Pharmacological Potential of Ampelopsin in Rattan Tea

Available online at www.sciencedirect.com

Food Science and Human Wellness 1 (2012) 14–18

Pharmacological potential of ampelopsin in Rattan tea

a a,b,∗

Xianjuan Kou , Ning Chen

College of Health Science, Wuhan Sports University, Wuhan 430079, China

The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA

Received 23 July 2012; received in revised form 28 July 2012; accepted 29 August 2012

Abstract

Rattan tea, made from the leaves of Ampelopsis grossedentata, may potentially perform multiple pharmacological roles, including anti-bacterial,

anti-cancer, antioxidant, hepatoprotective and anti-hypertension functions. These beneﬁcial functions of Rattan tea are strongly associated with

the bioactivity of ampelopsin, a major ﬂavonoid compound in Rattan tea. In this review, we summarize current research related to the bioactivity

and pharmacological mechanisms of ampelopsin, which will provide a better reference for its potential application in the prevention of chronic

diseases.

Keywords: Ampelopsin; Rattan tea; Flavonoid; Pharmacological potential; Chronic disease

1. Introduction functions and corresponding action mechanisms, as well as

potential human health beneﬁts of ampelopsin.

Rattan tea is a traditional Chinese herbal remedy prepared

from the stems and leaves of the plant Ampelopsis grossedentata.

2. Anti-bacterial and anti-inﬂammatory effects

Ampelopsin is one of the most important ﬂavonoids found in

Rattan tea. As a dihydromyricetin (DMY), ampelopsin was ﬁrst

Ampelopsin in crude plant extracts has been applied to alle-

isolated from Ampelopsis meliaefolia by Kotake and Kubota in

viate inﬂammatory diseases as a broad-spectrum anti-bacterial

1940, and was later reported as a major bioactive component in

drug for several centuries. The ampelopsin extract exerts strong

Ampelopsis grossedentata [1]. Today, ampelopsin from Rattan

inhibitory effects on Staphylococcus aureus and Bacillus sub-

tea is known for a broad range of biological functions including

tilis. In addition, ampelopsin is also sensitive to inhibit other

hypoglycemic [2], antioxidant [3,4], anti-inﬂammatory [5], anti-

pathogenic microorganisms such as Aspergillus ﬂavus, penicil-

tumor [6–8], hepatoprotective [4,9], and neuroprotective effects

lium and transport streptavidin [11]. Additionally, ampelopsin

[10].

can inhibit acute or sub-acute inﬂammation such as croton oil-

Because of these reported effects, research into the bioactivity

induced auricular edema or formaldehyde-induced paw edema

of ampelopsin in Rattan tea has gained increasing attention over

in mice, and carrageenan-induced paw edema in rats, as well as

the last decade, leading to increased understanding of its pharma-

abdominal capillary permeability [12]. Similarly, ampelopsin

cological functions and underlying mechanisms. In this review,

isolated from Salix sachalinensis also has a strong inhibitory

we summarize current research related to the pharmacological

effect on Cladosporium herbarum [13]. A structure–activity

relationship analysis has indicated that the hydroxyl groups at 5

∗ positions (i.e., 5, 7, 3 , 4 and 5 ) can signiﬁcantly enhance the

Corresponding author at: The Cancer Institute of New Jersey, 195 Little

anti-inﬂammatory activity of ampelopsin.

Albany Street, New Brunswick, NJ 08903, USA.

Inﬂammatory cytokines such as interleukin-1 beta (IL-1␤)

E-mail address: [email protected] (N. Chen).

and tumor necrosis factors (TNF-␣) can up-regulate the pro-

Peer review under responsibility of Beijing Academy of Food Sciences. duction of nitric oxide (NO) and prostaglandin E2 (PGE2),

thus stimulating the expression or activity of inducible NO

synthase (iNOS), cyclooxygenase-2 (COX-2) and microsomal

PGE synthase-1 (mPGES-1) in target cells. Ampelopsin has

been reported to inhibit NO production in lipopolysaccha-

Beijing Academy of Food Sciences. ride (LPS)-stimulated RAW264.7 macrophages and reduce

http://dx.doi.org/10.1016/j.fshw.2012.08.001 carrageenan-induced acute inﬂammation in vivo [14], which is

X. Kou, N. Chen / Food Science and Human Wellness 1 (2012) 14–18 15

consistent with another report that ampelopsin plays an impor- of Bel-7402, HL-60, and K562 cells in a dose-dependent man-

tant role not only in reducing the production of pro-inﬂammatory ner [23]. Interestingly, ampelopsin can also inhibit the growth

mediators such as IL-1␤, IL-6 and TNF-␣, but also in inhibi- of H22 cells with IC50 of 18.65 ␮g/mL, but the inhibitory rate is

ting the activity of iNOS. Moreover, ampelopsin can selectively negatively correlated with ampelopsin. Moreover, ampelopsin

inhibit the production of iNOS in LPS-stimulated macrophages also exhibits anti-tumor effect on bladder cancer in orthotopic

and RAW264.7 cells by suppressing the mRNA and protein xenograft models, which is mediated by cell cycle arrest [24].

