ABSTRACT: Green tea polyphenols may contribute to the prevention of cancer and other diseases. To learn more about the pharmacokinetics and interindividual variation of green tea polyphenols after oral intake in humans we performed a population nutrikinetic study of standardized green tea extract. 84 healthy participants took green tea extract capsules standardized to 150 mg epigallocatechin-gallate (EGCG) twice a day for 5 days. On day 5 catechin plasma concentrations were analyzed using non-compartmental and population pharmacokinetic methods. A strong between-subject variability in catechin pharmacokinetics was found with maximum plasma concentrations varying more than 6-fold. The AUCs of EGCG, EGC and ECG were 877.9 (360.8-1576.5), 35.1 (8.0-87.4), and 183.6 (55.5-364.6) h*?g/L respectively, and the elimination half lives were 2.6 (1.8-3.8), 3.9 (0.9-10.7) and 1.8 (0.8-2.9) h, respectively. Genetic polymorphisms in genes of the drug transporters MRP2 and OATP1B1 could at least partly explain the high variability in pharmacokinetic parameters. The observed variability in catechin plasma levels might contribute to interindividual variation in benefical and adverse effects of green tea polyphenols. Our data could help to gain a better understanding of the causes of variability of green tea effects and to improve the design of studies on the effects of green tea polyphenols in different health conditions.ClinicalTrials.gov: NCT01360320.
Project description:We examined the effects of the timing of acute and consecutive epigallocatechin gallate (EGCG) and catechin-rich green tea ingestion on postprandial glucose in mice and human adults. In mouse experiments, we compared the effects of EGCG administration early (morning) and late (evening) in the active period on postprandial glucose. In human experiments, participants were randomly assigned to the morning-placebo (MP, n = 10), morning-green tea (MGT, n = 10), evening-placebo (EP, n = 9), and evening-green tea (EGT, n = 9) groups, and consumed either catechin-rich green tea or a placebo beverage for 1 week. At baseline and after 1 week, participants consumed their designated beverages with breakfast (MP and MGT) or supper (EP and EGT). Venous blood samples were collected in the fasted state and 30, 60, 120, and 180 min after each meal. Consecutive administration of EGCG in the evening, but not in the morning, reduced postprandial glucose at 30 (p = 0.006) and 60 (p = 0.037) min in the evening trials in mice. In humans, ingestion of catechin-rich green tea in the evening decreased postprandial glucose (three-factor analysis of variance, p < 0.05). Thus, catechin intake in the evening more effectively suppressed elevation of postprandial glucose.
Project description:Tea contains a variety of bioactive chemicals, such as catechins and other polyphenols. These compounds are thought to be responsible for the health benefits of tea consumption by affecting the function of many cellular targets, not all of which have been identified. In a high-throughput screen for small molecule antagonists of the EphA4 receptor tyrosine kinase, we identified five tea polyphenols that substantially inhibit EphA4 binding to a synthetic peptide ligand. Further characterization of theaflavin monogallates from black tea and epigallocatechin-3,5-digallate from green tea revealed that these compounds at low micromolar concentrations also inhibit binding of the natural ephrin ligands to EphA4 and several other Eph receptors in in vitro assays. The compounds behave as competitive EphA4 antagonists, and their inhibitory activity is affected by amino acid mutations within the ephrin binding pocket of EphA4. In contrast, the major green tea catechin, epigallocatechin-3-gallate (EGCG), does not appear to be an effective Eph receptor antagonist. In cell culture assays, theaflavin monogallates and epigallocatechin-3,5-digallate inhibit ephrin-induced tyrosine phosphorylation (activation) of Eph receptors and endothelial capillary-like tube formation. However, the wider spectrum of Eph receptors affected by the tea derivatives in cells suggests additional mechanisms of inhibition besides interfering with ephrin binding. These results show that tea polyphenols derived from both black and green tea can suppress the biological activities of Eph receptors. Thus, the Eph receptor tyrosine kinase family represents an important class of targets for tea-derived phytochemicals.
Project description:Over the past decade many scientific and medical studies have focused on green tea for its long-purported health benefits. There is convincing evidence that tea is a cup of life. It has multiple preventive and therapeutic effects. This review thus focuses on the recent advances of tea polyphenols and their applications in the prevention and treatment of human cancers. Of the various polyphenols in tea, (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant, and active compound studied in tea research. EGCG inhibits several molecular targets to inhibit cancer initiation and modulates several essential survival pathways to block cancer progression. Herein, we describe the various mechanisms of action of EGCG and also discuss previous and current ongoing clinical trials of EGCG and green tea polyphenols in different cancer types.
Project description:BACKGROUND AND PURPOSE: Catechins, biologically active polyphenols in green tea, are known to have a protective effect against cardiovascular diseases. In this study, we investigated direct actions of green tea catechins on cardiac muscle function to explore their uses as potential drugs for cardiac muscle disease. EXPERIMENTAL APPROACH: The effects of catechins were systematically investigated on the force-pCa relationship in skinned cardiac muscle fibres to determine their direct effects on cardiac myofilament contractility. The mechanisms of action of effective catechins were investigated using troponin exchange techniques, quartz crystal microbalance, nuclear magnetic resonance and a transgenic mouse model. KEY RESULTS: (-)-Epicatechin-3-gallate (ECg) and (-)-epigallocatechin-3-gallate (EGCg), but not their stereoismers (-)-catechin-3-gallate and (-)-gallocatechin-3-gallate, decreased cardiac myofilament Ca(2+) sensitivity probably through its interaction with cardiac troponin C. EGCg restored cardiac output in isolated working hearts by improving diastolic dysfunction caused by increased myofilament Ca(2+) sensitivity in a mouse model of hypertrophic cardiomyopathy. CONCLUSIONS AND IMPLICATIONS: The green tea catechins, ECg and EGCg, are Ca(2+) desensitizers acting through binding to cardiac troponin C. These compounds might be useful compounds for the development of therapeutic agents to treat the hypertrophic cardiomyopathy caused by increased Ca(2+) sensitivity of cardiac myofilaments.
