Chemistry and Health Effect of Tea Polyphenol (â)-Epigallocatechin 3-O

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Chemistry and healthy effect of tea polyphenol, (-)-epigallocatechin 3-O-(3-O-methyl) gallate Man Zhang, Xin Zhang, Chi-Tang Ho, and Qingrong Huang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b04837 • Publication Date (Web): 16 Oct 2018 Downloaded from http://pubs.acs.org on October 18, 2018

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Journal of Agricultural and Food Chemistry

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Chemistry and healthy effect of tea polyphenol, (-)-epigallocatechin

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3-O-(3-O-methyl) gallate

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Man Zhanga, Xin Zhangb, *1, Chi-Tang Hoa, and Qingrong Huanga

4

aDepartment

of Food Science, Rutgers University, New Brunswick, NJ 08901, USA

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bDepartment

of Food Science and Engineering, Ningbo University, Ningbo 315211, P. R.

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China



Corresponding author: Xin Zhang; E-mail address: [email protected]

ACS Paragon Plus Environment


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Abstract

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Catechins are major polyphenols in tea and have been related to the health promotion of

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tea. Recently, a unique O-methylated catechin, (-)-epigallocatechin 3-O-(3-O-methyl)

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gallate (EGCG3"Me) has been identified in limited green and oolong teas.

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EGCG3"Me-enriched tea has shown distinct physiological functions in animal models

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and humans compared with common tea, including anti-allergy, anti-obesity, and the

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prevention of cardiovascular diseases risks, etc. This perspective aims to present current

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knowledge of EGCG3"Me, including its natural occurrence, chemical synthesis, chemical

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structure and bioavailability, as well as the molecular mechanisms underlying its

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biological activities.

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Key words: tea, EGCG3"Me, occurrence and synthesis, bioavailability, health benefits


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Introduction

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Tea is one of the most commonly consumed beverages in the worldwide, especially in

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Asian counties.1 According to the degree of fermentation during tea processing, tea can

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be clarified into: green tea (unfermented), oolong tea (semi-fermented) and black tea

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(fully fermented). Polyphenols are important bioactive compounds in tea, and tea

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catechins account for 60-80% of total tea polyphenols. (-)-Epigallocatechin-3-gallate

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(EGCG) is the most abundant tea catechin and is responsible for most of the beneficial

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effects of tea.2 In addition, the unique O-methylated form of EGCG, (-)-epigallocatechin

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3-O-(3-O-methyl) gallate (EGCG3"Me) identified in limited green and oolong teas

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receives increasing attentions for its distinct physiological functions.3,4

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For the identified EGCG3"Me enriched tea cultivars, the content of EGCG3"Me is

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about 1% (w/w) in dry weight tea, which is 3-7 times lower than EGCG. However,

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EGCG3"Me enriched teas have shown significantly higher bioefficacy compared with

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common teas with identical amount of tea catechins, in terms of bioactivities such as

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anti-allergy,5 anti-obesity,3 and the prevention of cardiovascular diseases (CVDs) risks.6

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In particular, the Japanese food labeling system, namely “Food with Function Claims”

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launched in 2015, has certified the anti-allergic effects of an O-methylated catechins

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enriched tea, ‘Benifuuki’.7 However, this is still a brand-new area for methylated tea

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catechins research. The structural and functional relationships of EGCG and its

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O-methylated derivatives need to be further investigated. This perspective aims to present

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current knowledge of EGCG3"Me, including its natural occurrence, chemical synthesis,



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chemical structure, and bioavailability, as well as the molecular mechanisms underlying

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its biological activities.

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Occurrence and Synthesis

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In order to further utilize EGCG3"Me in food and pharmaceutical industry, researchers

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have tried to either explore the natural occurrence of EGCG3"Me by screening amounts

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of tea cultivars or synthesize EGCG3"Me via chemical and enzymatic reactions.

