REVIEW

Green tea polyphenols and their potential role in healthand disease

M. Afzal1 • A. M. Safer1 • M. Menon2

Received: 25 April 2015 / Accepted: 6 June 2015 / Published online: 12 July 2015

� Springer Basel 2015

Abstract There is a growing body of evidence that plant

polyphenols such as resveratrol, anthocyanins, catechins,

and terpenes like taxol are effectively used in the treatment

of chronic conditions including cancer, Alzheimer,

Parkinsonism, diabetes, aging, etc. The link between

oxidative stress and inflammation is well accepted. Thus,

the mechanism of action of these natural products is partly

believed to be through their significant antioxidant prop-

erties. The main constituent of green tea, with clinical

significance, is epigallocatechin gallate (EGCG). It has

been associated with antitumor, anti-Alzheimer, and anti-

aging properties, improve redox status at the tissue level

possibly preventing system level structural damage. This

review focuses on EGCG and its potential therapeutic role

in health and disease.

Graphical abstract

Keywords Green tea � Epigallocatechin gallate �Inflammation � Cancer � Fibrosis � Alzheimer �Parkinsonism � Aging

Introduction

Polyphenols are commonly present at capricious level in

all green plants. Phenolic compounds are low molecular

weight molecules, widespread in nature and elaborated by

fungi, yeast, algae, lichen, prokaryotes, insects, and

mammals. In the producer organism, phenolic compounds

are present in small amounts but under stress (physi-

cal/chemical/biochemical) these compounds are produced

in relatively larger amounts. Thus, their role in the

organisms is of defense against predators, infection,

inflammation, and allelopathic interactions (Bhattacharya

et al. 2010).

& M. Afzal

Afzalq8@gmail.com

1 Department of Biological Sciences, Faculty of Science,

Kuwait University, Kuwait, Kuwait

2 Palmer University, Palmer College West Campus, San Jose,

CA, USA

Inflammopharmacol (2015) 23:151–161

DOI 10.1007/s10787-015-0236-1 Inflammopharmacology

123

Natural phenols are mostly water-soluble and can also be

volatile materials. These can be classified into many cate-

gories including simple monocyclic phenols. This may

include one or more phenolic hydroxyl functions and/or

carboxylic acid groups including cinnamic acid derivatives

(C6–C3) with diverse biological activities (Lin et al. 2014;

Pontiki et al. 2014) The second group of phenolic com-

poundsmay containmore complexmolecules with two rings

such as coumarins, isocoumarins, stilbens, chalcones, and

curcuminoids, with distinct biological activities (Torres et al.

2014; Passamani et al. 2014;Wong and Fiscus 2015; Sharma

et al. 2015). Curcuminoids are known potent anticarcinogens

(Wright et al. 2013). The third group of phenolic compounds

may be more complex such as flavonoids and isoflavonoids,

also called bioflavonoids, due to their biological activities

(Formagio et al. 2015). Phenyl propanoidsmay also include a

large number of catechins, cyanidins, and anthocyanins, the

later two classes being responsible for different colors and

biological activities of fruits, flowers, and vegetable (Bastos

et al. 2015). A comprehensive review is available on flavo-

noids and major natural polyphenols (Khan et al. 2014).

Catechins in tea

Green tea (Camellia sinensis, CS.) is a universal beverage

and is mostly consumed in China, Southeast Asia, and

Japan. In Southeast Asia, its postprandial consumption is

believed to metabolize fat (Peluso et al. 2014). However, in

Japan and China, green tea extract is prandially consumed

and is also believed to help in meat and fat digestion,

helping obesity and related health problems.

CS has several, in vitro and in vivo-antimetastasis and

osteolytic properties (Luo et al. 2014). The activities ofCSmay

be attributed to the presence of a number of catechins with

epigallocatechin-3-gallate (EGCG, Fig. 1) being the major

catechin component. Catechins are polyphenolic flavanol

molecules derived from C6–C3–C6, shikimate biosynthetic

pathway. Other catechins in green tea are epigallocatechin

(EGC), epicatechin gallate (ECG), and epicatechin (EC) and in

black tea polyphenols are theaflavins (TF) and thearubigins (He

et al. 2015).Black tea is rich in polysaccharides,while green tea

is rich in polyphenols including EGCG (Chan et al. 2009).

