84 The Open Complementary Medicine Journal, 2009, 1, 84-91 Open Access Hypolipidemic Activity of Extracts from Eriobotrya japonica and Olea europaea, Traditionally Used in the Greco-Arab Medicine in Maintaining Healthy Fat Levels in the Blood
Omar Said1,2,*, Bashar Saad2, 3, Stephen Fulder1, Riyad Amin5, Eli Kassis4 and Khaled Khalil1
1 Antaki Center for Herbal Medicine Ltd. Kfar Kana 16930, P.O. Box 2205 Israel 2Research and Development Regional Center - The Galilee Society, P.O. Box 437, Shefa Amr 20200, Israel; and Qasemi Research Center- Al-Qasemi Academic College, Baga Algharbiya, Israel 3 Faculty of Arts and Sciences, Arab American University Jenin, P.O. Box 240, Jenin, Palestine 4 Sprunk-Jansen, A/S Strandvejen 100, 2900 Hellerup Denmark 5 Department of Biochemstry and Molecular Biology, Alquds University - Palestine Abstract: Loquat (Eriobotrya japonica) and olive leaves (Olea europaea) were investigated for their safety, anti-oxidant, and anti-hypercholesterolemic properties. Therefore, a fixed combination of dry extracts of Eriobotrya japonica and Olea europaea was prepared into so called Cholevel tablets and tested for safety and efficacy in vitro and in vivo tests. No sign of toxicity (LDH-release) was observed in cultured human fibroblasts incubated with increasing concentrations of Cholevel. Similar results were seen in MTT assay in co-cultures of human hepatocytes and monocytes. In addition, a high level of safety was seen in rats with an LD50 of 17.3 g/kg. The extent of Lipid peroxidation in isolated human LDL frac- tions, rat liver homogenates, and ferrosulphate was substantial at low concentrations of Cholevel. Hypolipidemic proper- ties were assessed in a double blinded- randomized clinical study carried out among 41 human volunteers with hyperlipi- demia values. The volunteers were divided into three groups. They were asked to continue their usual diet and medica- tions unchanged and were evaluated for efficacy and tolerability of Cholevel for 3 months. Group 1 included 12 of per- sons who were at a fixed dose of statins therapy without fully responding to their medications they consumed Cholevel tablets 1 x 3 daily. Group 2 included 20 volunteers who consumed only Cholevel tablets 1 x 3 daily. Group 3 (control group) included 9 volunteers who consumed placebo tablets 1 x 3 daily. Cholevel was well tolerated by all subjects and no side effects were reported. Cholesterol levels were significantly reduced in groups 1 and 2 by 24% and 14.3% after three months of Cholevel consumption, respectively. Parallel reductions in both LDL and triglycerides levels and increments in HDL levels were observed. Taken together, results demonstrate safety, tolerability and efficacy of Cholevel that seems to have dual inhibition on both the absorption and production of cholesterol. Keywords:Eriobotrya japonica, olea europaea, cholevel, cholesterol, Greco-Arab medicine. INTRODUCTION
Atherogenesis is a multifactor process that includes oxi-
dative modification of LDL which triggers pathological
Hypercholesterolemia is often associated with obesity,
events through multiple pathways leading to atherosclerosis
diabetes mellitus and hypertension, each and all contribute to
. Research in recent years has been directed towards die-
elevated cardiovascular mortality . There is a general con-
tary antioxidants of plant-derived foods to normalize the
sensus that these metabolic disorders share hyperinsulinemia
augmented levels of cholesterol atherogenous fractions,
and insulin resistance as a common link [2,3] leading to both
mainly LDL, and of glucose in an attempt to reduce the car-
micro- and macro-angiopathies . During the last two dec-
ades, statins have been in clinical use as selective inhibitors of the key enzyme, Hydroxymethylglutaryl Coenzyme-A
Greco-Arab Herbal Medicines: Based on scientific and
(HMG-CoA)-reductase that determines the rate of choles-
traditional knowledge, there is little doubt that the concept of
terol synthesis in hepatocytes. In population studies, statins
Greco-Arab and Islamic herbal medicinal therapy has shown
have been evidenced to reduce cholesterol levels by about
remarkable success in healing acute as well as chronic dis-
25% and mortality due to myocardial infarction by about
eases. According to recent surveys, there are about 350-450
medicinal plants in the Eastern region of the Mediterranean
and about 230 medicinal plants in coastal Mediterranean region in Egypt. These plants are used by healers for the
*Address correspondence to this author at the Antaki Center For Herbal Medicine and R&D Center, The Galilee Society, P.O.Box: 2205, Kufur-
treatment and preventions of almost all types of human dis-
kana 16930, Israel; Tel: +972-4-6412712/015; Fax: +972-4-6412713;
eases, such as cancer; skin, respiratory, digestive, liver dis-
E-mails: firstname.lastname@example.org; email@example.com
1876-391X/09 2009 Bentham Open Hypolipidemic Activity of Extracts from Eriobotrya japonica The Open Complementary Medicine Journal, 2009, Volume 1 85
eases; diabetes; and others. These plants are sold or traded in
1% glutamine, 100 U/mL penicillin, and 10 g/mL strepto-
market places in the Mediterranean region or internationally.