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Several factors may influence the natural accumulation of EGCG3"Me in tea,

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including tea cultivars, leaf orders and processing methods. EGCG3"Me-rich tea cultivars

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have been identified in Asian countries (e.g. Japan, China, and Korea) through

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tremendous screening work. ‘Benifuuki’ was firstly identified as the most O-methylated

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catechins enriched cultivar (EGCG3"Me ≈ 0.8-2.5% w/w dry tea) in Japan.5 Later on,

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Chinese researchers found 4 tea cultivars containing more than 1% EGCG3"Me by

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screening 71 major tea cultivars in China, and most of the EGCG3"Me-enriched cultivars

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mainly distributed in the South China.8 Notably, these 4 cultivars were also suitable for

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Chinese oolong tea production, and that maybe the reason EGCG3’’Me was also

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identified in oolong tea. For example, oolong tea grown in the Phoenix Mountain in

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Guangdong province, China, was found to enrich EGCG3"Me ( ≈ 0.62-1.41% w/w dry

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tea).9 Additionally, EGCG3"Me ( ≈ 1% w/w) enriched tea cultivar was also found in

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Korea, namely Jangwon No.3.10 In addition, tea processing method also affected the

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content of EGCG3"Me. Green tea and oolong tea processing were able to preserve about

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90% EGCG3"Me in fresh tea leaves, while black tea processing could decrease


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EGCG3"Me by more than 90% of its original level.8

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Considering the rare occurrence and little accumulation of O-methylated catechins in

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nature, synthesis is another option for increasing their utilization. Recently, (+)-catechin

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3-(3-O-methylgallate) and (-)-epicatechin 3-(3-O-methylgallate) were synthesized

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chemically via reactions of equimolar catechins with 3-O-methylgallic acid.11 In addition,

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the gene of O-methyltransferase has been isolated from Camellia sinensis, whose

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identified cDNA fragment shows more than 89% identity with the caffeoyl-CoA

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O-methyltransferase in Petroselinum crispum, Vitis vinifera and Nicotiana tobacum.12 By

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cloning those O-methyltransferase, the O-methylated EGCG can be obtained via

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enzymatic reaction.

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Chemical Structure and Bioavailability of EGCG3"Me

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The chemical structure of EGCG and EGCG3"Me are shown in Fig. 1. EGCG3"Me is

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formed by substituting methoxy group at C-3 in D ring of EGCG instead of hydroxyl

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group. The presence and position of methoxy group enables EGCG3"Me distinct

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physiological properties, compared with EGCG and other methoxylated derivatives.13

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Previous studies have shown that EGCG3"Me has weaker antioxidant and

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antimicrobial ability than EGCG in vitro due to the loss of a hydroxyl group.12 However,

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our study finds that EGCG3"Me demonstrates weaker cytotoxicity but greater inhibitory

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effect on the differentiation of 3T3-L1 preadipocytes.14 Due to increased hydrophobicity,

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the methylated EGCGs have higher bioavailability than EGCG. Even though EGCG is

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mainly responsible for the health benefits of tea, its bioavailability is fairly low because



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of the highly polar properties resulting from the presence of multiple hydroxyl groups.

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The methoxyl group of polyphenols is reported to improve the transportation of

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biocompounds through biological membranes and increase their oral bioavailability.15

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From a pharmacokinetic analysis in rats by oral administration, the bioavailability of

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EGCG3"Me is 1.8 times and 2.7 times as much as EGCG4"Me and EGCG,

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respectively.16 After drinking ‘Benifuuki’, there is more available EGCG3"Me than

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EGCG in the plasma, even though the original concentration of EGCG is 4 times higher

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in the beverage.4 Thus, the distinct health benefits of drinking EGCG3"Me-enriched tea

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is partially resulted from its higher intestinal absorption rate and lower rate of

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disappearance in the blood than EGCG.

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Previous studies have demonstrated the potential of novel biomaterials in the

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promotion of intestinal transport of phytochemicals. For example, natural polymers such

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as proteins and polysaccharides have been used to form nanocomplexes for improving the

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delivery properties of EGCG.17 Our previous work has shown the promotional effect of

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phospholipids on the intestinal absorption of EGCG3"Me using Caco-2 cell monolayer.18

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These investigations may be fascinated in functional foods development with high

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content of EGCG3"Me and enhanced absorption properties.

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Biological Activities

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As EGCG3"Me is a minor catechin in tea and just identified in recent years, few studies

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have demonstrated its promising health effects. This perspective mainly discusses the

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health benefits of EGCG3"Me and EGCG3"Me-rich tea by focusing on bioactivities,


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such as anti-allergy, the prevention of CVDs risks, anti-obesity, and the modulation of gut

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microbiota.

