Life Extension Magazine

Life Extension Magazine January 2009

Abstracts

Theaflavin

Mechanisms of cancer prevention by green and black tea polyphenols.

Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-kappaB as a result of decreased IkappaB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor an-tagonist by directly binding the receptor’s molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.

Anticancer Agents Med Chem. 2006 Sep;6(5):389-406

Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a.

In vertebrates and invertebrates, relationships between diet and health are controlled by a conserved signalling pathway responsive to insulin-like ligands. In invertebrate models for example, forkhead transcription factor family O (FOXO) transcription factors in this pathway regulate the rate of aging in response to dietary cues, and in vertebrates, obesity and age-induced deficits in the same pathway are thought to contribute to dysregulation of hepatic gluconeogenesis through genes such as phosphoenolpyruvate carboxykinase (PEPCK). Recently, we have begun to screen for dietary constituents capable of regulating this pathway in our cell culture model. Here, we identify three black tea theaflavins, theaflavin 3-O-gallate, theaflavin 3’-O-gallate, theaflavin 3,3’di-O-gallate and thearubigins as novel mimics of insulin/IGF-1 action on mammalian FOXO1a, PEPCK and moreover we provide evidence that the effects on this pathway of the green tea constituent (-)-epigallocatechin gallate depend on its ability to be converted into these larger structures. With the exception of water, tea is the most popular drink globally, but despite this, little is known about the biological availability of black tea polyphenols in vivo or the molecular target(s) mediating the effects presented here. Further investigation in these two areas might provide insight into how age-related metabolic disease may be deferred.

Aging Cell. 2008 Jan;7(1):69-77

Tea polyphenols benefit vascular function.

Tea, the most popular beverage worldwide, is consumed in three basic forms; green tea, black tea and oolong tea. Tea contains over 4,000 chemicals some of which are bioactive. In recent years there has been a mounting interest in understanding the cardiovascular and metabolic benefits of polyphenolic flavonoids in tea, which can be used as a supplement among patients. Diverse cardioprotective effects of consuming tea or tea polyphenols have been described on pathological conditions, e. g. hypertension, atherosclerosis, diabetics, hypercholesterolemia, obesity, and are attributed to antioxidative, anti-thrombogenic, anti-inflammatory, hypotensive and hypocholesterolemic properties of tea polyphenols. This review focuses on cardiovascular benefits of tea polyphenols based on in vitro and in vivo studies on experimental animal models and on studies of human subjects in four areas: (1) vasorelaxant effect; (2) protective effect against endothelial dysfunction; (3) antioxidant effect and (4) hypolipidemic effect. We will briefly discuss the effects of tea on atherosclerosis and hypertension.

Inflammopharmacology. 2008 Sep 26

Anti-invasive effects of green tea polyphenol epigallocatechin-3-gallate (EGCG), a natural inhibitor of metallo and serine proteases.

Several reports have attributed to green tea chemopreventive and therapeutic properties. Epidemiological studies have linked the regular use of green tea to a reduced incidence of breast and colon carcinomas. Tea contains several antioxidants, including polyphenols of the catechin (green tea) and theaflavin (black tea) groups. Green tea derivatives have been shown to act in vitro and in vivo as anti-inflammatory, anti-viral and anti-tumor drugs. Despite the extensive body of data only few studies have investigated the molecular mechanisms underlying these effects. In this brief review we focus on the inhibitory activity of catechins derived from green tea toward proteases involved in tumor invasion.

Biol Chem. 2002 Jan;383(1):101-5

Theaflavin, a black tea extract, is a novel anti-inflammatory compound.