EGCG is known for its anti-inflammatory, hypoglycemic,

hypocholesterlemic, anticancer, antihypertensive, antioxidant,

antiviral, and pancreatic anticancer activities (Yousaf et al.

2014). Tea extract has been reported to show an inhibitory

effect on blood coagulation, prevent the onset of certain type of

cardiovascular diseases [atherosclerosis], dissolve fibrinogen,

inhibit platelet aggregation, (Liatsos et al. 2010) lower

endothelin level (Unger 2010), activate GSH-Px, protect LDL

oxidation (Wojciech et al. 2010), and improve glucose toler-

ance in diabetes (Zuo et al. 2014).

Green tea has anti-inflammatory and anticancerproperties

Oxidative stress/inflammation contributes to tissue injury

after hemorrhage/resuscitation, and natural polyphenolic

compounds are the drugs of choice for attenuation of injury

(Relja et al. 2012). Thus, theaflavin polyphenols from tea and

the flavonoid chrysin fromPotentilla evestita (Rosaceae) are

just two examples of polyphenols with antioxidant, antitu-

mor, and anti-inflammatory activities (Weerawatanakom

et al. 2015; Rauf et al. 2015). Polyphenols have also been

implicated in many other chronic conditions such as

Parkinson disease, Alzheimer’s disease, antinociceptive,

immune response, malignancy, anticalcification, hyperten-

sion, health and development, etc. (Zhang et al. 2015;

Srinivasan and Lahiri 2015; Rahman et al. 2015; Magrone

and Jirillo 2015; Signorelli et al. 2015; Wang et al. 2015;

Teles et al. 2015; Ly et al. 2015). There is a plethora of

information that reflects on the fact that activities of green tea

polyphenolic compounds can control chronic diseases that

are mediated through persistent inflammation. The role of

dietary polyphenols in the management of inflammation is

reviewed (Farzael et al. 2015).

The anti-inflammatory activity of polyphenols in green

tea extract (GTE) has been demonstrated in various models

of acute inflammation (Singh et al. 2010; Relja et al. 2012;

Shen et al. 2011, 2012), and numerous mechanisms have

been suggested for their anticancer activities including

suppression of NF-kappaB, inflammasome, and IL-1beta

secretion (Lamoral-Theys et al. 2010; Ellis et al. 2011).

Many malignancies are characterized by an activation of

interleukin-associated kinases, and several drugs targeting

specific kinases, both natural and synthetic, are being used

for cancer treatment (Guo et al. 2015; Kim et al. 2015). Polo-

like kinase (PLK1) interacts with green tea catechins

resulting in growth inhibition of several types on human

cancers (Shan et al. 2015). EGCG is a multi-cellular effector

that can inhibit development of numerous types of tumors

such as lung tumor (Mei et al. 2011) possibly by stabilizing

HIF-1 alpha, endometrial adenocarcinoma, and hepatocel-

lular carcinoma (Roomi et al. 2012; Wang et al. 2011).

Synergistic effect of EGCG, in combination drugs, has

been extensively studied, and it is claimed that green tea

extracts are synergists with anticancer drugs and micronu-

trients (Niedzwiecki et al. 2010). EGCG also has the ability

to sensitize the efficacy of numerous chemotherapy agents

such as doxorubicin (DOX) and chrysin in hepatic carci-

noma, gastric cancer, etc. (Chen et al. 2014a; Sun et al. 2011).

A preventive role of EGCG in cardiotoxicity induced by

DOX has been reported (Li et al. 2010). In addition, EGCG

plays a dose-dependent inhibitory role in autophagy signal-

ing and inhibits the cellular growth with a synergistic effect

152 M. Afzal et al.

123

(40–60 % increment) on cell death when combined with

doxorubicin (Chen et al. 2014a).

