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International Journal of Food Sciences and Nutrition,

2012; Early Online: 17

LDL cholesterol-lowering effects of grape extract used as a dietary


supplement on healthy volunteers

NOEMI YUBERO1, MARISA SANZ-BUENHOMBRE1, ALBERTO GUADARRAMA2,


N3, EIDER LARRARTE4, & CARLOS MORO2
SONIA VILLANUEVA2, JUAN M. CARRIO
1
Research and Development Department, Esdor Cosmeticos, Valladolid, Spain, 2Research and Development Department, Bodega
Matarromera, Valladolid, Spain, 3Chief of Service of Endocrinology and Nutrition, Hospital Nisa Pardo Aravaca, Madrid,
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Spain, and 4TECNALIA, Health Division, Parque Tecnologico de A lava, Minano, Spain

Abstract
The aim of this study was to evaluate the effects of Eminolw, the polyphenol-rich grape extract supplement (700 mg), on
cardiovascular risk and oxidant stress indicators in a sample of volunteers. A randomized, double-blind, placebo-controlled
clinical trial was performed over 56 days and included 60 volunteers. Thirty volunteers took 700 mg of the grape extract,
Eminolw (E), and 30 took the placebo (P). On comparison of the results, a decrease in total cholesterol (E: 213.77 ^ 4.1 mg/dl
and P: 245.57 ^ 4.1 mg/dl; p 0.01) and LDL cholesterol (E: 142.17 ^ 3.1 mg/dl and P: 165.13 ^ 3.1 mg/dl; p 0.02) levels
as well as an increase in antioxidant capacity (E: 65.63 ^ 5.8 mmol TE/mg and P: 57.80 ^ 7.7 mmol TE/mg; p , 0.01) and
vitamin E (E: 11.46 ^ 0.5 mg/ml and P: 9.06 ^ 0.5 mg/ml; p 0.018) was observed. This result indicates that the grape extract
For personal use only.

Eminolw modulated the lipid profile in terms of cardiovascular risk indicators, lowering total blood cholesterol and LDL
cholesterol levels.

Keywords: grape extract, polyphenols, cholesterol, LDL cholesterol, antioxidant capacity

Introduction
Polyphenols are component parts of the secondary 2010) and cardiovascular (Manach et al. 2005; Lecour
metabolism of vegetables. Most of them are potent and Lamont 2011; Wu and Hsieh 2011) diseases,
antioxidant substances, thanks to their ability to among others. So far, many studies have demonstrated
donate electrons, and thus to eliminate free radicals a relationship between the consumption of polyphe-
(Van Acker et al. 1995). In vitro studies have nols in the diet and various chronic pathologies such as
demonstrated that many polyphenols provide more cancer (Yang et al. 2001; Rajendran et al. 2011),
antioxidant power than vitamins E and C. Polyphenols diabetes (Bashmakov et al. 2011) and osteoporosis
are found in fruits and vegetables, for instance, apples, (Shen et al. 2008).
grapes and onions, and in beverages such as tea and Many studies have focused on cardiovascular
wine (Quideau et al. 2011), being therefore a common diseases since they are among those with the highest
constituent of the daily human diet. The polyphenols prevalence in developed countries and their incidence
ingested in the diet primarily belong to four families: is gradually increasing in developing countries. Several
flavonoids, phenolic acids, stilbenes and lignans epidemiological studies have shown that there is an
(Perez-Jimenez et al. 2010). inverse relationship between the intake of polyphenols,
Polyphenols are considered to contribute towards or food rich in polyphenols characteristic of the
the prevention of several illnesses such as degenerative Mediterranean diet, and the risk of suffering from
(Thomas et al. 2009), inflammatory (Sakurai et al. cardiovascular diseases (Mukamal et al. 2002;

Correspondence: Noem Yubero, Research and Development Department, Esdor Cosmeticos, S.L., Ctra. San Bernardo, s/n. Valbuena de
Duero 47359, Valladolid, Spain. Tel: 34 902430170. Fax: 34 302430189. E-mail: imasd@esdor.es

ISSN 0963-7486 print/ISSN 1465-3478 online q 2012 Informa UK, Ltd.


DOI: 10.3109/09637486.2012.753040
2 N. Yubero et al.

