Phytomedicine 16 (2009) 652658

SHORT COMMUNICATION
Lipid-lowering effects of polydatin from Polygonum cuspidatum
in hyperlipidemic hamsters
Jian Du
a
, Lian-Na Sun
a
, Wei-Wei Xing
a,b
, Bao-Kang Huang
a
, Min Jia
a
,
Jin-Zhong Wu
c
, Hong Zhang
a,
, Lu-Ping Qin
a,
a
Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road,
Shanghai 200433, PR China
b
Department of Pharmacognosy, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University,
Shenyang 110016, PR China
c
Academy of Integrative Medicine, Fujian College of Traditional Chinese Medicine, Fuzhou, Fujian 350108, PR China
Abstract
Hyperlipidaemias are common in obese people, and they increase the risk of cardiovascular diseases such as
coronary heart disease (CHD) and atherosclerosis (AS). Previous studies have shown that several drugs can depress
serum cholesterol. However, they could cause serious side effects in various clinical settings. The objective of the
present study was to evaluate the lipid-lowering effects of polydatin in high-fat/cholesterol (HFC)-fed hamsters. The
levels of lipids in hamsters were measured enzymatically before and after the administration of polydatin. Signicant
differences between HFC and HFC+polydatin were detected for those concentrations. Decreased levels of serum TC,
TG and LDL-C and the concentrations of hepatic TG were found. Experimental results also showed that polydatin
elevated LDL-C/HDL-C and TC/HDL-C ratios. In concert with other effects, serum cholesterol-lowering effect in
hamsters may contribute to the regulation properties attributed to polydatin.
r 2008 Elsevier GmbH. All rights reserved.
Keywords: Polydatin; Polygonum cuspidatum; Lipid lowering; Hyperlipidaemias; Hamster
Introduction
The prevalence of obesity is increasing throughout the
world. The concern with it is an increased risk for a
variety of chronic diseases, including coronary heart
disease (CHD) and atherosclerosis (AS). The results of
current investigations strongly suggest that most of the
relationship between body weight and CHD risk is
mediated through high total cholesterol (TC), and low
high-density lipoprotein cholesterol (HDL-C) (Ohlsen,
2004). Obese people often consume excessive calories,
which turned into triglycerides, leading to high serum
triglyceride (TG). Elevated levels of plasma TG and
low-density lipoprotein cholesterol (LDL-C) have de-
monstrated that the fatty acids and cholesterol in the
diet are primary determinants of diet-induced hyperch-
olesterolemia (Hegated et al., 1965). Changes in eating
habits and exercise are some of the most powerful
strategies for improving serum lipid proles; however,
compliance is a serious impediment.
The search for new drugs capable of reducing and/or
regulating serum cholesterol and triglycerides levels has
gained momentum over the years, resulting in numerous
reports on signicant activities of natural agents. Many
ARTICLE IN PRESS
www.elsevier.de/phymed
0944-7113/$ - see front matter r 2008 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2008.10.001