mycin. Cells were maintained in humidified atmosphere with
In many cases plant extracts are prepared into a mixture
5% CO2 at 37°C. The medium of cells from both cell lines
[9,10]. Several plant species have been investigated and bio-
was changed twice a week. At 70-80% confluence, cells
active ingredients extracted to treat various human diseases.
were trypsinized and seeded in 96-well plates in cell density
Plant parts used included leaves, flowers, stems, roots, seeds,
of 1.5 x 104 HepG2 cells and 5 x 103 THP1 cells. Twenty
four hours after cell seeding cells were exposed to various concentrations of the plant extracts in fresh serum-free me-
Olive and Loquat: Recent data have evidenced anti-
atherogenic and antioxidant activities of extracts from leaves from both olive  and loquat .
MTT Assay: The tetrazolium dye, MTT, is widely used
The safety of both herbs used in the present study is
to assess the viability and/or the metabolic state of the cells
documented by their use in traditional Greco-Arab medicine
[28,29]. This colorimetric assay is based on the conversion
through centuries [11,14]. The leaves of loquat are well
of the yellow tetrazolium bromide (MTT) to the red forma-
known and safe household remedy especially in the Far 
zan derivative by mitochondrial succinate dehydrogenase in
and Middle East . Extracts from these leaves have been
viable cells. Twenty four hours after cell seeding, cells were
reported to exhibit a significant hypoglycaemic effect both in
incubated with varying concentrations Cholevel for 24 hours
Italy [16-18] and Pakistan . They were also reported to
at 37°C. Following the removal of the media from each well,
have antiviral , antitumour effects  and to exhibit
cells were washed in phosphate buffered saline. The cells
cytotoxic effects against tumour cell lines but not against
were then incubated in serum free DMEM to which MTT
normal cells . Moreover, they have been evidenced as
(0.5 mg/mL) was added to each well (100 L), and incubated
potent natural antioxidants [13,22]. In all these scientific
for a further four hours. Then the medium was removed and
publications, no evidence of any adverse effects of loquat
the cells were incubated for 15 minutes with 100L of acidic
leaf extracts has been indicated. On the contrary, liver pro-
isopropanol (0.08 N HCl) to dissolve the formazan crystals.
tective effects of seed's extracts have been evidenced in ani-
The absorbance of the MTT formazan was determined at 570
mals . As for safety of olive leaf extracts, it has been
nm in an ELISA-reader. Viability was defined as the ratio
widely documented both in Europe [4, 12, 24-27] and in the
(expressed as a percentage) of absorbance of treated cells to
Middle East  and their anti-atherogenic, antioxidant and
antidiabetic properties have been evidenced both in Germany  and France .
Lactate Dehydrogenase:In the Lactate dehydrogenase
(LDH) assay the leakage of the cytoplasm located enzyme
The present study aimed at investigating the safety and
LDH into the extracellular medium is measured. The pres-
efficacy of a fixed mixture of both olive and loquat leaves.
ence of the exclusively cytosolic enzyme, LDH, in the cell
Safety studies were carried out in animals and in vitro whereas therapeutic efficacy was evaluated in human volun-
culture medium is indicative of cell membrane damage
teers. The study was undertaken in accord with legal and
ethical requirements as well as current scientific standards as
For the LDH assay, 1.5 x 104 HepG2 cells and 5 x 103
indicated by European Good Clinical Practice Guidelines
THP1 were seeded per well of 96-microtiter plates. Twenty-
four hour after cell seeding, cells were exposed to varying
MATERIAL AND METHODS
concentrations of the Cholevel. After 24h of treatment, the supernatants were collected from each well. Cell monolayers
Preparation of Cholevel: The leaves of loquat and olive
were then treated with a cell lysis solution for 30 minutes at
were collected from the Galilee region, dried under shade
room temperature to lyse. The cells and the lysate were col-
and powdered to a fine grade as extracts by Antaki Ltd.-
lected. LDH activity was measured in both the supernatants
laboratories, Kfar Cana, Israel. Cholevel (310 mg/tablet)
and the cell lysate fractions by using CytoTox 96 a nonra-
were prepared at Karmat Micro Encapsulation laboratories,
dioactive cytotoxicity assay kit (Promega, WI, USA) in ac-
Kibbutz Ramot Menashe, Israel. Each tablet contained 98mg
cordance with the manufacturer’s instruction. The intensity
loquat, 56mg olive,7 mg Vitamin C, 2 mg Vitamin E, and
of the color is proportional to LDH activity. The absorbance
is determined at 490 nm with 96-well plate ELISA reader.
