Biosci. Biotech. Res. Comm. 10(4): 623-630 (2017)
Resveratrol nano-capsule as an ef cient tool for blood
pressure regulation: A study on metabolic syndrome
induced mice
Alemeh Shahraki,
* Saeed Bahadorikhalili,
Mahmoud Hashemzaei,
Ali Afsharimoghaddam,
Farugh Sarani
and Omid Tajrobekar
Medicinal Plants Research Center, University of Medical Sciences of Zabol, Zabol, Sistan and Baloochestan, Iran
Department of chemistry, College of science, University of Tehran, Tehran, Iran
Department of Pharmacology and Toxicology, University of Medical Sciences of Zabol, Zabol, Sistan and
Baloochestan, Iran
Department of Basic Sciences, Faculty of Veterinary Medicine, University of Zabol, Zabol, Sistan and
Balochestan, Iran
Department of Microbiology and Parasitology, University of Medical Sciences of Zabol, Zabol, Sistan and
Baloochestan, Iran
Insulin resistance and overweight have been associated with major risk factors such as blood pressure (BP) for cardiovascular
disease. In this study the effect of Nano-capsules of resveratrol (RV-NC) on BP control is evaluated. RV-NC nanoparticles were
analyzed by SEM, Zeta sizer, Potentiometer and HPLC. The analysis resulted from RV-NC synthesis showed that the Nano cap-
sules have characteristics such as size of 207 nm, zeta potential of -7.15 and loading ef ciency of 99.54% ± 1.02. BP reduction
was associated with reduction of weight and enhance of QUICKI index which represents insulin resistance. RV-NC were prepared
by interfacial deposition and then its applicability was evaluated in metabolic syndrome induces mice. The effect of RV-NC was
studied on fourteen mice. Induction of syndrome by high fat diet and high BP was observed. The collected data were analyzed by
ANOVA and Turkey criteria were used to compare the distinction between the groups. Finally, the results indicated that RV-NC-
treated mice have regulated in systolic and diastolic blood pressure (compare to the other group (p< 0.05). The effective formula-
tion of nano-capsules for resveratrol delivery not only can be helpful in increasing the in vivo stability, but also in regulation of
the patient’s blood pressure with at least cost of therapy.
*Corresponding Author:
Received 10
Oct, 2017
Accepted after revision 12
Dec, 2017
BBRC Print ISSN: 0974-6455
Online ISSN: 2321-4007 CODEN: USA BBRCBA
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© A Society of Science and Nature Publication, 2017. All rights
Online Contents Available at:
DOI: 10.21786/bbrc/10.4/4
Alemeh Shahraki et al.
Hypertension (BP: 140/90 mmHg), as one of the main
symptoms of metabolic syndrome, can be caused by
fatty and high-calorie diet associated with obesity and
insulin resistance. This problem has been introduced as
a serious warning sign in patients with heart disease.
(Danaei et al, 2013; Jahandideh et al, 2016; Nonogaki
et al, 2016). Global Research has been found that,
approximately % 45 and 51% of deaths are resulted by
coronary stroke and artery disease, respectively (Brook,
2013; Movahed et al, 2016). The clinical studies have
shown that prescription of anti-hypertensive drugs for
the hypertensive patients might cause a number of side
effects. Therefore, medical researchers are interested in
using natural sources instead of chemicals for the pro-
duction antihypertensive drugs (Aluko et al, 2015; BC
Guidelines, 2016).
Recently, plant polyphenols such as resveratrol have
been successfully applied in improving the symptoms of
insulin resistance and obesity in metabolic syndrome,
and therefore it has opened a special place in global
trade as a medicinal compound in the regulation of
blood pressure in patients with heart problems, diabetes
and other diseases (Raj et al, 2013; Liu et al, 2015; Mova-
hed et al, 2016). However, the natural polyphenols suffer
from a number of disadvantages such as low biological
half-life, high volatility and rapid removal, which limits
the in vivo applicability of these compounds (Cottart et
al, 2015; Khaled et al, 2016)
Therefore, new studies have been conducted on the
basis of nanotechnology to achieve effective formu-
lation of pharmaceutical medicines (Smoliga, 2014;
Penalva et al, 2015; Reis et al, 2016; Jadhave et al 2016;
Shindikar et al, 2016). One methods are Nano capsule
formation by coating the unstable medicinal compounds
by biodegradable (Venturini et al ,2011; Frozza et al,
2013; Friedrich et al ,2015; Conte et al, 2016). Regard-
ing the advantages of Nano capsules, the main goal of
this study is to use an effective formulation of resvera-
trol in a stable Nano capsule to improve the  uctuations
problems in blood pressure. The effect of the capsulated
resveratrol is studied in mice with metabolic syndrome
by fat diet.
