Potency of Cape Gooseberry (Physalis Peruviana) Juice in Improving Antioxidant and Adiponectin Level of High Fat Diet Streptozotocin Rat Model

Abstract

Background and aims: Quercetin belonging flavonoid has a role to improve diabetic condition. Research aimed to examine and to compare Cape Gooseberry (CG) juice and quercetin supplement on Total Antioxidant Capacity (TAC) and adiponectin level of high fat diet-Streptozotocin (HFD-STZ) induced rat.
Material and method: CG juice 5 ml/kg/d (X1) and 25 ml/kg/d (X2) groups; and quercetin supplement 2.2 mg/kg/d (X3) and 30 mg/kg/d (X4) groups were compared with both of positive (K+) and negative (K-) control. Treatments were given by orally gavage for 28 days to 36 Wistar rats which each group consisted of 6 rats. TAC and adiponectin level were measured by ABTS and ELISA method respectively.
Results: There was significantly increase of TAC in treatment groups compared with K(+) (p<0.05). X2 had TAC level significantly higher than X1 (p=0.025). Moreover, adiponectin level of treatment groups were significantly higher than K(+) (p<0.05). Furthermore, X2 had adiponectin level significantly higher than X3 (p<0.001).
Conclusion: CG juice 25 ml/kg/d presented better effect than CG juice 5 ml/kg/d, although quercetin 30 mg/kg/d showed the best effects toward both of TAC and adiponectin.

Full text


 Desa Bae Bendo Rt4 Rw 2 Kecamatan Bae, Kabupaten Kudus, Jawa tengah, Indonesia (ZIP code: 59327).
Phone: +62823-2535-8329; corresponding author e-mail: luthfia.dewi2019@gmail.com
POTENCY OF CAPE GOOSEBERRY (PHYSALIS PERUVIANA) JUICE
IN IMPROVING ANTIOXIDANT AND ADIPONECTIN LEVEL
OF HIGH FAT DIET STREPTOZOTOCIN RAT MODEL
Luthfia Dewi 1, , Mohammad Sulchan 1, Kisdjamiatun 2
1 Department of Nutrition Science, Faculty of Medicine Diponegoro University,
Semarang, Indonesia
2 Department of Biomedical Science, Faculty of Medicine Diponegoro University,
Semarang, Indonesia
received:
May 15, 2018
accepted:
August 18, 2018
available online:
September 23, 2018
Abstract
Background and aims: Quercetin belonging flavonoid has a role to improve diabetic
condition. Research aimed to examine and to compare Cape Gooseberry (CG) juice and
quercetin supplement on Total Antioxidant Capacity (TAC) and adiponectin level of high
fat diet-Streptozotocin (HFD-STZ) induced rat. Material and method: CG juice 5 ml/kg/d
(X1) and 25 ml/kg/d (X2) groups; and quercetin supplement 2.2 mg/kg/d (X3) and 30
mg/kg/d (X4) groups were compared with both of positive (K+) and negative (K-) control.
Treatments were given by orally gavage for 28 days to 36 Wistar rats which each group
consisted of 6 rats. TAC and adiponectin level were measured by ABTS and ELISA
method respectively. Results: There was significantly increase of TAC in treatment
groups compared with K(+) (p<0.05). X2 had TAC level significantly higher than X1
(p=0.025). Moreover, adiponectin level of treatment groups were significantly higher
than K(+) (p<0.05). Furthermore, X2 had adiponectin level significantly higher than X3
(p<0.001). Conclusion: CG juice 25 ml/kg/d presented better effect than CG juice 5
ml/kg/d, although quercetin 30 mg/kg/d showed the best effects toward both of TAC and
adiponectin.
key words: adiponectin, high fat diet, Streptozotocin, total antioxidant capacity
Background and aims
Diabetes mellitus type 2 (DMT2) is
metabolic disease characterized by increasing
blood glucose. People possessed DMT2 have
higher comorbidity and mortality than healthy
people. Prevalence of diabetes increases these
decades. An estimated prevalence of diabetes
mellitus in Southeast Asia by International
Diabetes Federation is 151 billion by 2045 [1].
The incidence of diabetes in Indonesia was 10
million in 2015 [2]. Insulin resistance is the main
pathophysiology of DMT2 [3]. Insulin resistance
caused by high fat diet (HFD) contributes in
increasing of reactive oxygen species (ROS)
through fatty acid oxidized metabolism [4,5].
Adiponectin provides on glucose uptake and β-
oxidation through AMPK activation [6].
Nonetheless, low adiponectin synthesis occurs in
insulin resistance and DMT2 condition [7,8].
© 2018 ILEX PUBLISHING HOUSE, Bucharest, Roumania
http://rjdnmd.org
Rom J Diabetes Nutr Metab Dis. 25(3):253-260
doi: 10.2478/rjdnmd-2018-0029