The percent of LDH release from the cells was determined using the formula: LDH release = (Absorbance of the super-
Cell Culture:The effects of Cholevel on cell viability
was assessed in a cell culture system using cells from the
natant)/ (absorbance of the supernatant and cell lysate)*100.
mouse fibroblast cell line (3T3), the human hepatoplastoma
Determination of LD
cell line HepG2, and from the human monocyte cell line
THP1. HepG2 cell line retains differentiated parenchymal
Thirty-six male Sprague Dawley rats (average weight:
functions of normal hepatocytes, including the expression of
148 ± 16g) were divided into 4 groups. Large single doses of
P450 isoenzymes, thus permitting long-term studies to be
Cholevel were placed directly into the stomach of each group
performed. The cells from both cell lines were grown in Dul-
and observed for 14 days to determine the LD50. Animal
becco’s modified Eagle’s medium (DMEM) with a high
study approval was given from the Faculty of medical
glucose content (4.5 g/L) supplemented with 10% vol/vol
inactivated fetal calf serum, 1% nonessential amino acids,
86 The Open Complementary Medicine Journal, 2009, Volume 1 Said et al.
Fig. (1). MTT Assay in co-culture of HepG2 & THP1 cells after an overnight incubation with 10 μg and 100 μg Cholevel/mL. The absor- bance of the MTT formazan was determined at 570 nm in an ELISA reader. Cell viability was defined as the ratio (expressed as a percent- age) of absorbance of treated cells to untreated cells. Values given represent the mean ± standard deviations of three independent experi- ments carried out in triplicates. Oxidative Stress
general physician in five clinics in Galilee if they were moti-vated to take herbal supplements to maintain a healthy fat
Rat liver homogenates and human blood LDL fractions
level in the blood. Forty one human volunteers were chosen
were used to assess antioxidant effects of Cholevel.
carefully on the base of close hyperlipidemaia values and
Oxidative stress leads to generation of reactive oxygen
species (ROS) which play an important pathogenetic role in
Group 1: Included 12 volunteers who were at a fixed
different disease-states. Lipid peroxidation has damaging
dose of statins therapy but without therapeutically efficiency.
effects on liver cell membrane. The extent of lipid peroxida-
Volunteers continued their usual diet and medications un-
tion was measured using a technique based on the thiobarbi-
changed and consumed Cholevel tablets 1 x 3 daily for 3
turic acid reactive substances (TBARS) assay that detects
malondialdehyde (MDA), an end product of peroxidative decomposition of polyionic fatty acids in in-vitro systems.
Group 2: Included 20 volunteers who consumed only
To accurately quantify TBARS in the analytical procedure,
Cholevel tablets 1 x 3 daily for 3 months.
the protein was precipitated before the addition of thiobarbi-
Group 3: Included 9 volunteers who consumed placebo
turic acid to the reaction, while the antioxidant butylated
tablets 1 x 3 daily for 3 months. This group served as con-
hydroxytoluene was added before the heating of samples.
Rat Liver Homogenates: Rat liver homogenates were in-
After a thorough review of Cholevel-components, they
cubated with 100 μM FeSO4 as ROS generating system 
were asked to continue their daily activities and food habits
and with various concentrations of the product.
unchanged. An informed consent was obtained from each
Human Blood LDL Oxidation: Blood samples were col-
subject who was given a free of charge box containing 90
lected, into vacutainer tubes containing EDTA (1 g/L blood),
from normocholesterolemic adult volunteers, and centrifuged
At baseline, fasting cholesterol levels were estimated for
at 4°C (833 x g for 10 min) to isolate plasma. The LDL frac-
every subject who was scheduled for the next visit on 4
tion was isolated by ultracentrifugation through a KBr dis-
weeks and was asked to return the Cholevel box so that re-
continuous gradient and collected as the fraction floating at a
turned tablets could be counted as the only measure of pa-
density of 1.019–1.063 kg/L (1, 2). A rapid filtration through
tient compliance with the protocol. This was repeated during
disposable desalting columns was needed to remove the
each of the 3 consequent visits when fasting cholesterol lev-
EDTA, and LDL protein was measured by the method of
els were estimated and careful investigations of well being
Lowry et al.,  on the same day using bovine serum albu-
and of any adverse effect were undertaken.
min as the standard. Filtered LDL was immediately used for oxidation experiments.