Trans-resveratrol, PCL, Span 60 and Tween 80 obtained
from Stigma Aldrich. Other chemicals and solvents were
from analytical and pharmaceutical types. The Low Fat
Diet (LFD) was prepared from Khorasan Seedling Com-
pany and to prepare High Fat Diet (HFD), fat-tail was
used that had high levels of saturated fat. RV-NC was
prepared by interfacial deposition method as described
previously (Frozza et al, 2010). Brie y, to prepare the
aqueous phase, polysorbate (0.0380 g) was dissolved in
53 ml of distilled water. The organic phase was prepared
by vigorous stirring of RV, PCL, capric triglycerides, and
sorbitanmonostearate in 27 ml of acetone at 40
C. At
the end, the organic phase was added to the aquatic
phase and acetone was evaporated after 10 min and the
suspension was concentrated under reduced pressure
and  ltered by 8 micrometer  lter paper. Then, the non-
loaded B-CN Nano capsules suspension was synthesized
with the above method as the control formulation.
To determine the size, zeta potential and polydisper-
sity of the Nano capsules, zeta sizer and particle sizes
(20101 SA, made in Japan) with laser light scattering
method at 25
C were used. Before the experiment, the
sample was diluted with MilliQ water or 0.01 μM NaCl
and  ltered by MILLIPORE 0.45 μM. The measurement
was repeated for each formulation in triple mode. To
determine PH, AL-1703 and MUNCHEN an immersed
electrode in suspension were used at room temperature.
The concentration of the loaded active substance (RV)
in suspension Nano capsules was determined by HPLC
using CLC-C8 column and equipped with a UV detector
and using water and acetonitrile as mobile phase with
the  ow rate of 1.2 ml/min and inhibition time of 3.45
min. The capsulation ef ciency was calculated as below:
Here, resveratrol load and resveratrol in supernatant
are active and free substance concentrations respec-
tively. The free substance concentration was obtained
by acetonitrile and the active substance extraction from
suspension formulation was obtained by integrating
ultra ltration and centrifuge. 40 male mice (C57BL/6,
20-24 g, 4 weeks) were selected. The animals were kept
in vitro under standard conduction such as free access
to food and water in a room with controlled temperature
C) and on a 12 h-light/dark cycle. The experi-
mental protocol of this study was approved by Animal
Ethical Committee of Zabol University of Medical Sci-
ences. Before the experiment, all mice were acclimatized
for an adaptation period a week and then, all groups
except the control group (n=8, LFD), were kept under
high fat diets (n=32, HFD) for 12 weeks. Measuring the
parameters such as weight (each week), insulin levels
and glucose were done by FG4000, Cayman kit by ELISA
method, and ARKRAY, respectively.
The non-invasive blood pressure (BP) system (URIT,
Poland) with a tail-cuff sphygmomanometer was used
to measure systolic and diastolic (approximate measure-
ment) blood pressure. A clear plastic tube used to placed
mice and tail hole pieces secured at either end. A nerv-
ous, stressed animal may have diminished circulation in
Alemeh Shahraki et al.
the tail so the animals were placed in the holders at least
10 to 15 minutes prior to obtaining pressure measure-
ments. At this step, mice which have consumed high
fat diet randomly place in 4 groups which included; the
groups treated with resveratrol Nano capsule (RSV-NC;
5 mg/kg/day), blank Nano capsule (B-NC; 5mg/kg/day),
free resveratrol (RSV; 100 mg/kg/day), and metformin
(MET; 250 mg / kg / day). The measured variables were
done similarly at 3 steps: before and after induce syn-
drome and after treatment. The results are reported from
AVONA as mean and standard deviation for at least 3
different experiments (Mean ± SD) and accordingly, sig-
ni cant difference between the groups can be observed
(P<0.05). For between-group comparison, Tukey crite-
ria are used as suitable criteria in making distinction
between groups.
RSV-NC and B-NC were synthesized using biodegradable
materials such as poly- caprolactone (PCL) with no need
to additional steps with interfacial deposition method.
The physiochemical characteristics of Nano capsules are
mentioned in Table 1. The zeta potentials of RSV-NC and
B-NC were obtained as -7.15 and 6.21, respectively. The
negative values indicate the existence of polysorbate 80
in formulation that leads to their increased spatial resist-
ance in water/particle surface. Also, the Nano capsules
suspensions were analyzed by DLS and monomodal sta-
bility in size distribution and polydispersity index were
observed to be lower than 0.3, which shows the narrow
size. Particle size for RSV-NC and B-NC were about 200
nm and according to resulting of Friedrich et al, 2015 is
an acceptable size. In addition, the pH for the formula-
tions of both Nano capsules was larger than 6. HPLC
method showed the capsulation ef ciency of RSV-NC
to be %99.54±1.02. These results are consistent with the
new  ndings in this formulation.