Mennen et al. 2004). Likewise, it has been observed amount of polyphenols in fresh grape skin, also
that moderate wine consumption may help to prevent showing the relationship between Eminolw and fresh
or even lower cardiovascular risk (Di Castelnuovo grape skin.
et al. 2002), probably due to the high polyphenol
content. This relationship between moderate wine
Nutritional information
consumption and benefits to cardiovascular health
has grown in significance since the discovery of the In order to find out the nutritional composition of
so-called French Paradox in the 1990s (Renaud and the grape extract, the main components of the extract
de Lorgeril 1992). were calculated using the following methods:
However, most studies just consider the presence
of a limited number of polyphenols representing the . Water: internal method based on method number
wide range of molecules found in the diet (Neveu 731 Loss on Drying United States Pharmacopeia
et al. 2010; Perez-Jimenez et al. 2010). The results of (USP) 34.
these studies on volunteers have not always indicated . Sodium: internal method based on method number
a reduction in cardiovascular risk or a decrease in 851 Spectrophotometry and Light-scattering
target variables such as LDL cholesterol or total United States Pharmacopeia (USP) 34.
cholesterol (Boots et al. 2008). . Calcium: internal method based on method number
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In this study, the lowering effect of grape 851 Spectrophotometry and Light-scattering
polyphenols used as a dietary supplement on LDL United States Pharmacopeia (USP) 34.
cholesterol levels is assessed in a sample of healthy . Vitamin A: internal method based on method
volunteers. The grape extract Eminolw comes from number 621 Chromatography United States
grape skin after the vinification process. During red Pharmacopeia (USP) 34.
wine production, some of the polyphenols contained . Vitamin C: internal method based on method
in the grape pass into the wine, nevertheless, some are number 621 Chromatography United States
held in the skin, which can be used afterwards. Pharmacopeia (USP) 34.
To further evaluate the benefits of Eminolw grape
For personal use only.

extract, a sample of healthy individuals was given either


Clinical trials with volunteers
Eminolw or a placebo, both by oral administration,
in order to assess the primary variables involved in Individuals. A sample of 60 healthy volunteers aged
the risk of developing cardiovascular diseases. between 34 and 65 was studied. It was a representative
population of healthy men and women with normal
lifestyles and diets.
Materials and methods
The main recruitment criteria were as follows:
Grape extract appropriate cultural level and understanding of the
clinical study; body mass index (BMI) of between 19
The grape extract used in this trial was obtained from
and 30 kg/m2; not having taken any hypolipidaemic
grape pomace. This extract, registered as Eminolw,
drugs or any other medicines to treat hypercholester-
was obtained by means of a unique and new system
olaemia for 4 weeks prior to the start of the trial; LDL
developed and patented by Grupo Matarromera
cholesterol level of between 130 and 190 mg/dl, in the
(ES 2 309 032). The extract comes 100% from
event two or more cardiovascular risk factors are
the red grape Vitis vinifera variety Tempranillo,
detected, LDL cholesterol level of between 100 and
harvested from vineyards located in the central region
190 mg/dl; triglyceride level no higher than 350 mg/dl;
of Spain, specifically the Ribera de Duero Designation
not having presented any cardiovascular ischaemic
of Origin, in Castile and Leon.
events within the last 6 months; in women, not being
The composition of the grape extract Eminolw is
pregnant or lactating; not presenting hypersensitivity
included in Table I, and it is compared with the same
to any of the product components of the trial; not
having taken part in any other clinical trial for the
3 months prior to the start of the study.
Table I. Grape extract. Polyphenols characterized in Eminolw.
During the study period, volunteers were given a
Polyphenolic Eminolw Fresh grape Eminolw/grape typical Mediterranean diet.
compounds (mg/g) skin (mg/g) skin ratio

Total flavonols 2.61 0.636 4


Study design. An exploratory, randomized, double-
Myricetin 1.23 0.153 8 blind, placebo-controlled, parallel-group, clinical-
Quercetin 1.40 0.155 9 nutritional study was conducted in order to assess
Catechin 2.34 0.0128 183 the health properties and tolerability of the
Epicatechin 0.77 0.0154 50 polyphenolic extract Eminolw on different
Epigallocatechin 1.63 0.0075 217
Catechin gallate 0.11 0.0096 11
cardiovascular risk and oxidative stress indicators by
Ellagic acid 2.42 using a sample of healthy volunteers during an
experimental period of 56 days (8 weeks).
LDL cholesterol-effects of grape extract 3