OBJECTIVE: Tea has been around for centuries, and its medicinal properties have been purported in the literature but never fully confirmed. Interleukin-8 is a principle neutrophil chemoattractant and activator in humans. We determined the effects of theaflavin, a black tea-derived polyphenol, on tumor necrosis factor-alpha-mediated expression of the interleukin-8 gene in A549 cells. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: A549 cells. INTERVENTIONS: A549 cells were exposed to varying concentrations of theaflavin and analyzed for tumor necrosis factor-alpha-mediated interleukin-8 gene expression. MEASUREMENTS AND MAIN RESULTS: Theaflavin inhibited tumor necrosis factor-alpha-mediated interleukin-8 gene expression, as measured by luciferase assay and Northern blot analysis, at concentrations of 10 and 30 microg/mL. This effect appears to primarily involve inhibition of interleukin-8 transcription because theaflavin inhibited tumor necrosis factor-alpha-mediated activation of the interleukin-8 promoter in cells transiently transfected with an interleukin-8 promoter-luciferase reporter plasmid. In addition, theaflavin inhibited tumor necrosis factor-alpha-mediated activation of IkappaB kinase and subsequent activation of the IkappaB-alpha/nuclear factor-kappaB pathway. Theaflavin also significantly reduced tumor necrosis factor-alpha-mediated DNA binding of activator protein-1. CONCLUSIONS: We conclude that theaflavin is a potent inhibitor of interleukin-8 gene expression in vitro. The proximal mechanism of this effect involves, in part, inhibition of IkappaB kinase activation and activator protein-1 pathway.

Crit Care Med. 2004 Oct;32(10):2097-103

Theaflavin ameliorates cerebral ischemia-reperfusion injury in rats through its anti-inflammatory effect and modulation of STAT-1.

Theaflavin, a major constituent of black tea, possesses biological functions such as the antioxidative, antiviral, and anti-inflammatory ones. The purpose of this study was to verify whether theaflavin reduces focal cerebral ischemia injury in a rat model of middle cerebral artery occlusion (MCAO). Male Sprague-Dawley rats were anesthetized and subjected to 2 hours of MCAO followed 24 hours reperfusion. Theaflavin administration (5, 10, and 20 mg/kg, i.v.) ameliorated infarct and edema volume. Theaflavin inhibited leukocyte infiltration and expression of ICAM-1, COX-2, and iNOS in injured brain. Phosphorylation of STAT-1, a protein which mediates intracellular signaling to the nucleus, was enhanced 2-fold over that of sham group and was inhibited by theaflavin. Our study demonstrated that theaflavin significantly protected neurons from cerebral ischemia-reperfusion injury by limiting leukocyte infiltration and expression of ICAM-1, and suppressing upregulation of inflammatory-related prooxidative enzymes (iNOS and COX-2) in ischemic brain via, at least in part, reducing the phosphorylation of STAT-1.

Mediators Inflamm. 2006;2006(5):30490

Modulation of the oxidative stress and nuclear factor kappaB activation by theaflavin 3,3’-gallate in the rats exposed to cerebral ischemia-reperfusion.

The major pathobiological mechanisms of IR injury include excitotoxicity, oxidative stress, and inflammation. TF3, a major constituent of black tea, possesses biological functions such as anti-oxidative and anti-inflammatory activities. The purpose of this study was to verify the neuronal protective potential of TF3 and its mechanisms against cerebral IR injury in rats. TF3 administration (10 and 20 mg.kg-1) ameliorated the infarct volume. TF3 also decreased the content of MDA and NO. TF3 significantly increased the activity of SOD and GSH-Px, which were reduced by IR injury. Administration of TF3 decreased mRNA and protein expression of COX-2 and iNOS. DNA binding and Western blotting revealed an increase in NF-kappaB activation and IkappaB depletion in IR brain tissue. Pretreatment with TF3 markedly inhibited IRinduced increase in nuclear localization of NF-kappaB, and preserved IkappaB in the cytoplasm. The results show that TF3 exerts protective effects against cerebral IR injury by reducing oxidative stress and modulating the NF-kappaB activation.

Folia Biol (Praha). 2007;53(5):164-72

Theaflavins induced apoptosis of LNCaP cells is mediated through induction of p53, down-regulation of NF-kappa B and mitogen-activated protein kinases pathways.