This is further confirmed by a combination therapy with

rapamycin, an autophagy antagonist which impairs the anti-

cancer effect of either DOX by itself or in combination with

EGCG (Chen et al. 2014a). DOX encapsulated in 6-O-(3-

hexadecyloxy-2-hydroxypropyl)-hyaluronic acid nanoparti-

cles, 9HDHA-NPs, with EGCG significantly inhibits the

growth of Ehrlich ascites tumors (Ray et al. 2013). Further,

EGCG in combination with vitamin A or ascorbic acid has

been reported to show beneficial effects for B16 melanoma

and other types of cancer prevention (Gao et al. 2013; Lee

et al. 2010; Wel et al. 2003).

In numerous cell culture studies, EGCG induces apop-

tosis and suppresses subsequent cell growth in head and

neck cancers, human ovarian carcinoma cell lines

OVCAR3, multiple myeloma cells, human squamous car-

cinoma, SiHa human cervical cancer cell, and prostate

cancer (Huang et al. 2014; Al-Hazzani and Alshatwi, 2011;

Ren et al. 2011; Rao and Pagidas, 2010). It has been

demonstrated that EGCG inhibits OVCAR3 cell prolifer-

ation by activation of p38 MAPK and down-regulation of

protein expression of MMP2. Synergistic effect of EGCG

with curcumin for the control of human colon adenocar-

cinoma (HCT 15, HCT 116) and human larynx carcinoma

has been reported (Manikandan et al. 2012). A potential

Fig. 1 Molecular structures of

some catechins in tea

Green tea polyphenols and their potential role in health and disease 153

123

reduction in toxicity of platinum, used as an anticancer

agent, has been reported when co-administered with EGCG

(Mazumder et al. 2012). All these studies show an inor-

dinate potential of EGCG as an anticancer agent.

Mechanism of action of EGCG

EGCG and its underlying mechanism of action have been

extensively studied for anticancer activities. EGCG is bio-

activated after its conjugation with cysteine to form 20-cysteinyl-EGCG and 200-cysteinyl-EGCG. Both of these

products inhibit colon cancer in a dose-dependent manner,

and both metabolites prevent arachidonic acid release and

nitric oxide production indicating anti-inflammatory and

antioxidant activities (Lambert et al. 2010). In addition,

several synthetic analogs of EGCG have been prepared to

study structure–activity relationship, in order to define

potential molecular targets of EGCG (Chen et al. 2011).

Thus, several mechanisms of action of EGCG to target

cancer progression have been proposed. These include

cancer development and progression, invasion, metastasis,

chronic inflammation for increased risk of colorectal can-

cer, suppression of cell de-adhesion/migration, and

inhibition of other clinical parameters (Li et al. 2011). An

activation of phosphoinositide-3-kinase (PI3K) signaling

pathway in human cancer is known and binding of EGCG

with PI3K as a competitive inhibitor and competing ATP

binding for metastatic control of cancer is a good support

for EGCG as an anticancer agent (Van Aller et al. 2011).

For mechanistic reasons, biochemical pathways such as

gene expression, growth factor-mediated pathway, mito-

gen-activated protein kinase-dependent pathway, and the

ubiquitin/proteasome degradation pathways have been

investigated to explore role of EGCG in cancer control

(Chen et al. 2011). The ubiquitin-dependent degradation is

important in the up-regulation of cell proliferation and

down-regulation of cancer cell inhibition. Therefore, pro-

teasome inhibitors, such as flavonoid chrysin, are important

anticancer drugs, and targeting proteasomes is the appro-

priate strategy for cancer treatment (Sun et al. 2011).

Proteasome inhibitors and other anti-angiogenesis inhibi-

tors from several sources, such as marine, phytochemicals

such as flavonoids (phenoxodiol) and metal complexes for

use in anticancer therapy, have been investigated in detail

(Frezza et al. 2011; Howes et al. 2011).