All volunteers received verbal and written infor- . GGT: Gamma-glutamyl transferase (g-GT) levels
mation about the nature and purpose of the study, were determined using a commercially available
and all of them gave written consent for participation. kit: quantitative determination of gGT In Vitro
This study was undertaken in accordance with Diagnostic IVD, Ref. MI41288, from Spinreact
the Helsinki II declaration and was approved by the following manufacturers instructions.
Ethical Committee at Hospital Universitario Puerta de . GOTand GPT: The glutamic transaminase enzymes,
Hierro (Majadahonda-Madrid) on 24 March 2010. serum glutamic-oxalacetic (GOT) and serum
The promoter of this study was Grupo Matarromera glutamic-pyruvic (GPT) levels were determined
and the trial was performed under the scientific using a commercially available kit: quantitative deter-
co-ordination of doctors Juan Manuel Carrion Pastor mination of transaminases GOT and GPT IVD,
and Eider Larrarte Lazaro. Ref. 1001165 (GOT) & Ref. 1001175 (GPT) from
Volunteers were randomized into two groups, and Spinreact following manufacturers instructions.
each was given either a 700 mg Eminolw supplement
(two Esdor capsules of 350 mg) or 700 mg of placebo Plasma cholesterol levels: total cholesterol, Low Density
(two maltodextrin capsules of 350 mg). Both products Lipoprotein LDL cholesterol, High Density Lipoprotein
were supplied in 350 mg capsule form, and volunters HDL cholesterol and LDL/HDL ratio.
were instructed to take two capsules at breakfast over
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the 56 days. . Cholesterol: Plasma cholesterol levels were calculated


Volunteers filled in a questionnaire on their dietary using a commercially available kit: quantitativedeter-
habits and various parameters related to cholesterol mination of cholesterol IVD from SPINREACT
and antioxidant capacity were recorded before starting following manufacturers instructions.
the trial (T0), after 28 days (T28) and after 56 days . LDL cholesterol: Plasma LDL cholesterol levels
(T56). During the clinical trial, neither the volunteer, were calculated using a commercially available kit:
nor the researcher knew the type of supplement quantitative determination of LDL cholesterol
administered to the volunteer. IVD from SPINREACT following manufacturers
instructions.
Sample collection and analyses of endogenous parameters . HDL cholesterol: Plasma HDL cholesterol levels
For personal use only.

were calculated using a commercially available kit:


Sample collection. Blood samples were extracted from
quantitative determination of HDL cholesterol
volunteers and collected in the initial visit (T0), after
IVD from SPINREACT following manufacturers
28 days or the intermediate visit (T28) and after
instructions.
56 days or the final visit (T56) in order to analyse the
various endogenous parameters.
Data analysis

Analyses The sample size was calculated to detect differences


in cholesterol levels after treatment with 700 mg of
Biomarkers of antioxidant status and oxidative stress. Eminolw.
Intra-group time variations in the parameters were
. Oxygen radical absorbance capacity (ORAC): The analysed by applying a generalized linear model for
plasma antioxidant capacity was determined by repeated measurements. As for inter-group variations,
means of the commercial fluorescence method a Students t-test was carried out. In every hypothesis
called OxiSelecte Oxygen Radical Antioxidant testing process, when the p value was lower than 0.05,
Capacity (ORAC) Activity Assay (Catalogue significant differences were considered.
Number STA-345) from Cell Biolabs, following
manufacturers instructions.
. LDL oxidation: Anti-oxLDL autoantibodies were Results
determined using a commercially available ELISA
Nutritional information
kit (Biomedica, Vienna, Austria).
. Vitamin E: Plasma vitamin E levels were deter- Nutritional information is given in Table II. Energy
mined using a reagent kit for the HPLC analysis of intake from the recommended daily dose of Eminolw
vitamins A and E in serum/plasma from Chrom- (700 mg/day) is just 2.97 kcal. The composition of
Systems following manufacturers instructions. the Eminolw grape extract shows extremely high
. Ascorbic acid: Plasma vitamin C levels were deter- amounts of calcium (3.06 mg/700 mg) and dietary
mined using a commercially available Ascorbate fibre (0.13 g/700 mg).
Assay kit item num. 700420 from Cayman Chemical
Company following manufacturers instructions.
Clinical-nutritional trial
. Tumoral necrosis factor (TNF-a): Anti-TNF-a anti-
bodies were determined using a commercially avai- Of the 60 volunteers who participated in this study,
lable ELISA kit (R&D systems, Inc., Minneapolis, 29 were men and 31 were women aged between 34
MN, USA) and 64 (mean age 51 ^ 7 years old). No significant
4 N. Yubero et al.