expression of iNOS. Previous studies have demonstrated cancer speciﬁc pharma-

Nuclear factor-kappaB (NF-␬B), as a sensitive transcription cological activity of ampelopsin resulting in growth inhibition

factor for regulating the genes responsible for both innate and of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3)

adaptive immune response, has been identiﬁed as a major factor human prostate cancer cell lines in vitro. These anti-proliferative

involved in the regulation of pro-inﬂammatory cytokines such effects, which are not observed in normal prostate epithelial

␬

as iNOS and COX-2 [15]. Usually NF- B resides in the cyto- cells even at higher doses [6], are mediated by down-regulating

plasm associated with its inhibitor (I-␬B). Once the inhibitor cyclin-dependent kinase (CDK2) in LNCaP cells and cell cycle

is released, NF-␬B can be phosphorylated and then translo- 2 (CDC2) protein levels in PC-3 cells [6]. Since CDC2 is con-

cated to the nuclei. The inhibitory effect of ampelopsin on the sidered an essential molecular target for designing anti-cancer

induction and expression of iNOS is partially mediated through drugs [25], ampelopsin should be a promising molecule for the

inhibiting NF-␬B activity and reducing the expression of the development of anti-cancer drugs.

p65 subunit of NF-␬B in RAW264.7 cells under stimulation by

LPS [5]. MAPKs and PI3K/Akt are involved in the induction 3.2. Inhibition of apoptosis

of pro-inﬂammatory genes in activated macrophages [16,17].

However, ampelopsin can exert signiﬁcant inhibition of the The capacity to induce apoptosis in tumor cells is a pri-

PI3K/Akt signaling pathway without altering the activation of mary pharmacological mechanism of certain anti-tumor drugs

MAP kinases. Moreover, PI3K may act as an upstream regulator [26,27]. The overloading of calcium ions can result in the

of IKK/NF-␬B activation, and ampelopsin can inhibit NF-␬B- opening of mitochondrial permeability transition pores, thereby

regulated pro-inﬂammatory gene expression by blocking the inducing changes in osmotic pressure, ATP depletion and mito-

␬

PI3K/Akt/NF- B signaling cascades. chondrial shrinkage, and ﬁnally apoptosis [28]. Lung cancer is

Another contributor to cellular damage during inﬂamma- a serious threat to human health and ampelopsin can induce the

tion is oxidative stress [18]. The administration of ampelopsin apoptosis of lung adenocarcinoma cell line AGZY-83-a cells

can signiﬁcantly inhibit LPS-induced intracellular ROS levels. by promoting the increase in intracellular calcium levels and

On the other hand, as an inhibitor of ROS, N-acetyl-cysteine caspase-3 activity [29], although the mechanism associated with

(NAC) can greatly suppress the phosphorylation of Akt and IKK this has not yet been determined.

as well as the downstream I-␬B. The reported association of Ampelopsin also induces apoptosis in prostate cancer mainly

ampelopsin with these pathways further conﬁrms the potential through down-regulation of Bcl-2, an important regulator of

anti-inﬂammatory activity of ampelopsin. apoptosis that exhibits increased expression in both metastatic

and non-metastatic tumors [30,31]. Furthermore, ampelopsin in

3. Anti-tumor activity the concentration range of 2.2-14.84 mg/L can exert inhibitory

effects on the growth of gastric cancer cell line SGC-7901.

Currently, much attention has been paid to the anti-tumor The chemotherapeutic drug mitomycin (MMC), when combined

activity of ampelopsin in cell and animal studies [7,8]. The with ampelopsin, produces an obvious synergistic inhibition on

anti-metastatic effect of ampelopsin on melanoma and prostate the growth of SGC-7901 cells, which is also correlated with

cancer has been conﬁrmed via in vivo and in vitro studies the inhibitory expression of apoptotic proteins such as Bcl-2

[6,19,20]. In addition, reports suggest that ampelopsin may and survivin [32]. Therefore, the down-regulation of Bcl-2 can

suppress angiogenesis by inhibiting the secretion of vascu- be an important molecular mechanism of ampelopsin-induced

lar endothelial growth factor (VEGF) and basic ﬁbroblast apoptosis. The application of anti-cancer drugs combined

growth factor (bFGF) from human hepatocellular carcinoma with ampelopsin will be a novel therapeutic strategy for

cells in vitro. A similar strong inhibitory effect on the growth of cancers.

