Gloria Bonuccelli 1 , Federica Sotgia 1 , Michael P. Lisanti 1

• 1 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Greater Manchester, United Kingdom

received: May 15, 2018 ; accepted: June 21, 2018 ; published: August 23, 2018

https://doi.org/10.18632/aging.101483
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Copyright: Bonuccelli et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Author: Anna H. Wu, Darcy Spicer, Frank Z. Stanczyk, Chiu-Chen Tseng, Chung S. Yang and Malcolm C. Pike

There have been no controlled intervention studies to investigate the effects of green tea on circulating hormone levels, an established breast cancer risk factor. We conducted a double-blind, randomized, placebo-controlled intervention study to investigate the effect of the main green tea catechin, epigallocatechin gallate (EGCG), taken in a green tea extract, polyphenon E (PPE). Postmenopausal women (n = 103) were randomized into three arms: placebo, 400-mg EGCG as PPE, or 800-mg EGCG as PPE as capsules per day for 2 months. Urinary tea catechin and serum estrogen, androgen, lipid, glucose-related markers, adiponectin, and growth factor levels were measured at baseline and at the end of months 1 and 2 of intervention. On the basis of urinary tea catechin concentrations, compliance was excellent. Supplementation with PPE did not produce consistent patterns of changes in estradiol (E2), estrone (E1), or testosterone (T) levels. Low-density lipoprotein (LDL)-cholesterol decreased significantly in both PPE groups but was unchanged in the placebo group; the change in LDL-cholesterol differed between the placebo and PPE groups (P = 0.02). Glucose and insulin levels decreased nonsignificantly in the PPE groups but increased in the placebo group; statistically significant differences in changes in glucose (P = 0.008) and insulin (P = 0.01) were found. In summary, green tea (400- and 800-mg EGCG as PPE; ∼5-10 cups) supplementation for 2 months had suggestive beneficial effects on LDL-cholesterol concentrations and glucose-related markers.

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Author: Hea Jin Park, Ji-Young Lee, Min-Yu Chung, Young-Ki Park, Allyson M. Bower, Sung I. Koo, Charles Giardina and Richard S. Bruno

Nonalcoholic steatohepatitis (NASH) is characterized by oxidative stress and inflammatory responses that exacerbate liver injury. The objective of this study was to determine whether the antioxidant and antiinflammatory activities of green tea extract (GTE) would protect against NASH in a model of diet-induced obesity. Adult Wistar rats were fed a low-fat (LF) diet or high-fat (HF) diet containing no GTE or GTE at 1% or 2% (HF+2GTE) for 8 wk. The HF group had greater (P ≤ 0.05) serum alanine (ALT) and aspartate aminotransferases and hepatic lipids than the LF group. Both GTE groups had lower ALT and hepatic lipid than the HF group. In liver and epididymal adipose, the HF group had lower glutathione as well as greater mRNA and protein expression of TNFα and monocyte chemoattractant protein-1 (MCP-1) and NFκB binding activity than the LF group. Compared to the HF group, the HF+2GTE group had greater glutathione and lower protein and mRNA levels of inflammatory cytokines in both tissues. NFκB binding activities at liver and adipose were also lower, likely by inhibiting the phosphorylation of inhibitor of NFκB. NFκB binding activities in liver and adipose (P ≤ 0.05; r = 0.62 and 0.46, respectively) were correlated with ALT, and hepatic NFκB binding activity was inversely related to liver glutathione (r = −0.35). These results suggest that GTE-mediated improvements in glutathione status are associated with the inhibition of hepatic and adipose inflammatory responses mediated by NFκB, thereby protecting against NASH.

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Author: Mako Kurogi, Megumi Miyashita, Yuri Emoto, Yoshihiro Kubo and Osamu Saitoh

A characteristic astringent taste is elicited by polyphenols. Among the polyphenols, catechins and their polymers are the most abundant polyphenols in wine and tea. A typical green tea polyphenol is epigallocatechin gallate (EGCG). Currently, the mechanism underlying the sensation of astringent taste is not well understood. We observed by calcium imaging that the mouse intestinal endocrine cell line STC-1 responds to the astringent compound, EGCG. Among major catechins of green tea, EGCG was most effective at eliciting a response in this cell line. This cellular response was not observed in HEK293T or 3T3 cells. Further analyses demonstrated that the 67-kDa laminin receptor, a known EGCG receptor, is not directly involved. The Ca(2+) response to EGCG in STC-1 cells was decreased by inhibitors of the transient receptor potential A1 (TRPA1) channel. HEK293T cells transfected with the mouse TRPA1 (mTRPA1) cDNA showed a Ca(2+) response upon application of EGCG, and their response properties were similar to those observed in STC-1 cells. These results indicate that an astringent compound, EGCG, activates the mTRPA1 in intestinal STC-1 cells. TRPA1 might play an important role in the astringency taste on the tongue.