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Anti-allergic Activity

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The anti-allergic effect of EGCG3"Me is known as its most important biological activity.

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The pathway of EGCG3"Me acting on mast cell is shown in Fig. 1. In general, the

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crosslinking of high-affinity IgE receptor (FcεRI) with allergens and specific IgE on the

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surface of mast cell will lead to the release of inflammatory mediators, including

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cytokines, histamine, chemotactic factor and arachidonic acid metabolites. Tea catechin

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can act on the 67kDa laminin receptor (67LR), a cell-surface receptor that mediates both

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the anti-allergic and anti-cancer effect of tea catechin. The binding of tea catechin and

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67LR will lead to the prevention of FcεRI expression, myosin light chain phosphorylation

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and tyrosine phosphorylation of cellular protein. Thus, it is suggested that methylated tea

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catechins can inhibit mast cell degranulation (suppression of histamine/leukotriene

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release and interleukin secretion) via the illustrating pathways. 19

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The structure-activity relationship in the anti-allergic process has been discussed for

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tea catechins. EGCG3"Me, as well as EGCG4"Me, is able to suppress FcεRI expression

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in the cell surface, inhibit extracellular signal-regulated kinase1/2 phosphorylation

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(ERK1/2), and bind to the surface of KU812 cells, even though the suppression effect and

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binding activity of EGCG are better.20 However, the rank order for the inhibitory effect

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on histamine release is GCG3"Me > EGCG3"Me > GCG > EGCG at the same dosage in

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mast cells. Some cytokines, such as tumor necrosis factor alpha (TNF-α), are also



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involved in the allergy-associated pathophysiological changes by recruiting inflammatory

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cells to the site of allergen exposure. Methylated tea catechins enriched tea showed the

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best inhibitory effect on TNF-α and macrophage inflammatory protein 1-alpha (MIP-1α)

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stimulated by antigen in mast cells, compared with the sprouts extracts of broccoli, white

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radish, red cabbage and rucola.4

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For the in vivo studies, EGCG3"Me and EGCG4"Me have been found to lower the

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mice ear swelling ration than EGCG in the oxazolone-induced type IV allergy mice

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model.19 Besides, type I allergic reaction in mice sensitized with ovalbumin and Freund’s

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incomplete adjuvant can be significantly and dose-dependently inhibited by O-methylated

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catechins.4 Several randomized, double-bind and placebo-controlled clinical studies have

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shown that people drinking ‘Benifuuki’ for several months have improved allergic

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symptoms (e.g. stuffy nose, itchy eyes, nasal symptom score, ocular symptom-medication

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score, etc.) towards Japanese cedar pollinosis than people drinking common tea.21 Also,

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drinking ‘Benifuuki’ is found to prevent the increase of peripheral eosinophils in response

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to pollen exposure with no normal immune response affected. These results demonstrate

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that O-methylated tea catechins have great potentials to be used as functional food for

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alleviating allergic disorders.

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Preventing the Risk of Cardiovascular Diseases (CVDs)

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CVDs are a class of disorders that involves the heart and blood vessels. Recent studies

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have reported EGCG3"Me and EGCG3"Me-rich tea could prevent the risks of CVDs,

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including anti-hypertension, anti-atherosclerosis, anti-hyperlipidemia and reducing the


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development of diabetic nephropathy (Fig. 2).

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The aberrant renin-angiotensin pathway is a major mechanism for high blood

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pressure, since it is believed to cause 90% of the hypertension patients. The inhibition of

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angiotensin I-converting enzyme (ACE) is helpful to prevent high blood pressure.

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EGCG3"Me demonstrates a stronger inhibitory effect against ACE than EGCG, which

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has the strongest ACE inhibitory activities among the major tea catechins (EC, ECG, and

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EGC).5 Another clinical work with a relative large sample size (155 participants)

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demonstrates that EGCG3"Me enriched tea can effectively mitigate dyslipidemia

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syndromes for people with body mass index (BMI) > 25 kg/m2 and LDL > 3.10

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mmol/L.22 ‘Benifuuki’, compared with common tea, is also more effective to inhibit the

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lectin-like oxidized low-density lipoprotein receptor-1 containing apolipoprotein B

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(LAB), which is an aggravating factor in the development of atherosclerosis.22 Similar