human hepatocellular carcinoma in mice has also been reported

[21]. These reports indicate that ampelopsin exerts its anti-tumor 3.3. Inhibition of invasion and migration

effects by modulating multiple signaling pathways, including

apoptosis, cell cycle arrest, cell growth inhibition and metastatic Metastasis is the major cause of death associated with can-

inhibition at various cellular levels. cer, and many factors can affect the invasion and metastasis of

cancers. Ampelopsin can signiﬁcantly attenuate the metastatic

3.1. Regulation of proliferation and cell cycle arrest process of cancers by inhibiting the degradation of the base-

ment membrane. Ampelopsin can also inhibit the adhesion of

Ampelopsin-containing serum can inhibit the proliferation B16 mouse melanoma cells to ﬁbronectin, lamin, or matrigel,

of B16 cells by interrupting DNA synthesis [22]. Similarly, thus attenuating invasion into the reconstituted basement mem-

ampelopsin produces an obvious inhibition on the proliferation brane as demonstrated by in vitro experiments [19,20]. Matrix

16 X. Kou, N. Chen / Food Science and Human Wellness 1 (2012) 14–18

metalloproteinases (MMPs), a family of secreted or membrane- [40]. The hepatoprotective function of ampelopsin may therefore

associated proteins capable of digesting extracellular matrix provide a promising therapeutic strategy for hepatitis B [41].

components, are thought to play an essential role in can-

cer metastasis [33]. Moreover, the up-regulation of MMP-2/-9 5. Anti-hypertension effect

expression is the critical step of invasion and metastasis of can-

cer cells. Ampelopsin can inhibit the invasion of human breast In animal experiments, ampelopsin has been shown to antag-

cancer (MDA-MB-231) cells in a dose-dependent manner, and onize norepinephrine (NE) and high K -induced contraction of

the mechanism associated with this may involve down-regulated rabbit aorta, suggesting that ampelopsin can play a blockage

expression of MMP-2/-9 in both the extracellular matrix and the role in intestinal smooth muscle and aortic ␣-receptor [42]. Fur-

intracellular space [34]. Additionally, ampelopsin may inhibit ther studies have conﬁrmed that ampelopsin can signiﬁcantly

the expression of CXCR4, a protein associated with prostate can- inhibit the contractions associated with Ca release caused by

cer, resulting in inhibition of invasion and migration of prostate NE [43]. However, ampelopsin inhibitory effects on extracel-

cancer cells [6]. lular Ca release are observed only at higher concentrations.

Adriamycin (ADM) is a potent anti-tumor agent in clini- These ﬁndings suggest that ampelopsin may function as an anti-

cal cancer treatments. Unfortunately, the application of ADM hypertension drug by selectively blocking voltage-dependent

is limited due to its cytotoxicity to skeletal muscle, heart calcium channels (PDC).

and liver. In 4T1 breast cancer cells, the combination of

ampelopsin and ADM can inhibit tumor growth in S180- and 6. Regulation of plasma lipids and blood glucose

4T1-transplanted mice. Ampelopsin apparently sensitizes the

anti-tumor efﬁcacy of ADM, and attenuates ADM-induced tox- An anti-atherosclerotic effect of ampelopsin has also been

icity in heart and liver [35,36]. All of these investigations reported. The intragastric administration of Ampelsis grosseden-

further conﬁrm the anti-invasion potential of ampelopsin during tata reduces the levels of serum total cholesterol (TC) and

cancer treatments. In addition, ampelopsin can increases intra- triglyceride (TG), and increases serum high-density lipoprotein

cellular accumulation of chemotherapeutic drugs in multi-drug cholesterol (HDL-C) levels in rats, indicating a hypocholes-

resistance (MDR)-associated tumor cells, and correspondingly terolemic effect of ampelopsin. In accordance with these

reduces the cytotoxicity of chemotherapeutic drugs by inhibiting ﬁndings, a drink containing Ampelsis grossedentata at a dose

the efﬂux of drugs via permeability glycoprotein (P-gp), which of 9 g/day was administered to 100 patients with primary hyper-

suggests ampelopsin may also be a promising MDR modulator lipidemia, resulting in quantiﬁable reductions in TC, TG and

[37]. plasma lipid by 42%, 72% and 28% after 45 days administration,

respectively. In addition, ampelopsin can signiﬁcantly increase

the content of serum SOD, and reduce the content of MDA

[44], therefore, ampelopsin can prevent the invasion of vascular

4. Hepatoprotective function smooth muscle cells and matrix degradation, which correspond-

ingly contributes to protective effects against atherosclerosis and

Ampelopsin F and G isolated from Ampelopsis brevipedun- cancer.