It is known that pro-apoptotic proteins are accumulated

leading to cell death. The gap junction intercellular com-

munication (GJIC) tumor suppressor, connecxin (Cx),

along with EGCG, play an important role in targeting

human metastatic cancer cells (Choung et al. 2011).

The mechanism of apoptotic cell death is believed to be

through down-regulation and/or suppression of cell death-

inhibiting gene Bcl-xL (Sonoda et al. 2014). A down-regu-

lation of ku70 by interrupting its binding with Bax mRNA

and drug-metabolizing enzymes such as cytochrome P450

and peroxidoredoxin-V has been suggested as possible

mechanism of action for cancer treatment (Li et al. 2013;

Maliakal et al. 2011; Ren et al. 2011). EGCG also inhibits

specific proteins with significantly altered expression level

and signaling pathways such as EGFR and cell cycle in G0/

G1 phase arrest with an increase in G2M phase (Ma et al.

2014). This decreases the number of cells in ‘S’ phase con-

sequently suppressing tumor-promoting effect of human

peptidyl prolyl cis/trans isomerase (Urusova et al. 2011).

The altered proteins are known to be involved in drug

resistance, gene expression, motility, detoxification, and

metabolism in cancer cells. An inhibition of different cell

lines offering different pathways indicates that EGCG and

related compounds affect multiple pathways or global

networks in cancer therapy by making topoisomerase–

DNA complexes (Lopez-Lazaro et al. 2011).

Cytotoxicity of EGCG for colon cancer is known, due to

its inhibition of DNA methyltransferases and histone

deacetylases. While in human gastric cancer, EGCG con-

trols recepteur d’origine nantais (RON) expression and it

exerts its antineoplastic effects by antagonizing tumor-in-

duced myeloid-derived suppressor cells (Park et al. 2013).

The cytotoxic activity of EGCG is greatly enhanced when

used as nano-gold particles (EGCG-pNG), and its mecha-

nism of activity is shown to be through mitochondrial

pathway-mediated apoptosis (Chen et al. 2014b).

Several other mechanisms of action of EGCG and

theaflavin (TF3) in black tea extract have been proposed

for their cytotoxicity including extracellular signaling, such

as inhibition of Akt, NF-kappaB signaling by blocking

phosphorylation and down-regulation of cyclooxygenase2,

STAT3 signaling, down-regulation of TLR4 signal trans-

duction, activation of 67-kDa laminin receptor (67LR),

redox regulation, and genetic and epigenetic profile of

tumor cells (Yiannakopoulou, 2014; Wang et al. 2013;

Hong et al. 2010). The tumor-associated cell surface ubi-

quinone oxidase (ENOX2) is a cellular target for cancer

inhibition by EGCG and isoflavone, phenoxodiol. Human

carbonyl reductase 1(CBR1) is down regulated by EGCG

thus potentiating the effect of antitumor drug anthracycline

daunorubicin (DNR), by protecting it from reduction to its

alcohol form (Huang et al. 2010).

Therefore, a combination of EGCG and DNR has been

recommended for the treatment of hepatocellular carci-

noma. A combination of TF3 with ascorbic acid (AA) or

and EGCG plus AA is shown to enhance anticancer

activities of catechins, such as EGCG, especially in breast

cancer (Li et al. 2010).

The polypeptides (OATPs) 1B1 and 1B3 that assist

organic anion transport are commonly produced in

154 M. Afzal et al.

123

hepatocytes. These are also expressed in several cancer cell

types, and EGCG is known to modulate the function of

OATPs killing in OATP1B3-expressing cells (Zhang et al.

2013). Site-specific delivery of EGCG has been studied

using casein nanoencapsulated micelles in colon cancer

cells (Haratifar et al. 2014).

The CS aqueous extract has been shown to be effective

in bone protection against breast cancer cell proliferation

and its induced bone damage. CS has potent antitumor and

antimetastasis effect in breast cancer (Luo et al. 2014;

Yiannakopoulou 2014). However, lipid-soluble CS

polyphenols, polyphenols esterified with fatty acids, are

shown to be more potent in containing hepatoma and pre-

cancerous lesions by inhibition of cellular proliferation and

DNA damage (Shen et al. 2014).