Statistics Clinical Investigations
The Wilcoxon signed-rank test was used. Comparisons
between groups were performed by the Wilcoxon rank-sum
Selection of Volunteers and Clinical Protocol:Human
test. A 0.05 level of significance was set. Data obtained were
volunteers were selected on the basis of routine visits to their
expressed as mean ± standard error of mean (SEM).
Hypolipidemic Activity of Extracts from Eriobotrya japonica The Open Complementary Medicine Journal, 2009, Volume 1 87 Fig. (2). LDH-release in arbitrary units from cultured human fibroblasts at baseline (0) and during incubating the fibroblasts with 180 and 360 μg Cholevel/ml for 24, 48, and 72 hours. Values given represent the mean ± standard deviations of three independent experiments car- ried out in triplicates. Efficacy of Cholevel Safety of Cholevel Lipid Peroxidation: Lipid peroxidation induced by incu-
bating rat liver homogenates with ferrosulphate is expressed
LD50 in Rats: An extremely high dose of the Cholevel
in Fig. (3A) as the extent of MDA production. The addition
(17.3 g/kg) was necessary to obtain the LD50 value in rats.
of very low dose of the Cholevel (10 μg/ml) to the medium
In Vitro Cytotoxicity Assessments: MTT and LDH as-
significantly reduced MDA-release from 0.88 ±0.10 to 0.62
says were carried out with fibroblast cell line (3T3) and co-
± 0.05 nm/mg protein (p ‹ 0.01). Higher concentrations of
cultures of human hepatoplastoma cell line HepG2 and cells
the Cholevel (50 μg/ml) further reduced MDA release to
from the human monocyte cell line THP1. HepG2 cell line
0.32 ±0.03 nm/mg protein (p ‹ 0.001). No further antioxida-
retains differentiated parenchymal functions of normal hepa-
tive effects were seen by increasing Cholevel concentration
tocytes, including the expression of P450 isoenzymes thus
up to 100 μg/ml (Fig. 3A).
permitting long-term studies to be performed.
LDL Oxidation:In vitro inhibition of human LDL oxida- MTT Test: The metabolic activity can be evaluated by
tion by Cholevel in the presence of ferrosulphate is ex-
measuring the activity of a mitochondrial enzyme succinate
pressed in Fig. (3B) as the extent of MDA formation.
dehydrogenase using the MTT test. This test is widely used
Cholevel at low concentrations of 50, 100 and 400 μg/ml
in the in vitro evaluation of the toxicity of plant extracts. We
significantly inhibited the LDL oxidation and reduced the
applied the MTT test to evaluate the safety of Cholevel.
levels of MDA from 21 ± 3 to 15 ± 2, 12 ± 1.7 and 8 ± 1.5
Cells were exposed to 10 μg Cholevel/mL and 100 μg
Cholevel/mL of culture medium for 24h. No sign of any
Clinical Studies: Forty one human volunteers were re-
negative effects were observed after treatment with the two
cruited into the study, 12 of them were already on a fixed
concentrations (Fig. 1).
dose of statins therapy. All 41 subjects were evaluated for
LDH-Release Test: Membrane integrity can be evaluated
efficacy and tolerability during all scheduled visits as patient
by measuring lactate dehydrogenase activity. Lactate dehy-
compliance with the protocol was excellent. Cholevel was
drogenase, an enzyme located in the cytoplasm, catalyses the
well tolerated by all 32 subjects (groups 1+2) and no minor
conversion of lactate and pyruvate. When lactate dehydro-
or major adverse effect was noted by any subject. They all
genase is found within the media on the cells, there are two
tolerated Cholevel with other medications they were on es-
possible causes: The first is cellular death and the second is a
pecially those who were on statins therapy (group 1). In two
'leak' in a cell membrane. When cells are disrupted, the lac-
of the 32 subjects, cholesterol levels were not elevated at
tate dehydrogenase activity is elevated. Results obtained
baseline and did not substantially change during the 3
indicate no significant changes of the LDH levels in the cul-
ture medium after exposure to Cholevel at concentration up
Group1 (Cholevel + Statins): the cholesterol levels were
to 360 μg/ml (Fig. 2).