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effect has been found for the oolong tea in terms of the anti-atherosclerosis activity:

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drinking oolong tea can increase LDL particle size and plasma adiponectin in coronary

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artery disease (CAD) patients, and thus preventing the risk for atherosclerosis and CAD.23

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EGCG3"Me is also found to reduce the early development of diabetic nephropathy more

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effectively than EGCG by neutralizing carbonyl stress and alleviating the formation of

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insoluble ubiquitinated protein (IUP) aggregate.24

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Anti-obesity Activity

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Tea has been used as an anti-obesity therapy in China for more than a millennium.14 The

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mechanisms of the anti-obesity of tea catechins are supposed to associate with the



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modulation of energy balance, food intake, endocrine systems, lipid and carbohydrate

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metabolism, enzyme activities, activities in different cells (e.g. liver, fat, muscle and β

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pancreatic cells), and the modulation in gut microbiota.1

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In terms of the molecular mechanism of adipogenesis, CCAAT/enhancer-binding

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protein family members (C/EBP) and peroxisome proliferator-activated receptors

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(PPARγ) are two important transcriptional factors promoting the early stage of

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adipogenesis. Sterol regulatory element binding proteins (SREBPs) are another

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transcriptional factors responding to cellular lipogenesis, adipocyte differentiation and

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lipid homeostasis. In the terminal differentiation stage, the mRNA level of lipogenesis-,

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TG- and cholesterol-enzymes increases, such as acetyl-CoA carboxylase (ACC), fatty

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acid synthase (FAS), stearoyl-CoA desaturase (SCD), hydroxymethylglutaryl-CoA

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reductase (HMGCR) and hydroxymethylglutaryl-CoA synthase (HMGCS).1 EGCG3"Me,

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with lower cytotoxicity, shows a higher efficacy to inhibit the lipid accumulation than

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EGCG in 3T3-L1 preadipocytes.14 Currently, the influence of methylated tea catechins on

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the transcriptional factors and related-protein expression in adipocytes still need further

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investigation.

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EGCG3"Me enriched tea shows strong potential applications in obesity prevention.

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The molecular mechanism of its anti-obesity bioactivity is shown in Fig. 3. A recent

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study indicated that methylated catechins contributed to the stronger lipid-lowering

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activity of ‘Benifuuki’ tea, even though their amount is just about 8% of total tea

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catechins.4 In detail, supplementation of Benifuuki in diet remarkably decreases the liver


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and serum triglyceride, and suppresses adipogenesis-related transcriptional factors

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(SREBP, ACC, FAS, SCD) in the liver, compared with common tea.4 The anti-obesity

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activity of EGCG3"Me may also result from its interaction with digestive enzyme and

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gut microbiota. EGCG3"Me shows inhibitory effect on α-amylase and lipase, which

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indicates a slower digestion of carbohydrate and lipid. In addition, EGCG3"Me benefits

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the stability of the intestinal flora system, especially in an environment-triggered

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microbial disturbance in a high fat diet (HFD)-induced obesity mice model.25

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Modulatory Effect on Intestinal Microbiota

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The human gut is populated by an array of bacterial species with a remarkable effect on

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the nutritional and health status of the host.26 They form a stable microbial ecosystem

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which not only digest food, but also regulate the immune function. The disturbance of gut

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microbiota is associated with metabolic syndromes.

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Prebiotics are non-digestible food ingredients that beneficially affect the host by

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stimulating the growth and activity of specific intestinal bacteria.27 Recently, the

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modulation effect of EGCG3"Me on intestinal microbiota has been investigated, and

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results show that EGCG3"Me is able to promote the proliferation of beneficial bacteria

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and increase the biodiversity degree of gut microbiota (Fig. 3).3,28 In our previous study,

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EGCG3"Me

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Lactobacillus/Enterococcus groups and exhibited inhibitory effects on the growth of

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Bacteroides-Prevotella, Clostridium histolyticum and Eubacterium-Clostridium groups,

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without affecting the population of total bacteria. Moreover, the total short-chain fatty

promoted

the

growth

of

Bifidobacterium


spp.

and


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acids (SCFA) concentrations in cultures with EGCG3"Me were relatively higher than

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that of the control.28 Using a human-flora-associated HFD-induced obesity mice model

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by metagenomics analysis, we revealed that feeding an EGCG3"Me supplemented diet

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may ameliorate the HFD-induced intestinal microbial dysbiosis, and significantly

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decrease the ratio of Firmicutes/Bacteroidetes.25 Moreover, the Kyoto Encyclopedia of

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Genes and Genomes (KEGG) database is a good tool to study the differentially expressed

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genes in response to EGCG3"Me treatment. Our study showed that the enrichment of

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genes involved in the biosynthesis of amino acids, the two-component system,

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ATP-binding cassette (ABC) transporters, purine metabolism, and carbon metabolism

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(Fig. 4).