Corresponding authors. Tel.:/fax: +86 21 25074574 (H. Zhang),

Tel.:/fax: +86 21 25070394 (L.-P. Qin).
E-mail addresses: jydujian@163.com (J. Du), zhanghong@smmu.
edu.cn, huihong01@126.com (H. Zhang), lpqin@smmu.edu.cn
(L.-P. Qin).
classes of dietary components and natural compounds
have been tested to regulate serum lipid concentrations
with the aim of lowering the incidence of AS and CHD
(Martinez-Flores et al., 2004; Li et al., 2006; Ji and
Gong, 2007; Hakimoglu et al., 2007). More attention is
paid to bioactive components from plant substances in
recent years. Although plant extracts constitute poten-
tial candidates, they often contain highly complex
mixtures of many different compounds. The objective
of our study is to nd a puried compound.
Rhizoma Polygoni Cuspidati (RPC), the root and
rhizomae of Polygonum ccuspidatum sieb.et Zucc., used
in many combined decoction, is safe and effective in the
treatment of cardiovascular diseases. Many investiga-
tions show that Polygonum ccuspidatum has an anti-
diabetic effect (Fei et al., 2008; Gao et al., 2003; Shen
et al., 2004). Extensive chemical studies indicate that
polydatin (Fig. 1) is one of the main bioactive
constituents, which can protect the myocardium and
liver cells from injury (Jin et al., 2000; Shan et al., 1990),
inhibit platelet aggregation and improve microcircula-
tion (Shan, 1988). Polydatin, a derivative of resveratrol,
is the glycoside of resveratrol, whose content in RPC is
six times higher than that of resveratrol (Zhou et al.,
2005). However, most of the studies focus on the lipid-
lowering activity of resveratrol (Wilson et al., 1996). The
lipid-lowering activity of polydatin has not been studied,
as far as we know.
In the current study, we investigated the effects of
polydatin on the lipid prole of a diet-induced animal
model of hyperlipidemias. The serum levels of TC, TG,
HDL-C and LDL-C were measured enzymatically, and
hepatic TG concentrations were also evaluated in the
same way. Meanwhile, LDL-C/HDL-C and TC/HDL-C
ratios were investigated. After analysis, the lipid-lowering
property of polydatin was found.
Materials and methods
Preparation of polydatin
Polydatin, a white powder, was isolated and puried
from the root and rhizome of Polygonum cuspidatum by
Department of Pharmacognosy, School of Traditional
Chinese Materia Medica, Shenyang Pharmaceutical
University (Shenyang China). In this study, high-speed
counter-current chromatography (HSCCC) was applied
to separation and purication of polydatin from
Polygonum cuspidatum according to the method de-
scribed by Chen et al. (2001). Dry mass of the plant
was extracted by methanol, the mixture was centrifuged
and the supernatant was washed with light petroleum
(b.p. 6090 1C). The remaining methanol phase was
evaporated to form syrup. The syrup was then dissolved
and fractionated in EtOAc and water in the ratio of 1:1.
Then water solution was vacuum evaporated at 40 1C
and the crude extract was obtained.
The proper amount of the crude extract was inject
into HSCCC, and after two separation procedure with
EtOAcEtOH-water (10:1:10 and 70:1:70, v/v), respec-
tively, polydatin was obtained from P. cuspidatum with
the yield of 1.15%. The purity of polydatin was 91.3%.
Animals and grouping
Sixty male Syrian golden hamsters, obtained from
Shanghai Si-Lai-Ke Experimental Animal Co., Ltd.
(Shanghai China), with an initial body weight of
85710 g, were used in this study. They were housed in
a regulated environment (2272 1C), with a 12-h dark
and 12-h light cycle (08:0020:00, light). Food and water
were given ad libitum throughout the experiment. All
animal treatments were strictly in accordance with
international ethical guidelines and the National In-
stitutes of Health Guide concerning the Care and Use of
Laboratory Animals, and the experiments were carried
out with the approval of the Committee of Experimental
Animal Administration of the University.
After 3-d acclimation, animals were randomly divided
into 6 groups (n 10): one control group, one high-fat/
cholesterol (HFC) group, three groups treated with
polydatin (25, 50 and 100 mg kg
1
d
1
) and one group
treated with positive drug fenobrate (FEN, 100 mg
kg
1
d
1
, Shanghai Hengshan Pharmaceutical Co.,
Ltd.). The animals in control group were fed with a
basic diet and other groups of animals with a high-fat/
cholesterol diet for 15 d. Dietary ingredients are listed in
Table 1.
ARTICLE IN PRESS
Fig. 1. Chemical structure of polydatin.
Table 1. Composition of the basic diet and high-fat/
cholesterol diet (%).
Ingredients Basic diet High-fat/cholesterol diet
Corn 35 24.5
Wheat 35 24.5
Wheat bran 28.5 20
Salt 1.5 1.5
Straw our 0 10.5
Yolk 0 12
Cholesterol 0 2
Lard 0 5
J. Du et al. / Phytomedicine 16 (2009) 652658 653