culata Var. hancei can suppress carbon tetrachloride- (CCl4) During the investigation into the relationship between green

or galactosamine-induced liver injury in rats. Ampelopsin E tea and obesity-related insulin resistance syndrome, green tea

and cis-ampelopsin E exert an obvious inhibitory effect on was found to enhance insulin activity in vitro and reduce

hepatitis virus [38]. In galactosamine, d-galactosamine and hypertriacylglycerolemia in mice [45–48]. Currently, effec-

alpha-naphthylisothiocyanate (ANIT) induced acute liver injury tive drugs for treating diabetes, metformin and glibenclamide,

models, the administration of ampelopsin can inhibit the activity have been found to produce side effects during clinical use.

of serum transaminases such as alanine aminotransferase (ALT) Glibenclamide has been found to signiﬁcantly reduce blood

and aspartate aminotransferase (AST), and alleviate patho- glucose in normal mice [49]. Conversely, ampelopsin has no

logical damage of liver tissues. Ampelopsin can also reduce impact on blood glucose in normal mice, but can reduce blood

the production of malondialdehyde (MDA) in CCl4-induced glucose levels in alloxan-induced diabetic or hyperglycemic

liver injury, and increase superoxide dismutase (SOD) activity mice.

[39]. A diet containing ethanolic extract (1%) or ampelopsin Additionally, in d-galactose-induced impaired glucose toler-

(0.1%) can signiﬁcantly suppress the increase of serum lac- ance (IGT) animal models, intragastric injection of ampelopsin

tate dehydrogenase (LDH), ALT, AST and ␣-tocopherol levels can signiﬁcantly reduce the concentration of fasting blood

in rats with d-galactosamine-induced liver injury [4]. In addi- glucose, 2 h postprandial blood glucose and insulin levels.

tion, ampelopsin also has a protective effect against CCl4, This suggests a possible therapeutic role in the treatment of

d-galactosamine and LPS-induced liver cell damage in mice [9]. diabetes, which is characterized by the inability of insulin

Ampelopsin mainly inhibits the collagen formation of hepatic to inhibit the production of hepatic glucose [50]. More-

M cells. Following hepatic M cell transplantation in cultured over, ampelopsin exerts a protective effect on early renal

rat liver tissues, collagen ﬁbers are easily produced. However, damage by inhibiting the content of microalbuminuria and

ampelopsin can inhibit the formation of new collagen ﬁbers, the activity of LDH in kidney. These ﬁndings suggest that

and further disperse old collagen ﬁbers into small micro-blocks ampelopsin can effectively improve the health status of IGT

X. Kou, N. Chen / Food Science and Human Wellness 1 (2012) 14–18 17

rats and provide a protective function against early kidney dam- accomplishing the prevention of neurodegenerative diseases,

age. cardiovascular diseases, cancer and other diseases.

7. Neuroprotective effect 9. Conclusion

Oxidative stress is believed to be a primary factor in neu- Naturally occurring substances derived from diets or dietary

rodegenerative diseases, such as Alzheimer’s disease (AD), supplements such as Rattan tea provide a new approach for

Parkinson’s disease and Huntington’s disease, as well as the prevention or therapeutic treatment of chronic diseases.

amyotrophic lateral sclerosis [51,52]. ROS-associated with Ampelopsin, as the predominant compound in Rattan tea, pos-

oxidative stress can induce cell apoptosis through mito- sesses potent anti-inﬂammatory activity whereby it can inhibit

␬

chondrial dysfunction and damage to lipids, proteins and the activation of NF- B and PI3K/Akt pathways, and inhibit

DNA [53,54]. Therefore, antioxidants have gained tremen- oxidative stress by scavenging free radicals and attenuating

dous attention as promising therapeutics for neurodegenerative lipid oxidation as well as reducing ROS levels. Furthermore,

diseases. Rattan tea is a popular beverage worldwide, espe- ampelopsin appears to both reduce the risk of cancer and regulate

cially in China and other Asian countries. Ampelopsin in blood glucose and lipids, although the underlying mechanisms

Rattan tea is an antioxidant ﬂavonoid that can enhance cel- associated with the capabilities remain to be further explored.

lular antioxidant defenses through activation of ERK and Future in vitro experimental studies and in vivo clinical studies

Akt signaling pathways, induce heme oxygenase-1 (HO-1) should focus on not only the understanding these mechanisms,

expression and protect PC12 cells from H2O2-induced apo- but also the development of ampelopsin as a chemopreventive

ptosis [10]. In sodium pentobarbital-induced mouse hypnosis agent to treat a wide range of diseases.

experiments, ampelopsin can signiﬁcantly extend the incu-

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