254 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 25 / no. 3 / 2018
Furthermore, oxidative stress occurs in
hyperglycemia diabetic due to decreasing of
potency antioxidant [9]. Total antioxidant status
is suitable biomarker to assess oxidative stress
by giving applicable information of cumulative
antioxidant capacity in extracellular fluid
compared individual element [10].
Application of traditional medicine from
nature is popular these days [11]. Cape
gooseberry (Physalis peruviana) is an
uncommon consumed berry by Indonesian. Cape
gooseberry (CG), belongs to Solanaceae family,
was proved possessing anti-diabetic feature by
various mechanisms improving insulin
sensitivity; inhibiting intestinal carbohydrase
enzyme and β-cell pancreas defect [11-14].
Quercetin is one of flavonoid in CG whose
potency to suppress oxidative stress in DMT2.
CG juice contains 89.4 µg/mg quercetin (CG :
water = 1:5) [15]. Juice is one of easy methods
to consume fruit and an effective way to promote
fruit consumption [16].
To our knowledge, comparison between CG
juice and quercetin supplement research toward
Total Antioxidant Capacity (TAC) and
adiponectin concentration in DMT2 has not
examined yet, therefore present study was
carried out to show the role of CG juice in
DMT2 rat HFD-STZ model. TAC and
adiponectin level were investigated by ABTS
and ELISA method respectively.
Material and method
Plant Material
CG fruits were collected from Ciwidey,
West Bandung District, Indonesia in January
2018. The plant was identified and authenticated
by its taxonomy characteristics in Sistematika
Tumbuhan Laboratory, Biology Faculty of
Gadjah Mada University, Indonesia.
Chemicals and Reagents
STZ (C8H15N3O7) and nicotinamide were
purchased from Nacalai Tesque, Japan.
Cholesterol, Na-CMC, and Quercetin 2-(3,4-
Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-
benzopyran-one,3,3’,4’,5,6-Pentahydroxyl-
favone, Quercetin-3-O-rhamnoside were
purchased from Sigma-Aldrich, Japan. TAC kit
was purchased from Randox Laboratory, United
Kingdom. Rat adiponectin ELISA kit was
purchased from Bioassay Technology
Laboratory, China. NaCl was purchased from
Merck, Germany.
Preparation of CG Juice
Fruits in similar ripening stages were
selected in juice processing. First, CG fruits
were washed to get rid of impurities. Whole 70 g
CG fruits were blended in a blender (National,
Japan) without any water addition; therefore 1
mL juice contains 1.07 g CG fruits. The seeds
and skin residues were removed by filter and
cheesecloth. Juice was shaken before DPPH
radical scavenging activity and administration
(5 ml/kg/d and 25 ml/kg/d) by gavage [13].
DPPH Radical Scavenging Activity
DPPH radical scavenging activity assay is
subjected to determine the antioxidant capacity
of juice compared with quercetin supplement.
DPPH analysis used in the experiment was
according to Koleangan et al. (2013) [17].
Results were given in IC50 value. Data
presented in Table 1 shows that IC50 value of
CG juice and quercetin was 84.065 µg/mL and
7.869 µg/mL respectively.
Table 1. IC50 value of CG juice and quercetin
for antioxidant capacity.
Sample
IC50 (µg/mL)
CG juice
84.065
Quercetin
7.869

Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 25 / no. 3 / 2018 255
Animal Laboratory
Healthy male Wistar rat, 8-12 months,
weighing 150-200 g was purchased from Central
Food and Nutrition Laboratory, Yogyakarta,
Indonesia. Rats were housed in individual
stainless-steel cages at regulated temperature
(210C). They were kept under suitable
ventilation and a photoperiod 12-h light/ 12-h
darkness scheduled light from 6 a.m. to 6 p.m.
Rats were fed by 20 g/d standard laboratory
feeding Comfeed II (7% fat) during non-HFD
period. They were supplied by ad-libitum water
throughout the experiment. Animal laboratory
were provided the human care according to
Animal Laboratory Guideline of Pangan dan
Gizi Laboratory, Gadjah Mada University,
Indonesia.
Experimental Design
After a week acclimatization, rats were
divided into six groups (six rats each group).
Group 1 (K-): rats didn’t receive any treatments.
Group 2 (K+): rats received HFD-STZ. Group 3
(X1): rats received HFD-STZ and CG juice 5
ml/kg/d. Group 4 (X2): rats received HFD-STZ
and CG juice 25 ml/kg/d. Group 5 (X3): rats
received HFD-STZ and quercetin 2.2 mg/kg/d.
Group 6 (X4): rats received HFD-STZ and
quercetin 30 mg/kg/d. After two weeks on HFD
(43.6% fat), rats were fasted overnight and
treated with nicotinamide (NA: 110 mg/kg, i.p.)
and streptozotocin (STZ: 45 mg/kg, i.p.). HFD
treatment was suspected to lead insulin
resistance, while NA/STZ was suspected to
make β-cell impairment [18,19]. After dietary
manipulation, rats were injected intraperitoneally
by NA followed by STZ 15 minutes later. STZ
was dissolved into citrate buffer (pH 4.5). CG
juice and quercetin treatments were
administrated (three days after STZ-induced) by
oral gavage for four weeks. Quercetin was
dissolved into 0.5% sodium carboxymethyl
cellulose.
This experimental design was reviewed and
approved by Medical Faculty of Diponegoro
University-Dr.Kariadi Semarang Hospital
research committee proved by ethical clearance
certificate number 06/EC/FK-RSDK/I/2018.
Blood Sampling
Three days after STZ injection and the end
of experiment (seven weeks), overnight fasting
blood glucose was taken through plexus orbitals.
Blood samples were collected in centrifugation
tube and were centrifuged 4000 rpm in 15
minutes. TAC and adiponectin level were
analyzed by ABTS and ELISA method
respectively.
Statistical analysis
Results were expressed as either mean ± SD
or median (interquartile ranges). Statistical
significance was calculated using one-way
analysis of variance (ANOVA) followed by post
hoc Bonferroni regarding of distributed data
normally. Nevertheless, Kruskal wallis followed
by Mann Whitney was used to calculate
statistical significance of abnormal data
distribution. All the statistical analysis was
analyzed by SPSS 21 software. Differences data
were considered significant at p<0.05 and
confidence interval 95%.
Results
All rats were still alive during the study. The
body weight and blood glucose level in the end
of acclimatization on average were 178.56 g and
74 mg/dL respectively. HFD-STZ successfully
increased body weight (221.52 g; p<0.001) and
blood glucose (218.44 mg/dL; p<0.001).
The effect of CG juice as well as quercetin
treatment on TAC level in the experimental
group of HFD-STZ induced rat is shown in
Figure 1 followed by Table 2. K(+) rats