Project description:Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate sodium iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of sodium iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2? generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after sodium iodate insult, among which EGCG is the most active constituent.
Project description:The anticancer activity of immune checkpoint inhibitors is attracting attention in various clinical sites. Since green tea catechin has cancer-preventive activity in humans, whether green tea catechin supports the role of immune checkpoint inhibitors was studied. We here report that (-)-epigallocatechin gallate (EGCG) inhibited programmed cell death ligand 1 (PD-L1) expression in non?small-cell lung cancer cells, induced by both interferon (IFN)-? and epidermal growth factor (EGF). The mRNA and protein levels of IFN-??induced PD-L1 were reduced 40?80% after pretreatment with EGCG and green tea extract (GTE) in A549 cells, via inhibition of JAK2/STAT1 signaling. Similarly, EGF-induced PD-L1 expression was reduced about 37?50% in EGCG-pretreated Lu99 cells through inhibition of EGF receptor/Akt signaling. Furthermore, 0.3% GTE in drinking water reduced the average number of tumors per mouse from 4.1 ± 0.5 to 2.6 ± 0.4 and the percentage of PD-L1 positive cells from 9.6% to 2.9%, a decrease of 70%, in lung tumors of A/J mice given a single intraperitoneal injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In co-culture experiments using F10-OVA melanoma cells and tumor-specific CD3+ T cells, EGCG reduced PD-L1 mRNA expression about 30% in F10-OVA cells and restored interleukin-2 mRNA expression in tumor-specific CD3+ T cells. The results show that green tea catechin is an immune checkpoint inhibitor.
Project description:Epidemiological and laboratory studies have shown that green tea and green tea catechins exert beneficial effects on a variety of diseases, including cancer, metabolic syndrome, infectious diseases, and neurodegenerative diseases. In most cases, (-)-epigallocatechin gallate (EGCG) has been shown to play a central role in these effects by green tea. Catechins from other plant sources have also shown health benefits. Many studies have revealed that the binding of EGCG and other catechins to proteins is involved in its action mechanism. Computational docking analysis (CMDA) and X-ray crystallographic analysis (XCA) have provided detailed information on catechin-protein interactions. Several of these studies have revealed that the galloyl moiety anchors it to the cleft of proteins through interactions with its hydroxyl groups, explaining the higher activity of galloylated catechins such as EGCG and epicatechin gallate than non-galloylated catechins. In this paper, we review the results of CMDA and XCA of EGCG and other plant catechins to understand catechin-protein interactions with the expectation of developing new drugs with health-promoting properties.
Project description:Green tea and its major polyphenols constituents, tea catechins, have been shown to have many health benefits including cancer prevention. Tea catechins and tea catechin metabolites/catabolites are bioavailable in the systemic circulation after oral intake of green tea or green tea catechins. The metabolites/catabolites identified in humans include glucuronide/sulfate conjugates, methylated tea catechin conjugates, and microflora-mediated ring fission products and phenolic acid catabolites. Plasma levels of unchanged tea catechins in humans are mostly in the sub-?M or nM concentration range, which is much lower than the effective concentrations determined in most in vitro studies. However, some of the catechin metabolites/catabolites are present in the systemic circulation at levels much higher than those of the parent catechins. The contribution of catechin derived metabolites/catabolites to the biological effects associated with green tea is yet to be defined. A limited number of chemoprevention trials of green tea or green tea catechins have been conducted to date and have observed potential preventive activity for oral, prostate, and colorectal cancer. Emerging data from multiple ongoing intervention trials will further contribute to defining the cancer preventive activity of green tea or green tea catechins.
Project description:Cost-effective and functionalized scaffolds are in high demand for stem-cell-based regenerative medicine to treat refractory bone defects in craniofacial abnormalities and injuries. One potential strategy is to utilize pharmacological and cost-effective plant polyphenols and biocompatible proteins, such as gelatin. Nevertheless, the use of chemically modified proteins with plant polyphenols in this strategy has not been standardized. Here, we demonstrated that gelatin chemically modified with epigallocatechin gallate (EGCG), the major catechin isolated from green tea, can be a useful material to induce bone regeneration in a rat congenial cleft-jaw model in vivo when used with/without adipose-derived stem cells or dedifferentiated fat cells. Vacuum-heated gelatin sponges modified with EGCG (vhEGCG-GS) induced superior osteogenesis from these two cell types compared with vacuum-heated gelatin sponges (vhGS). The EGCG-modification converted the water wettability of vhGS to a hydrophilic property (contact angle: 110° to 3.8°) and the zeta potential to a negative surface charge; the modification enhanced the cell adhesion property and promoted calcium phosphate precipitation. These results suggest that the EGCG-modification with chemical synthesis can be a useful platform to modify the physicochemical property of gelatin. This alteration is likely to provide a preferable microenvironment for multipotent progenitor cells, inducing superior bone formation in vivo.
Project description:Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3-mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.