Fat diet: Ruminant fat was used to induce metabolic
syndrome in mice. The HFD and LFD components are
presented in Table 2. The diet in this study has 30% car-
bohydrate, 45% fat and 25% protein that is almost simi-
lar to the diets in various societies.
The weight means of HFD and LFD groups before
and after induced metabolic syndrome were com-
pared. According to the statistical results obtained from
ANOVA, the signi cance level between the two groups
is lower than 0.05. This states that there is a signi cant
difference between the weights of HFD (n=32) and LFD
(n=8), due to the higher level of saturated fat, that the
HFD group have received ( g.2). Analyzing the results
by Tukey test show that, HFD subgroup (RV-NC, B-NC,
RV and MET, n = 8), had higher weights which was
because of receiving high levels of saturated fat for 12
than control group that used standard diet. According
to the  ndings in  g 2, the weight means of RV-NC,
RV and MET groups show a signi cant reduction during
4 weeks of treatment and among these, group RV-NC
showed a weight loss in a shorter time.
The QUICKI index was the main index for the insulin
resistance measurement, which is directly obtained from
glucose and insulin values. In this study, the results of
g3, show that there is a signi cant difference between
HFD group compared to the control group (P<0.05). HFD
groups have the highest value in glucose and insulin
and therefore have the lowest QUICKI index. Results of
testing between groups, Tukey test, show that glucose
and insulin levels in 5 groups of RV-NC, B-NC, RV, MET
and control are different. In this study, B-NC group has
the highest levels of insulin and glucose and the lowest
values QUICKI index, in contrast to the control group.
Table 1. The physiochemical characteristics of Nano
capsules containing RV-NC and B-NC
Size (nm) 205± 0.05 207±0.03
PDI 0.12±0.09 0.12±0.04
Zeta potential
(mv) -6.21± 0.45 -7.15± 0.19
PH 6.47± 0.02 6.22±0.04
Encapsulation ef ciency (%) - 99.54±1.02
Table 2. Composition of High Fat Diet (HFD) and Low Fat Diet (LFD)
Present of total
kcal (kcal%)
Present of total
mass (g%)
Present of total
kcal (kcal%)
Present of total
mass (g%)
4542.5 1013.15Fat
4.263.02total (kcal/g)
Alemeh Shahraki et al.
FIGURE 1. Size distribution graph for resveratrol – loaded Nano capsules (RV-NC)
obtained by (a) DLS and (B) SEM photomicrographs.
FIGURE 2. Weight changes in 5 different groups in 20 weeks. All data are
expressed as mean ± standard deviation (n=8) and different letters show a sig-
ni cant difference at p < 0.05.
In the RV-NC group, QUICKI index reach normal range,
while the glucose and insulin values were normal. RV
and MET groups have also the same result, relatively.
Generally, it can be understood that RV-NC group oper-
ate better in increasing QUICKI index in shorter period
of time.
Since the blood pressure is one of the main symptoms
of the metabolic syndrome, this parameter was investi-
gated in mice fed fat diet for 12 weeks and 4-week treat-
ment compare to control group. The results of changes in
values systolic and diastolic blood pressure which Sta-
tistical analysis by ANOVA, in Figure 4, section A and B
respectively, show that there was signi cant difference
between HFD group and LFD groups in values of systolic
and diastolic blood pressure (P<0.05). After separation
the animals HFD into 5 subgroups (RV-NC, B-NC, RV,
MET) and conducted treatment phase, Tukey method for
compare between groups were used. The results show
a signi cant reduction of systolic and diastolic blood
pressure in RV-NC, RV and MET groups. B-NC group
which has used Nano capsules without pharmaceuti-
cal active ingredient, have the highest amount in blood
pressure, while not observed in the control group signif-
icant changes over time. It appears that changes in Sys-
tolic blood pressures are more obvious than diastolic. It
is clear that the group RV-NC in the regulation of blood
pressure in Comparisons between groups of RV-NC, RV,
MET, is better.
This study assessed the potential effects of resveratrol
–loaded Nano capsules suspension on insulin to resist-
ance (IR) and systolic and diastolic blood pressure in
metabolic syndrome induced in mice. The results show
that there is a major association between the resist-
ance to the effects of insulin on both glucose uptake
and insulin-induced vasodilatation in obese hyperten-
sive patients, which are in accordance with the previ-
ous  ndings (Ferrannini et al, 1987; Laakso et al, 1989;
Alemeh Shahraki et al.
FIGURE 3. Changes in insulin (a), glucose (b) and QUICKI index (c) values in 5 different groups
in three stages. All data are expressed as mean ± standard deviation (n=8) and Different letters
show a signi cant difference at p < 0.05.