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Even though the bioavailability of EGCG3"Me is higher than EGCG, the absorption

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rate is still limited and the majority of EGCG3"Me is metabolized by intestinal bacteria.28

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Colon is an important organ for the metabolism of phytochemicals, and the metabolites

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bio-transformed by colonic microbiota may be more active than the parent compounds.29

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However, microbial catabolic pathways of EGCG3"Me are still under investigation.

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Studies performed with microbe-derived metabolites of flavan-3-ols have revealed that

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they could have an effect beyond their antioxidant properties by interacting with signaling

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pathways involved in the development of metabolic syndromes.30 Therefore,

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understanding the cross talks of these pathways may help us further elucidate the clinical

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use of EGCG3"Me in the prevention and treatment of intestinal malfunction.

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Summary and Future Direction


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In this perspective, we discussed physiological properties of EGCG3"Me, identified in

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limited green tea and oolong tea. Due to its higher bioavailability and stability than

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EGCG, EGCG3"Me exhibit greater healthy benefits in vivo study, in terms of

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anti-allergy, anti-obesity and prevention from CVDs. Therefore, the EGCG3"Me-rich tea

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shows great potential for the functional food development.

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Several aspects are encouraged for future studies for better development of

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EGCG3"Me-rich tea and understanding the mechanisms underlying its bioactivities.

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Firstly, recent studies have identified methylated catechins-enrich tea cultivars in some

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Asian countries, and more work with advanced techniques, such as genetic, metabolic

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and proteomic analysis, are encouraged to apply for better tea breeding or cultivation in

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the future. Secondly, as the bioavailability of tea catechins is influenced by substantial

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and interrelated factors, delivery systems are worthy to investigate for enhancing the

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bioavailability of EGCG3"Me. Food-derived materials are potential to be utilized as the

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encapsulated vehicle to improve the stability, bioavailability and bio-efficacy of tea

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catechins. Thirdly, the studies about the metabolism of EGCG3"Me in vivo are still

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limited. Particular attentions should be paid to colonic metabolites as well as their

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contribution to the overall bioavailability of tea catechins. Fourthly, the interactions

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between specific functional bacteria and EGCG3"Me along with its colonic metabolites

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need further exploration. In addition, more investigations need to elucidate the intricate

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gut microbiota-host relationship, especially the microbiota-gut-brain axis and gut-liver

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axis.



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Funding

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This work was sponsored by the National Natural Science Foundation of China

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(31501473), Key Research and Development Project of Zhejiang Province (2017C02039

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& 2018C02047), and the K.C. Wong Magna Fund at Ningbo University.

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Notes

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The authors declare no competing financial interest.


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354

Figure Captions

355

Figure 1. The pathway of EGCG and EGCG3"Me acting on mast cell.

356

Figure 2. The target molecules of EGCG3"Me acting on CVDs.

357

Figure 3. The molecular mechanisms of EGCG3"Me acting on obesity and gut

358

microbiota.

359

Figure 4. KEGG analysis of differentially expressed genes between fecal samples

360

collected from the HFD-EGCG3"Me group after 0 (EGCG3"Me-0) and 8 weeks

361

(EGCG3"Me-8).


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TOC Graphic



Figure 1. The pathway of EGCG and EGCG3"Me acting on mast cell.


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Figure 2. The target molecules of EGCG3"Me acting on CVDs.



Figure 3. The molecular mechanisms of EGCG3"Me acting on obesity and gut microbiota.


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Figure 4. KEGG analysis of differentially expressed genes between fecal samples collected from the HFDEGCG3"Me group after 0 (EGCG3"Me-0) and 8 weeks (EGCG3"Me-8).


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