Prostate cancer (PCA), the most frequently diagnosed malignancy in men, represents an excellent candidate disease for chemoprevention studies because of its particularly long latency period, high rate of mortality and morbidity. Infusion of black tea and its polyphenolic constituents have been shown to possess antineoplastic effects in androgen dependent PCA in both in vivo and in vitro models including transgenic animals. In the present study, we report that black tea polyphenol, Theaflavins (TF)-induced apoptosis in human prostate carcinoma, LNCaP cells is mediated via modulation of two related pathways: up-regulation of p53 and down-regulation of NF-kappa B activity, causing a change in the ratio of pro-and antiapoptotic proteins leading to apoptosis. The altered expression of Bcl-2 family member proteins triggered the release of cytochrome-C and activation of initiator capsase 9 followed by activation of effector caspase 3. Furthermore, TF also affected the protein expression of mitogen activated protein kinases (MAPK) pathways. Our results demonstrated that TF treatment resulted in down-regulation of phospho-extracellular signal-regulated protein kinase (Erk1/2) and phospho-p38 MAPK expressions. We conclude that TF induces apoptosis in LNCaP cells by shifting the balance between pro-and antiapoptotic proteins and down-regulation of cell survival pathways leading to apoptosis. Further extending this work, we also showed that TF induces apoptosis in androgen independent PCA cell line, PC-3 through caspases and MAPKs mediated pathways. Thus, effect of TF on PCA cell lines seems to be irrespective of their androgen status.

Life Sci. 2007 May 16;80(23):2137-46

Theaflavins attenuate hepatic lipid accumulation through activating AMPK in human HepG2 cells.

Black tea is one of the world’s most popular beverages, and its health-promoting effects have been intensively investigated. The antiobesity and hypolipidemic effects of black tea have attracted increasing interest, but the mechanisms underlying these phenomena remain unclear. In the present study, the black tea major component theaflavins were assessed for their hepatic lipid-lowering potential when administered in fatty acid overload conditions both in cell culture and in an animal experimental model. We found that theaflavins significantly reduced lipid accumulation, suppressed fatty acid synthesis, and stimulated fatty acid oxidation. Furthermore, theaflavins also inhibited acetyl-coenzyme A carboxylase activities by stimulating AMP-activated protein kinase (AMPK) through the LKB1 and reactive oxygen species pathways. These observations support the idea that AMPK is a critical component of decreased hepatic lipid accumulation by theaflavin treatments. Our results show that theaflavins are bioavailable both in vitro and in vivo and may be active in the prevention of fatty liver and obesity.

J Lipid Res. 2007 Nov;48(11):2334-43

Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial.

BACKGROUND: Tea consumption has been associated with decreased cardiovascular risk, but potential mechanisms of benefit are ill-defined. While epidemiologic studies suggest that drinking multiple cups of tea per day lowers low-density lipoprotein cholesterol (LDL-C), previous trials of tea drinking and administration of green tea extract have failed to show any impact on lipids and lipoproteins in humans. Our objective was to study the impact of a theaflavin-enriched green tea extract on the lipids and lipoproteins of subjects with mild to moderate hypercholesterolemia. METHODS: Double-blind, randomized, placebo-controlled, parallel-group trial set in outpatient clinics in 6 urban hospitals in China. A total of 240 men and women 18 years or older on a low-fat diet with mild to moderate hypercholesterolemia were randomly assigned to receive a daily capsule containing theaflavin-enriched green tea extract (375 mg) or placebo for 12 weeks. Main outcome measures were mean percentage changes in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels compared with baseline. RESULTS: After 12 weeks, the mean +/- SEM changes from baseline in total cholesterol, LDL-C, HDL-C, and triglyceride levels were -11.3% +/- 0.9% (P =.01), -16.4% +/- 1.1% (P =.01), 2.3% +/- 2.1% (P =.27), and 2.6% +/- 3.5% (P =.47), respectively, in the tea extract group. The mean levels of total cholesterol, LDL-C, HDL-C, and triglycerides did not change significantly in the placebo group. No significant adverse events were observed. CONCLUSION: The theaflavin-enriched green tea extract we studied is an effective adjunct to a low-saturated-fat diet to reduce LDL-C in hypercholesterolemic adults and is well tolerated.

Arch Intern Med. 2003 Jun 23;163(12):1448-53