256 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 25 / no. 3 / 2018
significantly decreased in TAC level compared
with K(-) rats (p=0.007). An increase of TAC
level was recorded in treatment groups compared
with K(+) (p<0.05), although quercetin 30
mg/kg/d showed the highest TAC level in the
end of study. CG juice treatment in X2 improved
TAC level better than CG juice treatment in X1
(p=0.025), but that was not significantly
different with TAC level in X3 (p=0.906).
Moreover, TAC level in K(-) showed a slightly
decrease in the end of study (-0.15 mmol/L).
Figure 1. Effect of CG juice and quercetin supplement towards TAC (mmol/L) level.
TAC level change (mmol/L) before and after treatment in X1, X2, X3,X4, K(+), and K(-) were 0.15 (0.00-
0.44); 0.59 (0.30-0.59); 0.47 (0,15-0,59); 0.78 (0.59-0.88); -0.14 ((-0.30)-0.00); and -0.15 ((-0.30)-0.00).
Table 2. Mann Whitney test of TAC level change (mmol/L) before and after
treatment in X1, X2, X3, X4, K(+), and K(-) groups.
Groups
p value
X1
X2
X3
X4
K(+)
K(-)
X1
-
0.025*
0.043*
0.009*
0.023*
0.014*
X2
-
-
0.906
0.017*
0.008*
0.007*
X3
-
-
-
0,017*
0,008*
0,007*
X4
-
-
-
-
0.008*
0.008*
K(+)
-
-
-
-
-
0.007*
K(-)
-
-
-
-
-
-
*p<0.05 = significant level
Both of CG juice and quercetin treatment
also successfully improved adiponectin level of
HFD-STZ induced rats (Figure 2 followed by
Table 3). Figure 2 showed that HFD-STZ
ameliorated adiponectin level of K(+) compared
with K(-) (p=0.044). Adiponectin level in X4
rats significantly elevated among other treatment
groups (p<0.05). Our results also revealed that
treatment in X2 rats significantly improved
adiponectin level compared with both of CG
juice treatment in X1 (p<0.001) and quercetin
supplementation in X3 (p<0.001). Furthermore,
adiponectin level of K(-) in the end of study
attenuated by 1.5 mg/L.

Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 25 / no. 3 / 2018 257
Figure 2. Effect of CG juice and quercetin supplement towards adiponectin (mg/L) level.
Adiponectin level change (mg/L) before and after treatment in X1, X2,X3, X4, K(+), and K(-) were -
0.5±0.67; 4.4±0.50; 6.3±0.36; 1,9 ± 0,43; -1.9±1.04; -1.5±0.43.
Table 3. Post-hoc Bonferroni test of adiponectin level change (mg/L) before
and after treatment in X1, X2, X3, X4, K(+), and K(-) groups
Groups
p value
X1
X2
X3
X4
K(+)
K(-)
X1
-
0.000*
0,000*
0.000*
0.021*
0.237
X2
-
0,000*
0.001*
0.000*
0.000*
X3
-
-
-
0,000*
0,000*
0,000*
X4
-
-
-
-
0.000*
0.000*
K(+)
-
-
-
-
-
0.044*
K(-)
-
-
-
-
-
-
*p<0.05 = significant level
Discussion
In the present study, it was observed that CG
juice and quercetin supplement treatment
enhanced TAC and adiponectin level in HFD-
STZ induced rats. Experimental results suggest
that CG juice and quercetin supplement
treatment could improve diabetic condition in
HFD-STZ rat model. In this study, HFD-STZ
exerts possible stress oxidative overproduction
as verified by the decrease of TAC level. One of
modeling DMT2 in rats is using HFD-STZ [18-
20]. Hyperglycemia in diabetes leads antioxidant
status disturbance related to ROS overproduction
and subsequently disrupts body defense. Low
antioxidant status and body defense disruption
induce stress oxidative production [9,21]. Low
antioxidant enzymes activity such as catalase,
superoxide dismutase, glutathione peroxidase,
and glutathione reductase, are affected by
hyperglycemia in diabetes [22]. ROS possesses
toxic properties related to its high reactivity to
enzymes and results in tissue damage [23].
Moreover, NADPH activity is high in
uncontrolled diabetes. Consequently, it results
anion radical superoxide elevation and
subsequently increases stress oxidative
production [24].
Dietary antioxidant in food that present in
significant amounts is able to increase
antioxidant system in body and subsequently