Administration
Polydatin, extracted from RPC, was dissolved in
distilled water prior to administration. Three treatment
groups of animals were orally administered 25, 50,
100 mg kg
1
d
1
of polydatin by intubation, respec-
tively, for 15 d. FEN was suspended in distilled water;
animals in the positive control group were orally
administered 100 mg kg
1
d
1
of FEN for 15 d in the
same way. Other groups of animals were orally
administered distilled water of same volume, and they
were run concurrently with polydatin-treated groups.
Administration and HFC diet were carried out at the
same time.
Body weight
Body weight was measured on days 0 and 15 after
experiment. To reduce the error originating from
feeding, all animals were fasted (water was not
restricted) for 12 h before measurement.
Measurement of serum and hepatic lipids
An hour after the last administration, animals were
anesthetized by intraperitoneal injection of ethyl carba-
mate (1.0 g kg
1
) and their blood was collected from
cervical veins for subsequent lipid prole measurements.
Meanwhile, their livers were excised, cleansed and also
prepared for the measurements of lipid levels.
After those blood samples were put at room
temperature for 1 h, the serum samples were separated
by centrifugation at 1500g for 15 min. Total lipids were
extracted from liver according to the method described
by Folch et al (1957). Serum sample and lipid exacts
from liver were kept under nitrogen in glass tubes. The
levels of serum TC, TG, HDL-C, LDL-C and hepatic
TG were measured by the colorimetric enzymatic
method using commercial kits purchased from Nanjing
Jiancheng Bioengineering Institute (Nanjing, China)
(Cho et al., 2008).
Statistical analysis
The data were analyzed using a SPSS 11.0 statistical
package. The data for multiple comparisons were
performed by one-way ANOVA followed by Dunnett
t-test. A value of po0.05 was considered statistically
signicant and all results are presented as the mean7-
s.e.m.
Results
Effects of polydatin on the body weight of hamsters
There was no difference in initial hamster weight for
all treatments (Table 2). The body weight of the animals
fed the high-fat/cholesterol diet was greater than that of
animals fed basic diet. The body weight of hamsters in
the groups treated with polydatin was less than that of
hamsters in the HFC group. But there was no
statistically signicant difference in body weight among
all groups.
Effects of polydatin on serum lipid prole levels of
hamsters
As can be seen in Fig. 2, the HFC diet resulted in a
signicant increase of serum lipids, including TC, TG
and LDL-C, compared with those in the control group.
As expected, the serum levels of TC, TG and LDL-C
were signicantly lower in the groups of animals treated
with polydatin for 15 d than that of the HFC group.
However, the HDL-C levels in HFC animals given 25,
50, 100 mg kg
1
d
1
of polydatin for 15 d changed little
compared with those observed in the HFC group of
animals.
Effects of polydatin on TC/HDL-C and LDL-C/
HDL-C in hamsters
Fig. 3 showed two indexes: LDL-C/HDL-C and TC/
HDL-C. It was shown in Fig. 3 that both LDL-C/HDL-
C and TC/HDL-C in HFC group of animals were
ARTICLE IN PRESS
Table 2. Results (mean7s.e.m.) of polydatin on hamsters body weight.
Group Animals (number) Doses (mg kg
1
) 0 d (g) 15 d (g)
Control 10 86.3071.37 91.0071.67
HFC 10 86.7071.14 93.3071.51
HFC+FEN 10 10 85.6071.78 92.7071.97
HFC+low polydatin 10 25 86.2071.00 90.8071.63
HFC+middle polydatin 10 50 87.1071.27 91.6071.69
HFC+high polydatin 10 100 86.4071.19 90.4071.16
J. Du et al. / Phytomedicine 16 (2009) 652658 654
signicantly higher than those observed in control
group. Although there was no statistically signicant
difference in the serum HDL-C levels, both LDL-C/
HDL-C and TC/HDL-C markedly decreased in poly-
datin-treated groups of animals when compared with
the values observed in the HFC group.
Effects of polydatin on hepatic TG in hamsters
As compared with the control group of animals, the
hepatic TG levels signicantly increased in the group of
animals fed high-fat/cholesterol diet for 15 d. While after
administration of polydatin for 15 d, the hepatic TG
levels signicantly declined in both middle-dose group
and high-dose group compared with those observed in
HFC group of animals. However, low dose of polydatin
(25 mg kg
1
d
1
) had no signicant inuence on hepatic
TG levels in hamsters fed high-fat/cholesterol diet
(Fig. 4).
Discussion
Male Golden Syrian hamster, a widely used model in
studying atherosclerosis and cholesterol metabolism in
response to dietary fat manipulations, possesses many
similar features in cholesterol metabolism compared to
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0
2
4
6
8
10
12
14
16
18
20
C
o
n
t
r
o
l
T
C

