarius, Streptococcus mutans).5 The mechanism proposed for these antimicrobial activities is that bactericidal catechins primarily act on and damage bacterial membranes.6 Also, as shown in Figure 1, the immunostimulatory capacity has been shown in studies that have documented EGCG stimulating the immune system to produce splenic B lymphocytes in mice7 and T lymphocyte and natural killer cell activity in tumor-bearing mice.8 The possible way in which these polyphenols function has been demonstrated by an animal study.9 As shown in Figure 2, oral or intravenous nutrients including immunomodulating nutraceuticals are sensed by nutrientspecific receptors or sensors in the portohepatic area which, through afferent vagal fibers, project onto the dorsomotor nucleus and interact with the hypothalamus. Changes in vagal afferent firing rate occur. An increase in vagal thymic and vagal lymph node efferent activity occurs, stimulating the increased release of T cells. Simultaneously, decrease in splenic efferents occurs, inhibiting the uptake of lymphocytes. The net effect is an increase in circulating cellular and humoral immunity. Evidence of the anticarcinogenic capacity of green tea is based on accumulated epidemiologic human studies10–12 and numerous animal models.13–16 In a prospective study in a Japanese population, a negative correlation was observed between green-tea consumption and the onset age of cancer. Among women, consumption of more than 10 cups (1800 mL; approximately 300–400 mg of EGCG) per day was associated with a significant decrease in cancer incidence with age.10 In a Chinese-population-based case-control study, newly diagnosed cancer patients (931 colon, 884 rectum, and 451 pancreas) and 1552 cancer-free individuals as a control showed an inverse correlation between daily consumption of green tea and risk of rectal and pancreatic cancers.11 The consumption of the brew from green-tea leaves (.300 g/mo in men and 200 g/mo in women) was associated with a significant reduction in these cancers. In another epidemiologic study, stage-I and -II breast cancer patients in Japan who consumed more than 5 cups (about 750 mL) per day had a significantly lower recurrence rate (16.7%) and longer disease-free years (3.6 y) than did patients who consumed fewer than 4 cups per day (24.3% and 2.8 y, respectively).12 The anticarcinogenic capacity of green tea has also been reported in experimental animal studies: in tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice,13 in N-nitrosomethylbenzylamineinduced esophageal tumors in rats,14 in ultraviolet-induced skin tumors in hairless mice,15 and in N-butyl-N-(4-hydroxybutyl)nitrosamine induced urinary tumors in rats.16 It is likely that green tea acts on various kinds of cancers in different organs. Possible mechanisms for the anticancer properties of green tea have been proposed from several laboratories. Parshad et al.17 reported the protective action of polyphenols. Green tea polyphenols significantly decreased fluorescent light-induced chromatid breaks in human fibroblasts GM5757 cells (19.3 versus 34.0 chromatid breaks/ 100 metaphase cells).17 Using computer modeling with the urokinase active site serving as a template EGCG, Jankun et al.18 reported the inhibitory effect of EGCG on urokinase, a proteolytic enzyme necessary for invading tissue and/or metastasizing neoplastic cells, resulting in prevention of tumor growth and metastasis.18 Another possible mechanism proposed by Ahmad et al. was an induction of apoptosis and cellcycle arrest by EGCG.19 In that study, human epidermoid carcinoma A431 cells treated with 160 mg/mL EGCG resulted in increased apoptosis to 80.9% versus 1.5% in vehicle-treated cells as analyzed by flow cytometry. Further, 80 mg/mL EGCGtreated cells contained 74% of G0 and G1 cycle cells versus 41% in vehicle-treated cells. Green tea also has a known antiinflammatory effect. Because tumor necrosis factor-a (TNF-a) among numerous kinds of cytokines plays a major role in inflammatory response, Yang et al.20 reported the effect of EGCG on lipopolysaccharideinduced TNF-a gene expression in the macrophage cell line, RAQ264.7, and the activity of nuclear factor-kB, an oxidative stresssensitive transcription factor that controls the expression of different kinds of genes active in inflammation including cytokines.20 Pretreatment with 100 mmol/L EGCG decreased lipopolysaccharideinduced TNF-a mRNA expression to 50%, its production to 45%, and nuclear factorkB-binding activity by 30% as compared with non-pretreatment control. This mechanism of the antiinflammatory effect of EGCG is the same as that of other known antiinflammatory agents (e.g., sodium salicylate, dexamethasone), suggesting that green tea could be effective for various kinds of inflammatory diseases, including Crohn’s disease.21 The protective effect of green tea against cardiovascular diseases was reported in a Japanese epidemiologic study.22 In that study, in Japanese men older than 40 y (n 5 1371), increased consumption of green tea, especially more than 10 cups (about 1500 mL) per day, was associated with a decreased concentration of serum total cholesterol and low-density lipoprotein and with an increased concentration of high-density lipoprotein, and thus with a decreased atherogenic index (ratio of low-density to high-density lipoprotein). In mice fed an atherogenic diet, green-tea extract prevented an increase of serum lipid peroxides in a dose-dependent manner.23 Moreover, green-tea extract at 0.5 mmol/L concentration increased the lag time of low-density lipoprotein oxidation to 211 min from baseline (79 min) in an in vitro low-density Correspondence to: Tomoi Sato, MD, Department of Surgery, SUNY Health Science Center, University Hospital, 750 East Adams Street, Syracuse, NY 13210, USA. E-mail: satot@mailbox.hscsyr.edu