Tea has anti-Alzheimer and anti-Parkinsonismactivity

Neurodegenerative diseases like Alzheimer’s disease

(AD) and Parkinson’s disease (PD) are among the front

runners as a cause of mortality in the United States

(Betzaida et al. 2013). AD is characteristically marked

by cognitive decline and etiologically related to amyloid

deposition (Ho et al. 2005). Green tea consumption has

been found to be a significant risk reducer for cognitive

decline in AD (Kuriyama et al. 2006). EGCG’s neuro-

protective mechanism in AD may be categorized as

follows. EGCG inhibits the amyloid plaque formation

(Bastienetto et al. 2006) and its toxicity through multiple

pathways. Interference with the amyloid protein assem-

bly and disruption/inhibition of fibril aggregation of

amyloid plaques have been postulated (Ferreira et al.

2011). This destabilizes the amyloid plaque in the pipe

line by altering the optimal binding of metals like Cu,

needed for stability, leading to an alteration of amyloid

fibril shape diminishing its neurotoxicity. Other neuro-

protective and/or neuromodulator actions of EGCG may

include protection against hydrogen peroxide-induced

toxicity (Okello et al. 2011) and mitochondrial protec-

tion from amyloid toxicity (Dragicevic et al. 2011). It

also ameliorates the amyloid toxicity on N-methyl-D-

aspartate (NMDA) receptor function in brain cells.

Aggregation of amyloid beta-protein stimulates the pro-

duction of reactive oxygen species (ROS) through

mitochondrial dysfunction, in neurons through NMDA-

dependent pathway. This increase in ROS is quenched

by EGCG helping AD suffering patients (He et al. 2011).

It influences cell survival through down-regulation of

pro-apoptotic genes (He et al. 2011) and promotes neural

progenitor cell proliferation (Levites et al. 2002a). Green

tea extract has also been shown to enhance the neuronal

activity in the prefrontal cortical areas of brain con-

cerned with processing of working memory (Borgwardt

et al. 2012).

Oxidative stress and associated ROS generation, con-

tributing to inflammation, may be implicated as one of the

pathways in neurodegenerative diseases (Halliwell 2001).

Both AD and PD pathology may show oxidative damage

and increased iron accumulation in certain specific areas of

brain (Reiderer et al. 1989). Similarities in pathology in

AD and PD may include oxidative stress, increased lipid

peroxidation, reduced mitochondrial activity, increased

iron concentration, a-synuclein aggregation leading to

neuronal toxicity, mitochondrial and cytochrome c oxidase

malfunction (Recchia et al. 2004; Perry et al. 2002).

Tea drinking is associated with a moderate risk reduc-

tion for PD (Checkoway et al. 2002). Population studies

including wide geographic areas have indicated a lower

prevalence of PD in areas where tea drinking is more

common (Zhang and Roman 1993). Neuronal protection by

green tea extract has been demonstrated by experimental

studies as well. Both EGCG and green tea extract have

shown dopaminergic neuronal protection and prevention of

striatal dopamine depletion against PD symptom complex

inducing neurotoxin (Levites et al. 2001). Catechol amines

in general are metabolized by COMT and MAO (Deleu

et al. 2002). COMT inhibitors are often used in the clinical

management of PD to improve bioavailability of levodopa

in the brain (Bonifati and Meco 1999). Experimental,

in vitro studies have revealed that EGCG has an inhibitory

effect on COMT activity (Lu et al. 2003). However, more

recent in vivo studies using high doses of EGCG did not

show any impairment of COMT activity (Lorenz et al.

2014). The role of metal accumulation, like iron, copper,

etc., related to oxidative stress in neurodegenerative dis-

eases, is well established (Jomova et al. 2010). EGCG has

shown possible neuroprotective property as an iron chelator

(Temlett et al. 1994).