258 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 25 / no. 3 / 2018
decreases ROS production in diabetic rat
laboratory animal. Dietary antioxidants
commonly in fruits have protective effect of
oxidative damage in diabetes [25]. CG is one of
berries that suggested has potent antioxidant
because of its flavonoid content. Dkhil et al.
(2014) demonstrated that flavonoid content in
CG extract was 93.7 mg quercetin equivalent/g
extract [11]. Hydrogen donor from exogenous
antioxidant scavenging radical component is part
of hydroxyl group, hence it forms stable radical
fenoxil [26]. Quercetin is part of flavonoid,
therefore it considered as an exogenous
antioxidant that binds Fe and subsequently
prevents ROS production in Harber-Weiss/
Fenton reaction. Additionally, quercetin can
protect the cell through superoxide forming in
enzymatic reaction[27]. CG juice and quercetin
supplement may help improvement of
endogenous antioxidant synthesis to protect
cells. In this context, elevated antioxidant
activity of catalase, superoxide dismutase, and
glutathione peroxidase in quercetin
supplementation was reported by Suganya et al.
(2018)[28]. Elevating TAC level in CG juice
treatment groups may also be affected by its
quercetin content. Hassan et al. (2017) reported
that quercetin presence in CG juice belongs to
substantial flavonoid compound[29]. The main
flavonoids identified in CG fruits are quercetin
(0.1-10.9 mg/kg), rutin (1.7-6.7 mg/kg),
myricetin (1.1-1.3 mg/kg), epicatechin (0.2-0.6
mg/kg), and catechin (3.8-6.7 mg/kg)[28–30].
CG juice also contains bioactive compounds
such as withanolides and carotenoid[28,31].
Moreover, the decrease of TAC in K(-) might be
the standardized laboratory diet lack of
antioxidant content, therefore it is essential for
healthy condition to intake exogenous
antioxidant, thus endogenous antioxidant can be
maintained. A study performed by Egert et al.
(2008) related quercetin supplementation to
healthy subjects enhanced quercetin plasma
quercetin concentrations [33].
Adiponectin belongs to hormone involved in
glucose metabolism and is secreted by adipocyte
that has role in insulin sensitivity improvement
through its receptor binding [6,32]. Adiponectin
helps glucose uptake and β-oxidation through
AMPK activation, but its synthesis declines in
insulin resistance condition and DMT2 [6-8]. In
the present work, HFD-STZ decreased
adiponectin level, but CG juice and quercetin
supplement treatments successfully ameliorated
adiponectin level. Low adiponectin level in the
present study considered as increasing oxidative
state and was associated with high ox-LDL level
in DMT2 [34]. The present work results are in
accordance with another study reporting that
quercetin supplementation 25 mg/kg/d
significantly elevated adiponectin level
compared with HFD-induced rat group [35].
Furthermore, the study undertaken by Jeong et
al. (2012) reported that quercetin treatment
0.08% of diet successfully increased
adiponectin percentage by 34% [9]. A
mechanisms that could possibly explain
quercetin role in increasing adiponectin level is
elevation of mRNA PPAR-γ concentration [35].
Moreover, bioactive contents in CG juice were
postulated that those have main role in elevating
adiponectin level. The previous study by
Esfahani et al. (2014) reported that there was
positive association between low adiponectin
and low GSH [34]. Adiponectin level of K(-) in
the end of study (11.9 mg/L) was considered as
normal although it decreased 1.5%. Normal
adiponectin level in normal subject is 7-12 mg/L
[36]. Decreasing of adiponectin level in the end
of study was postulated the standard diet
laboratory Comfeed II containing low
antioxidant that led adiponectin level decrease.
We provide new insight by which CG juice
improving TAC and adiponectin in HFD-STZ

Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 25 / no. 3 / 2018 259
induced rat. Further studies are needed to
understand the plausible mechanism by which
CG juice attenuates both TAC and adiponectin
level.
Conclusions
In conclusion, these results performed the
beneficial effect of CG juice in improving
antioxidant and adiponectin level of HFD-STZ
rat model.
Disclosure. The author declares no conflict
in interest.
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