FIGURE 4. Changes in systolic (a) and diastolic (b) blood pressure values in 5 differ-
ent groups in three stages. All data are expressed as mean ± standard deviation (n=8)
and Different letters show a signi cant difference at p < 0.05.
Natali et al, 1997; Lastra et al, 2010; Horita et al, 2011,
Zhou et al, 2012).
The homeostasis model assessment-estimated insu-
lin resistance (HOMA-IR) has been widely used for the
estimation of IR in research (Matthews et al, 1985). It
is calculated multiplying fasting plasma insulin (FPI)
by fasting plasma glucose (FPG), then dividing by the
constant 22.5, i.e. HOMA-IR = (FPI×FPG)/22.5 (Wallace
et al, 2004). index that we used to determine IR is the
quantitative IR check index (Quicki index) which that is
a novel mathematical transformation of fasting blood
glucose and insulin levels and useful index of IR in sub-
jects with hypertension, obesity, type 2 diabetes, gesta-
tional diabetes, pregnancy, PCOS, premature adrenarche,
hyperandrogenism, and nonalcoholic steatohepatitis
(Katz et al, 2000; Hui et al, 2003).
Alemeh Shahraki et al.
Lifestyle factors such as excess body fat, excess
dietary fat (total, Trans, and saturated fat), fake carbo-
hydrates, smoking, stress and insuf cient exercise are
causes IR. This problem is a central part of a cluster of
metabolic abnormalities called the metabolic syndrome.
Candidate mechanisms whereby this metabolic syn-
drome might lead to hypertension include stimulation of
sympatho-adrenergic activity, altered cellular electrolyte
transport and composition, growth promoting effects,
renal sodium retention and vascular hyper responsive-
ness (Lithell et al, 1998; Velliquette et al, 2003). In per-
son with IR, the cells do not respond to insulin normally
and glucose cannot easily enter the cells. As a result,
the insulin level in blood will be high. Finally, the body
will not be capable of building enough insulin to control
blood glucose at normal level and diabetes, cardiovas-
cular disorder and others occurs (Borkman et al, 1993;
Vessby et al, 2001; Risérus et al, 2009; Sandeep et al,
2010). The diet used in this study consisted of proteins
(25%), carbohydrates (30%) and saturated fat (45%) that
is almost similar to the diets in most of the societies. The
available diets for animal model almost contain 60% fat
so that insulin resistance can be observed, but is not
similar to the diets that are used by Individuals and can-
not be generalized simply (Nishina et al, 1990; Surwit
et al, 1995).
Several studies have been conducted on the edible
containing the active ingredient in the prevention and
treatment of insulin resistance and blood pressure regu-
lation .The results show that edibles containing polyphe-
nolic compounds (such as Red Grapes, Dark Chocolate
and Blueberries) could be effective in this (Dauchet et al.
2005; Hu and Willett, 2002). Since Polyphenols such as
resveratrol which that improve the risk factors of cardio-
vascular disorders (Poulsen et al, 2013), diabetes (Hause-
nblas et al, 2014) and pathologic conditions (Fernández
et al,2011) is unstable in vivo and so use it expensive for
patients (Joseph et al, 2006), Studies developed towards
to produce new formulations to improve protecting and
reaching acceptable level of bioavailability (Finley et al,
2010 and Francioso et al, 2014)
Nowadays, scientists could be using new technolo-
gies, especially nanoscience for drug delivery of active
ingredients unstable to form of nanocapsules (Contri et
al, 2016; Scognamiglio et al 2016 and Vivienne et al,
2016). Some of the advantages this method, Include the
development of controlled-release system, maintaining
the drug concentration in blood plasma for a long time,
the possibility of developing drugs with very low dose
and stability and ef cacy impressive. In this study, we
prepared protected form of resveratrol in the coating of
biodegradable polymer PCL (poly-caprolacton) with a
size of approximately 200 nm. However, the results of
experiments in this plan highlight the successful perfor-
mance of RV-NC compared to other groups to reduction
of IR and regulation of blood pressure.
This is the  rst study on the effect of resveratrol loaded
Nano capsule (RV-NC) on insulin resistance (IR) and
blood pressure pro les in animal model metabolic syn-
drome. The results demonstrated that using high satu-
rated fat in daily diet can cause IR and hypertension.
On the other hand, RV-NC regulates blood pressure and
reduces IR by reducing the amount of the fat in whole
body. These  ndings suggest that further studies should
be conducted on the effect of RV-NC on animal and
human induced hypertension models, obesity, type 2
diabetes, gestational diabetes, pregnancy, PCOS, prema-
ture adrenarche, hyperandrogenism, and nonalcoholic
The  ndings of this study are obtained by the  nan-
cial support of Medical University of Zabol. The authors
express their gratitude to Dr. Zahra Sepehri, the Deputy
of Research and Technology of the university.
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