Further, role of oxidative stress in PD has been experi-

mentally demonstrated using Paraquat, a powerful REDOX

agent and especially toxic to nigrostriatal dopaminergic

system (Liou et al. 2001). EGCG has shown a protective

effect by inhibiting or attenuating peroxidation (Higuchi

et al. 2003), cytotoxic cytokine release (McGeer andMcgeer

1995), binding inhibition, and nuclear translocation of NF-

jB or its down-regulation (Levites et al. 2002b). Neuronal

protective effects of EGCG also include their ability to

increase the activity of two major antioxidant enzymes,

super oxide dismutase and catalase in the neostriatum of

experimental animals (Chen et al. 2000), their ability to alter

cell signaling pathways, and decrease or diminish pre-

apoptotic gene expression (Weinreb et al. 2003).

Green tea polyphenols and their potential role in health and disease 155

123

Green tea is anti-fibrotic

In this section, the results obtained in our laboratories are

described. Green tea extract therapy detracts hepatic

fibrosis induced by a combined exposure to carbon tetra-

chloride and ethanol, as shown by our histopathological

studies (Safer et al. 2012). Hepatic fibrosis is a condition in

which scar formation occurs in the liver. The process

occurs during an excessive formation of extracellular col-

lagenous matrix (ECM) (Bataller and Brenner 2005), or

during a scar formation to replace normal tissue lost

through injury, infection, or chronic liver insult. Specifi-

cally, hepatic fibrosis is a result of the inhibition of

synthesis and degradation of the matrix due to insult

occurring in the mesenchymal cells (MSCs) involved in the

synthesis of various components of the ECM, including

collagen types I–VII (Paz and Shoenfeld 2010). Results

from our laboratories show that green tea extract (GTE)

plays a beneficial role in controlling the fibrotic effects of

reserpine (Al-Bloushi et al. 2009). Our results also show

that the effect of hepatic fibrosis inducers such as carbon

tetrachloride (CCl4) and ethanol may also be avoided by

GTE.

Inflammation often results in hepatic stellate cellular

over-activity and this activity triggers ECM synthesis and a

deposition of collagen fibers in the extracellular spaces of

the liver cells. In this process, blood infusion is lost and the

tissue hardens, leading to liver fibrosis (Wu and Zern

2000). Currently, there is no effective treatment for hepatic

fibrosis, and a number of patients develop a progressive

form of hepatic cirrhosis. We administered GTE to control

the hepatic fibrosis-induced animal model. Hepatic fibrosis

was induced by 4 weeks of CCl4 aqueous solution

administration to rats followed by GTE treatment, and we

Fig. 2 Scanning electron

microscope images of the rat

liver extracellular matrix

(ECM). a with collagen fiber

formation due to CCl4 and

ethanol (arrows). b with

reduced presence of collagen

fibers due to the effect of CCl4,

ethanol, and GTE. Hepatic

fibrosis is evaluated by several

criteria including external

features of the animal, weight,

and gross anatomy of the

affected animal tissue. But, the

key features of all are the serum

enzymes AST and ALT

Fig. 3 a AFM images (5 9 5 um) taken from an area of rat liver

extracellular matrix (ECM) taken from hepatic fibrosis rat liver

caused by CCl4 and ethanol. Note collagen fibers with random

orientation in the amplitude height image (left) and thickness profile

of 270 nm (right). When treated with CCl4, ethanol, and nano-GTE,

no trace of such fibers was found (b)

156 M. Afzal et al.

123

observed a decrease in the rate of damage to collagen

fibers. Ethanol is also a hepatotoxin with a significant

effect on the liver causing hepatic fibrosis (Yasuda et al.

2009). We investigated the therapeutic effect of GTE on

the combined exposure to CCl4 and ethanol, and results

were analyzed with three–dimensional (3D) scanning

electron microscopy. The data collected showed a pro-

gressive hepatic recovery from cirrhosis (Fig. 2). Analysis

of our data shows that GTE chitosan nanoparticles are

more effective in removing all the extracellular collagen

fibers induced by CCl4 in hepatic fibrosis.