Table II. Nutritional information for Eminolw grape extract and Furthermore, and in accordance with the anti-
grapes. oxidant activity of the polyphenols contained in the
Nutritional Per 100 g Per daily dose Per 100 g grape extract Eminolw, the plasma antioxidant
information of Eminolw (two capsules) of grape(31) capacity (ORAC) and the blood levels of vitamin E
increased during treatment with the grape extract
Energy 320.92 kcal 2.97 kcal 6767.1 kcal
(1341.45 kJ) (12.42 kJ) (280 kJ) Eminolw, comparing T0 with T56, and with the
Carbohydrates 58.32 g 0.54 g 1516 g volunteers who took the placebo (Table III).
Sugars 4.12 g 0.038 g 1516 g The evolution of the LDL cholesterol/HDL
Total polyphenols 13 g 0.12 g 0.130 0.154 g(32) cholesterol ratio decreased (T0: 3.84 ^ 0.16 mg/dl;
Proteins 0.29 g 0.003 g 0.60.7 g
Fats 2g 0.02 g 0.60.7 g
T56: 3.08 ^ 0.14 mg/dl) whereas the HDL choles-
Dietary fibre 13.57 g 0.13 g 0.4 g terol levels increased (T0: 44.23 ^ 1.60 mg/dl; T56:
Water 4.8 g 0.04 g 8183.2 g 47.10 ^ 1.60 mg/dl) among the volunteers who took
Sodium 12.9 mg 0.12 mg 2 mg 700 mg of the grape extract Eminolw, comparing
Calcium 331 mg 3.06 mg 4 mg
Vitamin C ,5 mg ,0.05 mg 4 mg
T0 with T56 where a significant difference was
Vitamin A ,25 mg ,0.23 mg 3 10 mEq noted. Nevertheless, there was no significant differ-
ence when comparison was made with the group who
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took the placebo.


differences were found between treatments and age
( p 0.971).
A descriptive analysis of the basal variables was Table III. Results from the clinical trial on variables related to lipid
carried out, calculating the mean and the standard profile, oxidative stress and inflammation.
deviation for the quantitative variables and performing
Eminolw Placebo
a frequency analysis for the qualitative variables. P between
As demonstrated in Table III, at the beginning of Average Error Average Error groups
the trial no significant differences were found between
Total cholesterol P 0.01
the group of volunteers who took the grape extract
T0 247.43 5.05 252.63 5.05
For personal use only.