(
m
m
o
l
/
L
)
0
2
4
6
8
10
12
14
16
18
20
T
G

(
m
m
o
l
/
L
)
Polydatin (mg/kg)
0
0.5
1
1.5
2
2.5
3
3.5
H
D
L
-
C

(
m
m
o
l
/
L
)
0
2
4
6
8
10
12
L
D
L
-
C

(
m
m
o
l
/
L
)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0
C
o
n
t
r
o
l
Polydatin (mg/kg)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0
C
o
n
t
r
o
l
Polydatin (mg/kg)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0
C
o
n
t
r
o
l
Polydatin (mg/kg)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0
Fig. 2. Effects of polydatin on the serum lipid prole in hyperlipidemic hamsters. The serum lipid levels of the experimental animals
is described. The high-fat/cholesterol diet resulted in signicant increasing of serum lipids including the TC, TG, HDL-C and LDL-
C. (A) The TC level was signicantly lower in the groups fed with polydatin than that of the HFC group, and the TC level in the
hamsters treated with middle and high dose of polydatin were lower than that of the HFC group. (B) The concentration of serum
TG was signicantly lower in low-dose polydatin-fed groups than that of the HFC group, and the TG level in the hamsters treated
with middle and high dose of polydatin were lower than that of the HFC group. (C) There was no signicant difference between the
level of HDL-C in the HFC hamsters treated with polydatin and that in the HFC group. (D) LDL-C levels in the hamsters treated
with middle and high doses of polydatin were signicantly depressed compared with the HFC group.
nn
po0.01 compared with the
control group, *po0.05, **po0.01 compared with the HFC group. Data are expressed as the mean7s.e.m. for 10 samples per
treatment group.
J. Du et al. / Phytomedicine 16 (2009) 652658 655
that of humans (Kris-Etherton and Dietschy, 1997).
Since the effects of dietary cholesterol and fat on plasma
lipid proles are similar in hamsters and humans, and
the levels of serum lipids elevated in HFC group of
hamsters after fed high-fat/cholesterol diet for 15 d
compared with those observed in the control group (Fig.
2); therefore, this is a useful model for studying
hyperlipidaemias. Previous studies using the hamster
model also showed that animals consumed approxi-
mately the same amount of feed had no signicant
differences in their nal body and liver weights (Khor
and Chieng, 1996).
Polygonum cuspidatum is an important Chinese
medicine, which also proved to be safe and effective in
the treatment of liver injure (Xue, 2000; Wu and Lu,
2005). A unique feature of this study is that, to our
knowledge, this is the rst report on the effects of
polydatin extracted from RPC on the lipid prole of
hyperlipidemic hamsters. In the current study, treatment
with polydatin resulted in a marked reduction in the
serum levels of TC, TG, LDL-C, and a decrease in
hepatic TG concentration.
One possible mechanism for the above results could
be related to protective effects of polydatin on liver
(Browning and Horton, 2004). There was a possibility
that polydatin decreased serum cholesterol by inhibiting
cholesterol synthesis and affecting hepatic LDL-C
receptor activity with reference to the effects of
polydatin on hepatic Acyl-CoA (ACAT) inhibition,
such as the inhibition of the lipoprotein-secretion
and the stimulation of bile acid production. This
suggests the direct effect of polydatin on liver. ACAT
is the key enzyme that controls cholesterol esterication
(Windmueller and Spaeth, 1967). The primary location
of this enzyme is liver, although it is also found in
intestine, adrenal, ovary and aorta. Liver is the most
important organ for the intermediary metabolism of
lipids, which also manufactures cholesterol for normal
body functions.
ARTICLE IN PRESS
0
1
2
3
4
5
6
7
C
o
n
t
r
o
l
L
D
L
-
C

/

H
D
L
-
C
(
R
a
t
i
o
)
0
1
2
3
4
5
6
7
8
9
10
T
C

/

H
D
L
-
C
(
R
a
t
i
o
)
Polydatin (mg/kg)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0
C
o
n
t
r
o
l
Polydatin (mg/kg)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0
Fig. 3. Effects of polydatin on LDL-C/HDL-C and TC/HDL-C
ratios. Two indexes: LDL-C/HDL-C and TC/HDL-C are
shown. The concentrations of indexes in hamsters of the HFC
group were signicant difference compared with those in the
control group. (A) LDL-C/HDL-C ratios were signicantly
lower in the hamsters administrated with polydatin than the
hamsters in the HFC group. (B) TC/HDL-C ratios were
signicantly lower in the hamsters administrated with poly-
datin than the hamsters in the HFC group.
nn
po0.01
compared with the control group, *po0.05, **po0.01
compared with the HFC group. Data are expressed as the
mean7s.e.m. for 10 samples per treatment group.
0
0.5
1
1.5
2
2.5
3
3.5
C
o
n
t
r
o
l
H
e
p
a
t
i
c