From the nano-GTE perspective, it is obvious that it is

very effective in healing and curing hepatic fibrosis with

virtually no trace of fibers in the ECM (Safer et al. 2015).

Nano-green tea and hepatic fibrosis

Nano-green tea, as chitosan encapsulated particles, has

been recently used as an efficient method to control hep-

atofibrosis. We assessed this by Atomic Force Microscopy

(AFM) in rat hepatic fibrosis model (Safer et al. 2015).

AFM images revealed an abundance of collagen fibers of

250–300-nm width in the fibrotic liver samples while those

of green tea chitosan nanoparticles (GTE-CS NPs) were

clear of these fibers and were comparable with the control

group (Fig. 3).

In our studies, healing effect quantification in hepatic

fibrosis induced by GTE-CS NPs in rat model was carried

out by analyzing data obtained by transmission (TEM) and

Fig. 4 Computational Image Analysis of the images of the ultra-thin

section of the livers of rats from the four groups. Selected area with

damaged cytoplasm and cytoplasmic organelles are colored in red.

a Control cells, with normal architecture of hepatocytes (no damage).

b, c, d are images with cells treated with CCl4/Ethanol, CCl4/Ethanol

and nano-GTE and CCl4/Ethanol chitosan, respectively. The red

colored area represents the selection of the damaged cytoplasm and

cytoplasmic organelles in the cells (threshold). Note that the simple

visual comparison of image c clearly indicates the significant healing

of cytoplasm and cytoplasmic organelles. d representing group when

compared to c very minor healing process. Pie charts and histograms

below are the pictorial representation of the percentage damage (in

red) and the undamaged regions (in gray) of adjacent cells belonging

to the same groups

Green tea polyphenols and their potential role in health and disease 157

123

scanning electron microscopy (SEM). A fixed volume of

*150 nm-sized chitosan-encapsulated GTE1 solution was

orally administered to a group of adult rats for 3 weeks,

after an individual treatment with CCl4 and ethanol for

identical periods of time. Images of ultra thin sections of

the liver samples were recorded using TEM (Fig. 4). Using

computational analysis, the images were quantitatively

probed revealing that chitosan nano-GTE healed nearly

25 % of the sub-cellular area infected with hepatic fibrosis

suggesting a significant therapeutic value of Chitosan

nano-green tea extract. SEM study showed the topo-

graphical changes of cell surface as well as the

extracellular matrix network between the hepatocytes.

Measurement and comparative analyses of data were

carried out with various sets of TEM images of control

healthy hepatic cells with undamage cell cytoplasm. The

results were supported by the SEM images. The architec-

ture of the healthy tissue showed some uneven, rough, and

discrete ‘pebble’-like surface, with some irregular invagi-

nated portions seen as black regions. However, surface of

the damaged cells appeared as perforated and meshy and

had lost integrity as compared with the control tissues.

Contrarily, treatment with nano-green tea clearly showed

significant improvement, eliminating perforation, meshy

regions, and the formation of ‘pebble’-like structures with

good resemblance to the healthy tissue.

A computational analysis of the TEM images showed

marked differences in the percentage of the damaged area

in the hepatic cells among the different groups of rats. The

worst damage was with the dual effect of CCl4 and ethanol,

followed by the effect of CCl4? ethanol and chitosan nano-

GTE. A substantial improvement was detected in the group

of rats, which was exposed to CCl4? ethanol and chitosan

nano-GTE.

Acknowledgments The authors (MA & AMS) thankfully

acknowledge assistance of their research lab. workers, Mrs. S. Oom-

men, Mr. Nomani and other workers in the nanoscopy unit of KU for

their assistance. Dr. Vinod George, St. John’s Medical College,

Bangalore, India, for his generous donation of the picture, tea leaf

picking in India, is thankfully acknowledged. We are also grateful to

RA, Kuwait University, for their support for the non-funded research

projects.

Conflict of interest The authors declare no conflict of interest.

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