Eminolw (two capsules of 350 mg) and the group who T28 232.83 4.60 245.83 4.60
took the placebo with regard to antioxidant capacity T56 213.77 4.07 245.58 4.07
and oxidative stress parameters or biomarkers, such as LDL cholesterol P 0.02
total cholesterol, LDL cholesterol, HDL cholesterol, T0 166.67 3.76 168.40 3.76
T28 154.93 3.51 164.93 3.51
oxidized LDL, plasma antioxidant capacity and T56 142.17 3.12 165.13 3.12
vitamins C and E blood levels. These data confirmed LDL oxidation P 0.06
the homogeneous distribution of the individuals T0 54.69 1.92 56.42 1.92
included in the study. T28 51.41 1.85 55.91 1.85
T56 47.23 1.65 55.38 1.65
After 56 days of intake, the volunteers who took ORAC P , 0.01
700 mg of the grape extract Eminolw presented a signifi- T0 51.23 4.80 56.70 7.71
cantly lower total cholesterol level (213.77 ^ T28 61.10 5.05 57.93 7.74
4.07 mg/dl) compared with the volunteers who took T56 65.63 5.79 57.80 7.71
Vitamin E P 0.018
the placebo (245.57 ^ 4.07 mg/dl), with a significance
T0 9.87 0.44 9.00 0.44
level of p 0.01. Moreover, the decrease in total T28 10.41 0.46 9.05 0.46
cholesterol level was also significant for the volunteers T56 11.46 0.46 9.06 0.46
who consumed the grape extract Eminolw, comparing Vitamin C P negligible
the first visit (T0 247.43 ^ 5.05 mg/dl) and the last T0 9.80 0.41 9.65 0.41
T28 9.88 0.40 9.63 0.40
visit (T56 213.77 ^ 4.07 mg/dl). T56 10.13 0.41 9.64 0.41
With regard to the previous result, LDL LDL/HDL ratio P 0.243
cholesterol levels and oxidized LDL levels also T0 3.84 0.16 3.81 0.16
decreased, as observed in Table III. In the case T28 3.56 0.15 3.70 0.15
T56 3.08 0.14 3.70 0.14
of LDL cholesterol, this decrease was statistically HDL cholesterol P 0.599
significant when comparing the volunteers who T0 44.23 1.60 46.27 1.60
took 700 mg of the grape extract Eminolw T28 44.73 1.60 46.70 1.60
(142.17 ^ 3.1 mg/dl) with the volunteers who took T56 47.10 1.60 46.67 1.60
TNF-a P negligible
the placebo (165.13 ^ 3.1 mg/dl), with a significance
T0 4.63 0.24 4.83 0.24
level of p 0.02. Moreover, it was also observed T28 4.54 0.24 4.86 0.24
that the decrease in LDL cholesterol was statistically T56 4.51 0.24 4.87 0.24
significant when comparing the values from the Fasting glucose P negligible
T0 93.13 2.50 90.27 2.32
first day of Eminolw grape extract consumption (T0:
T28 93.60 2.71 90.27 2.30
54.68 ^ 1.9 mg/dl) with the values from the last day, T56 92.63 2.68 89.70 2.28
after 2 months of treatment (T56: 47.23 ^ 1.6 mg/dl).
LDL cholesterol-effects of grape extract 5

Table IV. Results from the clinical trial on weight, percentage of With regard to the clinical trial carried out to
body fat and BMI. evaluate the health properties of the grape extract
Eminolw Placebo Eminolw on human health, the results of the study
showed that consuming the grape extract Eminolw
Average Error Average Error over a period of 56 days led to a statistically significant
Weight
decrease in total cholesterol, LDL cholesterol and
T0 73.62 1.54 72.93 1.54 oxidized LDL cholesterol concentrations in plasma,
T28 73.49 1.53 72.83 1.53 which are the main metabolic variables indicating
T56 73.40 1.53 72.66 1.53 cardiovascular risk. This reduction in total cholesterol
% Body fat and LDL cholesterol levels was very likely due to the
T0 23.60 0.71 23.57 0.71
T28 23.51 0.71 23.47 0.71
action mechanisms of polyphenols found in the
T56 23.38 0.70 23.30 0.70 polyphenolic extract which include the inhibition of
BMI the specific uptake/transporters for cholesterol, such as
T0 26.92 0.39 26.46 0.39 Niemann-Pick C1 Like 1 cholesterol transporter
T28 26.90 0.39 26.45 0.39 (Leifert and Abeywardena 2008).
T56 26.86 0.39 26.40 0.39
The decrease in cholesterol levels through the
administration of grape polyphenols had already been
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demonstrated both in works with cellular models and


In the case of other variables such as fasting glucose animals (Leifert and Abeywardena 2008; Ikeda et al.
or TNF-a, no significant differences were found bet- 2010; Peluzio Mdo et al. 2011). Hence, evidence
ween the trial groups (Eminolw vs. placebo) (Table III). already existed relating to the reduction in the risk of
Regarding weight, body fat percentage or BMI, suffering from cardiovascular diseases and the intake
no significant differences between the groups were of antioxidants, specifically polyphenols, which are
found either; including the volunteers in the protocol considered to be cardio-protective elements (Zern and
obviously did not modify their total calorie intake Fernandez 2005). However, effects on cardiovascular
(Table IV). risk factors had not always been observed in clinical
Finally, from the results obtained it is worth noting
For personal use only.

