Medical

Communication

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,

Mohammadreza

Hajinezhad,

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

4,5,6

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

ABSTRACT

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.

KEY WORDS: RESVERATROL, NANO-CAPSULATION, CARDIOVASCULAR DISEASE, DRUG DELIVERY

623

ARTICLE INFORMATION:

*Corresponding Author:

Received 10

Oct, 2017

Accepted after revision 12

Dec, 2017

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007 CODEN: USA BBRCBA

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2017: 4.31 Cosmos IF: 4.006

reserved.

Online Contents Available at:

http//www.bbrc.in/

DOI: 10.21786/bbrc/10.4/4

624 RESVERATROL NANO-CAPSULE AS AN EFFICIENT TOOL FOR BLOOD PRESSURE REGULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Alemeh Shahraki et al.

INTRODUCTION

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.

MATERIAL AND METHODS

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

(20-24

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

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS RESVERATROL NANO-CAPSULE AS AN EFFICIENT TOOL FOR BLOOD PRESSURE REGULATION 625

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.

RESULTS AND DISCUSSION

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

Formulation

B-NC R-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)

HFDLFD

Present of total

kcal (kcal%)

Present of total

mass (g%)

Present of total

kcal (kcal%)

Present of total

mass (g%)

2525.843028.1protein

3034.696058.04carbohydrate

4542.5 1013.15Fat

4.263.02total (kcal/g)

Alemeh Shahraki et al.

626 RESVERATROL NANO-CAPSULE AS AN EFFICIENT TOOL FOR BLOOD PRESSURE REGULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

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.

DISCUSSION

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.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS RESVERATROL NANO-CAPSULE AS AN EFFICIENT TOOL FOR BLOOD PRESSURE REGULATION 627

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.

628 RESVERATROL NANO-CAPSULE AS AN EFFICIENT TOOL FOR BLOOD PRESSURE REGULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

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.

CONCLUSION

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

steatohepatitis.

ACKNOWLEDGEMENT

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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