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Author: Usha Gundimeda, Thomas H. McNeill, Albert A. Elhiani, Jason E. Schiffman, David R. Hinton and Rayudu Gopalakrishna

As the development of synthetic drugs for the prevention of stroke has proven challenging, utilization of natural products capable of preconditioning neuronal cells against ischemia-induced cell death would be a highly useful complementary approach. In this study using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in PC12 cells, we show that 2-day pretreatment with green tea polyphenols (GTPP) and their active ingredient, epigallocatechin-3-gallate (EGCG), protects cells from subsequent OGD/R-induced cell death. A synergistic interaction was observed between GTPP constituents, with unfractionated GTPP more potently preconditioning cells than EGCG. GTPP-induced preconditioning required the 67-kDa laminin receptor (67LR), to which EGCG binds with high affinity. 67LR also mediated the generation of reactive oxygen species (ROS) via activation of NADPH oxidase. An exogenous ROS-generating system bypassed 67LR to induce preconditioning, suggesting that sublethal levels of ROS are indeed an important mediator in GTPP-induced preconditioning. This role for ROS was further supported by the fact that antioxidants blocked GTPP-induced preconditioning. Additionally, ROS induced an activation and translocation of protein kinase C (PKC), particularly PKCϵ from the cytosol to the membrane/mitochondria, which was also blocked by antioxidants. The crucial role of PKC in GTPP-induced preconditioning was supported by use of its specific inhibitors. Preconditioning was increased by conditional overexpression of PKCϵ and decreased by its knock-out with siRNA. Collectively, these results suggest that GTPP stimulates 67LR and thereby induces NADPH oxidase-dependent generation of ROS, which in turn induces activation of PKC, particularly prosurvival isoenzyme PKCϵ, resulting in preconditioning against cell death induced by OGD/R.

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Author: Ping-Han Wu, Sze-Kwan Lin, Bor-Shiunn Lee, Sang-Heng Kok, Jyh-Horng Wang, Kuo-Liang Hou, Hsiang Yang, Eddie Hsiang-Hua Lai, Juo-Song Wang and Chi-Yuan Hong

Objective. To assess the effects of epigallocatechin-3-gallate (EGCG) on cytokine-induced Cyr61 synthesis in human osteoblastic cells and the associated signalling pathways. The therapeutic effect of EGCG on CIA in rats was also studied. Methods. The expression of Cyr61 and NF-κB pathway molecules was examined by western blotting. CCL2 expression was assessed by northern blotting and ELISA. Interaction between NF-κB and Cyr61 promoter was evaluated by electrophoretic mobility shift assay. In rat CIA, osteoblastic expression of Cyr61 was examined by immunohistochemistry and disease progression was assessed by clinical, radiographic and histological examinations. Results. EGCG inhibited Cyr61 expression stimulated by cytokines in primary human osteoblasts and human osteoblastic cell line U2OS. In U2OS, oncostatin M (OSM) induced IκB-α degradation through the mTOR/rictor/Akt pathway, and EGCG attenuated the action. Electrophoretic mobility shift assay revealed that the OSM-enhanced NF-κB/DNA binding was reduced by EGCG, possibly through abrogating nucleus localization of p65 and p50. Cyr61 enhanced OSM-induced expression of CCL2. Moreover, EGCG diminished OSM-stimulated CCL2 expression at least partially via suppressing Cyr61 induction. Co-distribution of CD68+ macrophages and Cyr61+ osteoblasts in osteolytic areas was obvious in the CIA model. Clinical, radiographic and immunohistochemical analyses revealed that administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the number of Cyr61-synthesizing osteoblasts. Conclusion. By modulating the mTOR/rictor/Akt/NF-κB pathway, EGCG attenuated Cyr61 production in osteoblastic cells and in turn diminished macrophage chemotaxis. Our data support the therapeutic potential of EGCG on arthritis.