trials (Hansen et al. 2005). This fact should be applied


that there were no significant differences in terms of to both the origin and the composition of the
safety variables when comparing the groups who took polyphenolic extract from the grape. Thus, it was
or did not take the grape extract Eminolw and widely known that moderate variations may be seen in
comparing the beginning (T0) and the end (T56) of the polyphenolic composition and content of grapes
the treatment. The safety variables analysed were depending on the crop, as well as influence from the
creatine and transaminases (GPT, GGT and GOT) geographical location and the climatic conditions
levels (Table V). (Rathel et al. 2007; Preedy et al. 2011). Our study
proves that the extracted and concentrated polyphe-
nols in the grape extract Eminolw, found in the skin of
Discussion grapes cultivated in central Spain, in the Ribera del
This study comprises a clinical trial that has been Duero Designation of Origin, have the capacity of
performed in order to assess the effect of the grape lowering total cholesterol, LDL cholesterol and
extract Eminolw on human health, mainly on lowering oxidized LDL cholesterol levels. On the other hand,
the total cholesterol and LDL cholesterol. the results presented in the INTERHEART study
support the theory stating that the antioxidants
consumed in a normal diet protect against coronary
Table V. Results from the clinical trial on creatine and
diseases (Yusuf et al. 2004) and, therefore, the
transaminases (GPT, GGT and GOT).
consumption of complex blends of antioxidants
Eminolw Placebo found in vegetables may probably be more beneficial
than the ingestion of large doses of only one
Average Error Average Error
antioxidant (Boots et al. 2008; Khan et al. 2011).
GPT Oxidized low-density lipoproteins, atherogenic
T0 14.78 0.75 15.70 1.03 lipoproteins that play an important role in pro-
T28 15.00 0.75 15.80 1.05 inflammatory reactions, are key elements in the
T56 15.15 0.76 16.03 1.07
GGT
atherosclerosis development process (Khan et al.
T0 17.63 0.88 16.73 0.97 2011). This is due to the fact that they are particles
T28 17.47 0.91 16.83 1.01 that favour the response of macrophages in the arteries
T56 17.77 0.95 17.07 1.03 and thus promote atherosclerosis processes (Fraley
GOT and Tsimikas 2006). Our results showed a statistically
T0 15.20 0.68 15.90 0.91
T28 15.28 0.70 15.93 0.94
significant decrease in the plasma oxidized LDL
T56 15.57 0.72 16.13 0.96 cholesterol concentration in the volunteers who took
the grape extract Eminolw compared with those who
6 N. Yubero et al.

took the placebo. This reduction in plasma-oxidized influence on antioxidant stress indicators, increasing
LDL cholesterol could be explained by the fact that the antioxidant capacity in plasma and vitamin E
some ingested polyphenols may combine with LDL levels.
cholesterol particles in the plasma, thus preventing
their oxidation (Rios et al. 2003).
Moreover, the results of the study proved a trend in Acknowledgements
the significance that a bigger n would probably be This research has been carried out within the
significant in the plasma HDL cholesterol concen- framework of the project (SENIFOOD-Industrial
tration on the volunteers who took the grape extract research on diets and foods with specific character-
Eminolw. The intra-group difference was statistically istics for older people) funded by the CDTI, Ministry
significant; however, the inter-group difference was of Economy and Competitiveness (Spain). We thank
not statistically significant. HDL cholesterol has an the Ministry of Agriculture and Livestock of the
anti-inflammatory function, so an increase in the HDL Autonomous Government of Castile and Leon for
cholesterol and a decrease in the plasma LDL the funding awarded to develop the previous studies.
cholesterol would favour the inhibition of atheroma- We also thank Quantum Experimental for coordi-
tous plaque formation. The increase in HDL nating the study, and Hospital Txagorritxu (Vitoria-
cholesterol due to polyphenol intake has been widely Spain) and Hospital Puerta de Hierro (Madrid-Spain)
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described (Ohtsuki et al. 2003). Hence, it is well for participating in the study.
known that polyphenols, such as genistein, can
increase the expression of the main protein component Declaration of interest: The authors report no
of HDL, apolipoprotein A1, on rats (Lamon-Fava conflicts of interest. The authors alone are responsible
2000). So, the flavonoids contained in the grape for the content and writing of the paper.
extract Eminolw were supposed to be absorbed and a
slight upward trend was observed in the HDL
cholesterol levels from the beginning of the adminis- References
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LDL cholesterol-effects of grape extract 7

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