significantly reduced within the first month of Cholevel con-
88 The Open Complementary Medicine Journal, 2009, Volume 1 Said et al. Fig. (3). Effects of different concentrations (10, 50, and 100 μg/ml) of Cholevel upon malondialdehyde (MDA) release that reflects the ex- tent of lipid peroxidation in rat liver cells incubated with 100 μM ferrosulphate (A) and in vitro inhibition of human LDL oxidation by Cholevel in the presence of ferrosulphate (B). Values given represent the mean ± standard deviations of three independent experiments car- ried out in triplicates.
sumption by 13% and by 18.3% and 24.2% in the two other
30.56 mg% at baseline to 206.42 ± 16.23 mg% at 3 months
months of treatment respectively (Table 1). In group 1, cho-
(Table 1 and Table 4).
lesterol levels were 287.6 ± 17.9 mg% at baseline and de-
Group 2 (Cholevel Only): cholesterol levels were 282.2
creased to 249.5 ± 13, 229.4 ± 14 and 217.7 ± 11 mg% at 1,
± 13.8 mg% at baseline and decreased to 268.3 ± 14, 254.6 ±
2 and3 months of Cholevel intake. These reductions are
12.8 and 241.7 ± 10.6 mg% at 1, 2 and 3 months of Cholevel
highly significant. As shown in Table 1, LDL levels de-
intake (Table 2). As shown in Table 2, LDL levels decreased
creased from 169.83 ± 7.17 mg% at baseline to 136.5 ± 7.35
from 175.05 ± 5.79 mg% at baseline to 149.25 ± 5.53 mg%
mg% at 3 months, whereas, HDL levels increased from
at 3 months, whereas, HDL levels increased from 36.8 ±
40.08 ± 7.03 mg% to 48.83 ± 5.56 mg% at 3 months. These
5.33 mg% to 42.3 ± 5.43 mg% at 3 months. These changes
changes were accompanied by significant reductions in the
were accompanied by significant reductions in the levels of
levels of triglycerides after the study 3 months from 258 ±
triglycerides after the study 3 months from 272.4 ± 28.5
Hypolipidemic Activity of Extracts from Eriobotrya japonica The Open Complementary Medicine Journal, 2009, Volume 1 89 Table 1 (Group 1). Fasting Lipid Levels in the 12 Subjects Using Statin Medications at Baseline and During Each of the 3 Months Study While Consuming One Cholevel Tablet Three Times Daily. Values Given Represent the Mean in mg% ± Standard Deviations Volunteers (n=12) Before Treatment After 1 Month After 2 Months After 3 Months Improvements (%)
Table 2 (group 2). Fasting Lipid Levels in the 20 Subjects at Baseline and During Each of the 3 Months Study While Consuming One Cholevel Tablet Three Times Daily. Values Given Represent the Mean in mg% ± Standard Deviations Volunteers (n=20) Before Treatment After 1 Month After 2 Months After 3 Months Improvements (%) Table 3 (group 3). Fasting Lipid Levels in the 9 Control Subjects at Baseline and During Each of the 3 Months Study While Consum- ing One Placebo Tablet Three Times Daily. Values Given Represent the Mean in mg% ± Standard Deviations Volunteers (n=9) Before Treatment After 1 Month After 2 Months After 3 Months Improvements (%)
mg% at baseline to 235.95 ± 21.91 mg% at 3 months (Table
Group 3 (Control): No significant changes were ob- 2 and Table 4).
served in the control group (Table 3 and Table 4). 90 The Open Complementary Medicine Journal, 2009, Volume 1 Said et al. Table 4.Fasting Lipid Levels after 3 Months Study While Consuming in the Three Groups Improvements Treatments Cholesterol Triglycerides DISCUSSION
fact that Cholevel was well tolerated by all studied subjects and no adverse effect could be traced.
The results disclose that Cholevel is safe and well toler-
ated by all 32 studied subjects and is therapeutically efficient
Taken together, results obtained indicate safety and hy-
as substantial and incremental reductions of cholesterol lev-
polipidemic properties of Cholevel, consisting of extracts
els were observed during each of the study 3 months. At 3
from Eriobotrya japonica and Olea europaea, traditionally
months, baseline cholesterol levels in group 1 (Cholevel +
used in the Greco-Arab medicine [9, 9,11,35,36].
statins) subjects were reduced by 24% which is comparable
to that of 25% observed during simvastatin therapy . Vol-unteers who consumed Cholevel without statins, (group 2)
The authors would like to thank Mr. Assad Dahamshe
showed significant reduction in cholesterol levels (14.3%)
and Mr. Bahaa Hadieh from Antaki Center for Herbal Medi-
after three months of the clinical test. Combination therapy
cine Ltd. Kfar Kana for preparing the figures.
of Cholevel with statins is efficient and can be helpful to
those hyperlipidamics who don’t fully respond to statin medications.
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