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      New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate

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          Abstract

          Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.

          Graphical abstract

          Molecular mechanisms for beneficial health effects of EGCG. Low concentrations of EGCG have beneficial effects on cardiovascular and metabolic functions in normal physiology and pathophysiology. Low concentrations of EGCG directly and indirectly stimulate cellular events including intracellular signaling, nuclear and mitochondrial functions, and lysosomal autophagy. By contrast, high concentrations of EGCG may cause severe stress that damages cellular integrity and disrupts nuclear and mitochondrial function and lysosomal autophagy. These actions can be applied to cancer therapy by inducing cell death. Green oval ( ) indicates EGCG that directly binds or is transported into the indicated organelles.

          Highlights

          • Many biological actions of EGCG are mediated by specific mechanisms other than its well-known anti-oxidant properties.

          • EGCG is a pro-oxidant per se in some biological contexts.

          • EGCG directly interacts with cell surface membrane proteins and specific known receptors.

          • Treatment of cells with EGCG regulates specific intracellular signaling pathways and transcription.

          • Specific biological actions of EGCG are regulated in a concentration-dependent manner.

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          Most cited references116

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          Autophagy: in sickness and in health.

          The degradation of intracellular components in lysosomes (autophagy) has recaptured the attention of cell biologists in recent years. The main reason for this renewed interest is the dissection of the molecular machinery that participates in this process, because the identification of new intracellular elements involved in autophagy has provided new tools to trace, quantify and manipulate autophagy in a growing number of organisms. As a result, a better understanding of the physiological roles of autophagy, the consequences of its malfunctioning and its participation in different pathological processes has emerged. This article reviews our current knowledge of the role of autophagy in disease and the efforts to reconcile its proposed dual function as both a cell protector and a cell killer.
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            Autophagy and aging: the importance of maintaining "clean" cells.

            A decrease in the turnover of cellular components and the intracellular accumulation of altered macromolecules and organelles are features common to all aged cells. Diminished autophagic activity plays a major role in these age-related manifestations. In this work we review the molecular defects responsible for the malfunctioning of two forms of autophagy, macroautophagy and chaperone-mediated autophagy, in old mammals, and highlight general and cell-type specific consequences of dysfunction of the autophagic system with age. Dietary caloric restriction and antilipolytic agents have been proven to efficiently stimulate autophagy in old rodents. These and other possible experimental restorative efforts are discussed.
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              Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway.

              EGCG [(-)epigallocatechin-3-gallate], a green tea-derived polyphenol, has been shown to suppress cancer cell proliferation, and interfere with the several signaling pathways and induce apoptosis. Practically, there is emerging evidence that EGCG has a potential to increase the efficacy of chemotherapy in patients. We hypothesized that EGCG may exert cell cytotoxicity through modulating AMPK (AMP-activated protein kinase) followed by the decrease in COX-2 expression. EGCG treatment to colon cancer cells resulted in a strong activation of AMPK and an inhibition of COX-2 expression. The decreased COX-2 expression as well as prostaglandin E(2) secretion by EGCG was completely abolished by inhibiting AMPK by an AMPK inhibitor, Compound C. Also, the activation of AMPK was accompanied with the reduction of VEGF (vascular endothelial growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells. These findings support the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells. Furthermore, we have found that reactive oxygen species (ROS) is an upstream signal of AMPK, and the combined treatment of EGCG and chemotherapeutic agents, 5-FU or Etoposide, exert a novel therapeutic effect on chemo-resistant colon cancer cells. AMPK, a molecule of newly defined cancer target, was shown to control COX-2 in EGCG-treated colon cancer cells.
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                Author and article information

                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                10 January 2014
                10 January 2014
                2014
                : 2
                : 187-195
                Affiliations
                [a ]Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
                [b ]Department of Cell, Developmental and Integrative Biology, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
                [c ]Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
                Author notes
                [* ]Corresponding author at: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Tel.: +205 934 4128; fax 205 975 9372. jakim@ 123456uab.edu
                Article
                S2213-2317(14)00005-6
                10.1016/j.redox.2013.12.022
                3909779
                24494192
                bb53cb52-dda8-4b7d-a48b-8027f191a11f
                © 2014 The Authors
                History
                : 12 December 2013
                : 20 December 2013
                : 20 December 2013
                Categories
                Mini Review

                egc, epigallocatechin,egcg,ec, epicatechin,egcg, epigallocatechin 3-gallate,ecg, epicatechin gallate,pro-oxidant,polyphenol,anti-oxidant

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