T
G

(
m
m
o
l
/
L
)
Polydatin (mg/kg)
H
F
C
H
F
C
+
F
E
N
H
F
C
+
2
5
H
F
C
+
5
0
H
F
C
+
1
0
0

**
**
*
Fig. 4. Effects of polydatin on hepatic TG levels in hyperlipi-
demic hamsters. The concentration of hepatic TG is shown.
The concentration of hepatic TG in hamsters of the HFC
group was signicant difference compared with those in the
control group. Although the concentration of hepatic TG in
the hamsters treated with low dose of polydatin showed no
signicant difference compared with that of the hamsters fed
with single high-fat/high-cholesterol diet, it was signicant
lowered in the hamsters fed with middleand highdoses of
polydatin.
nn
po0.01compared with the control group,
*po0.05, **po0.01compared with the HFC group. Data are
expressed as the mean7s.e.m. for 10 samples per treatment
group.
J. Du et al. / Phytomedicine 16 (2009) 652658 656
Another possibility is that polydatin could circulate
the levels of lipoproteins. In blood, cholesterol and
triglycerides are complexed with protein and then
transported as lipoproteins, HDL, LDL and very low-
density lipoprotein (VLDL) (La-Du et al., 1993).
Oxidatively modied forms of LDL can be metabolized
and their atherogenicity could be inactivated by para-
oxonase-1 (PON1), an enzyme produced in liver
parenchymal cells and carried in plasma on HDL
(Mackness et al., 1991, 1993, 1998, 2001; Watson
et al., 1995; Leitinger et al., 1999). Although our study
did not nd that the concentration of HDL was
enhanced by polydatin in the hypercholesterolemic
hamsters compared with hamsters in the control group
(Fig. 2C), the LDL-C: HDL-C and TC: HDL-C ratios
were signicantly lowered (Fig. 4), which was agreed
with our design in terms of health benets. As the LDL-
C: HDL-C ratio might be positively correlated with the
risk of CHD even when total cholesterol concentration
is elevated (Kazi-Aoul and Benmiloud, 1987), and
TC:HDL-C ratio is a sensitive predictor of AS, so low
ratios in hamsters given polydatin suggested the anti-
atherogenic potential of polydatin. However, the lipid-
lowering action of polydatin is complex and warrants
further investigation in a clinical setting.
Polydatin, as a stilbene, potentially has antioxidant
activity, as do many polyphenols. Changes in LDL
properties by oxidation of polyunsaturated fatty acids
are believed to play a major role in atherosclerosis.
Oxidation affects the protein moiety (apoB) of LDL
particles, impairing LDL catabolism by the regulated
apoB/E receptor system. Therefore, the protective role
of foods rich in phenolic compounds has been attributed
to their antioxidant properties (Rice-Evans et al., 1997).
A signicant lipid-lowering effect of polydatin could be
due to its antioxidant effect.
Our study demonstrates a dose-dependent decrease in
cholesterol by polydatin. In a hypercholesterolemic
model of hamsters induced by a high-fat/cholesterol diet,
a high dose of polydatin (100mg kg
1
) decreased serum
and hepatic cholesterol close to normal levels with a
tendency of body weight reduction. Furthermore, even a
low dose of polydatin (25 mg kg
1
) inhibited body
cholesterol levels, with a tendency toward decreased
body weight. Greater effects on body weight could be
identied with a longer treatment period. These ndings
suggest that polydatin may be effective in the prevention
of hyperlipidaemias with the complication of adiposity.
To conclusion, polydatin isolated from RPC was
found to have pronounced lipid-lowering and cholester-
ol-lowering effects. The consumption of polydatin could
decrease the concentrations of serum TG, serum TC,
and hepatic TG. The above discussions suggested that
the lipid-lowering and cholesterol-lowering actions of
polydatin were attributed to its ability to protecting liver
and modulate lipid metabolism. Meanwhile, polydatin
could be used in the case of hypercholesterolemic
patients with the complication of adiposity, and it may
play an important role in the prevention of CHD and
AS. As the polydatin of large quantity extracted from
RPC is available with the developed methods, it is worth
exploiting polydatin as a promising lipid-lowering drug
to fulll the increasing demand.
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