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Author: Mohammed Ehsanul Hoque Mazumder, Philip Beale, Charles Chan, Jun Q. Yu and Fazlul Huq

In this study, synergism in activity from the sequenced combinations of three trans-palladiums (denoted as TH5, TH6 and TH7) with green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), as well as that with cisplatin, was investigated in a number of human ovarian tumour models as a function of sequence of administration. Cellular accumulation of platinum and palladium, and the levels of platinum-DNA and palladium-DNA binding were also determined for the 0/4 h and 0/0 h sequences of administration. The results of the study show that co-administration of cisplatin with EGCG (0/0 h) produces weak synergism in both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780(cisR)) cell lines whereas (0/4 h) administration produces pronounced synergism in both. In contrast, bolus administration of EGCG with TH5, TH6 and TH7 produces marked antagonism except that with TH5, in the A2780(cisR) cell line, where a mild synergism is observed. In the case of TH5, TH6 and TH7, administration of drugs with a time gap (0/4 h or 4/0 h combinations) produces sequence-dependent synergism in both A2780 and A2780(cisR) cell lines, whereas in the case of cisplatin, marked antagonism is observed with the 4/0 h sequence of administration in the A2780 cell line. Whereas the highly synergistic 0/4 h sequence of combination of cisplatin with EGCG is found to be associated with pronounced cellular accumulation of platinum and a high level of platinum-DNA binding, no such clear trend can be seen for any of the combinations of TH5, TH6 and TH7 with EGCG. The results of the present study provide support to the idea that sequenced combinations of platinum drugs and tumour-active palladium compounds with selected phytochemicals such as EGCG may provide a means of overcoming drug resistance.

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Author: Christopher Masterjohn , Richard S Bruno

Nonalcoholic fatty liver disease (NAFLD) is a constellation of progressive liver disorders that are closely related to obesity, diabetes, and insulin resistance and may afflict over 70 million Americans. NAFLD may occur as relatively benign, nonprogressive liver steatosis, but in many individuals it may progress in severity to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure or hepatocellular carcinoma. No validated treatments currently exist for NAFLD except for weight loss, which has a poor long-term success rate. Thus, dietary strategies that prevent the development of liver steatosis or its progression to nonalcoholic steatohepatitis are critically needed. Green tea is rich in polyphenolic catechins that have hypolipidemic, thermogenic, antioxidant, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD. This review presents the experimental evidence demonstrating the hepatoprotective properties of green tea and its catechins and the proposed mechanisms by which these targeted dietary agents protect against NAFLD.

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Author: Sarah C. Forester, Yeyi Gu and Joshua D. Lambert

Scope Green tea has been shown to ameliorate symptoms of metabolic syndrome in vivo. The effects could be due, in part, to modulation of postprandial blood glucose levels. Methods and results We examined the effect of coadministration of (−)-epigallocatechin-3-gallate (EGCG, 100 mg/kg, i.g.) on blood glucose levels following oral administration of common corn starch (CCS), maltose, sucrose, or glucose to fasted CF-1 mice. We found that cotreatment with EGCG significantly reduced postprandial blood glucose levels after administration of CCS compared to control mice (50 and 20% reduction in peak blood glucose levels and blood glucose area under the curve, respectively). EGCG had no effect on postprandial blood glucose following administration of maltose or glucose, suggesting that EGCG may modulate amylase-mediated starch digestion. In vitro, EGCG noncompetitively inhibited pancreatic amylase activity by 34% at 20 μM. No significant change was induced in the expression of two small intestinal glucose transporters (GLUT2 and SGLT1). Conclusions Our results suggest that EGCG acutely reduces postprandial blood glucose levels in mice when coadministered with CCS and this may be due in part to inhibition of α-amylase. The relatively low effective dose of EGCG makes a compelling case for studies in human subjects.

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Author: S. Monzen and I. Kashiwakura

Epigallocatechin-3-gallate (EGCg) is widely recognised as a powerful antioxidant and free radical scavenger. This study examined the radioprotective effects of EGCg on human granulopoiesis and erythropoiesis. Highly purified human CD34(+) haematopoietic stem/progenitor cells were prepared from human placental/umbilical cord blood. The cells were exposed to X rays at a dose rate of ∼1 Gy min(-1) and then cultured in a medium supplemented with either granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO). EGCg (100 nM) was added to the culture immediately before or after X-irradiation. The concentration of 100-nM EGCg was determined in the authors' previous study. The number of granulocyte and erythrocyte colonies generated by X-irradiated CD34(+) cells decreased in a dose-dependent manner. Although EGCg addition yielded an ∼2-fold increase in the proliferation of each haematopoietic progenitor, no significant protective effect was observed in the surviving fraction of granulocyte progenitors (G-CSF alone: D(0)=1.06 Gy, n=1.14). However, EGCg addition before or after irradiation conferred a significantly higher protective effect on erythrocyte colony formation compared with the control (EPO alone: D(0)=0.66 Gy, n=1.56; EGCg (before): D(0)=0.43 Gy, n=5.48). EGCg addition before irradiation significantly improved the survival of erythroid progenitors subjected to radiation of <1 Gy. These results suggest that EGCg is more protective of erythropoiesis than granulopoiesis from radiation damage.

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