Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : February 5, 2018
Accepted : April 20, 2018
Published online : May 12, 2018
doi:10.24659/gsr.5.2_95

Original article

Effect of mangosteen pericarp extract on skin moisture and arterial stiffness:
Placebo-controlled double-blinded randomized clinical trial
Kazuhiro Maejima 1), Rei-ichi Ohno 2), Ryoji Nagai 2, 3), Shuji Nakata 4)1) Food Development Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan
2) Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, Kumamoto, Japan
3) Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, Kumamoto, Japan
4) Medical Corporation Bokushinkai Clintexe Clinic, Tokyo, Japan

Abstract

Purpose: Glycative stress further enhances defects of skin and blood vessels caused by aging. This research investigated
how the intake of water extract of mangosteen pericarp (WEM) affected skin moisture and arterial stiffness, as antiglycative effect of WEM had already been identified.
Method: Subjects that participated in this research were forty healthy females from 25 to 59 years of age (20 subjects
in WEM group and 20 subjects in the placebo group). After they took 200 mg of WEM or placebo per day for 12
weeks, a blood test, a skin moisture test and a vascular function test were conducted before intake as well as 4, 8 and
12 weeks after intake. To evaluate the efficacy of WEM, a placebo-controlled double-blinded randomized clinical trial
was performed.
Results: In WEM group (19 accomplished the trial), levels of blood sugar and HbAlc did not decrease after the intake of
WEM, compared with the levels examined before intake. Concerning serum concentrations of pentosidine, no significant
difference between WEM and the placebo groups were identified. However, compared with the level obtained before intake,the value of WEM group decreased significantly 8 weeks after intake, while no significant change was confirmed in theplacebo group. Regarding moisture content in cheek skin, WEM group significantly increased by taking WEM, comparedwith the placebo group (19 accomplished the trial). In addition, owing to WEM intake, in terms of API (Arterial Pressurevolume Index), an indicator of arterial stiffness, WEM group showed a lower value than the placebo group 8 weeks after
intake.
Conclusion: The results of this study suggested that the ingestion of WEM decreased healthy women’s glycative stress andimproved their skin moisture content as well as arterial stiffness.

KEY WORDS: mangosteen (Garcinia mangostana), glycative stress, advanced glycation endproducts (AGEs),		skin moisture, arterial stiffness

Introduction

Protein non-enzymatically reacts to saccharides,
produces Amadori compound in the intermediate process andforms advanced glycation endproducts (AGEs) 1). Stress on ahuman body, which is caused by excessive sugar reduction
associated with metabolic disorders and the production ofcarbonyl compound, is called “glycative stress” 2, 3) and isconsidered to be one of the aggravating factors in aging. It isalso known that the accumulation of AGEs in the human bodyproceeds in an age-dependent manner 4, 5) and enhanced by theonset of diabetic complications 6-10) and arteriosclerosis 11-15).
Pentosidine, is a cross-linking compound of AGEs,

accumulating with aging in long-lived tissue proteins,
including collagen, a primary structural protein, which forms
skin, blood vessels and bone 16). Since pentosidine forms
cross-links between molecules in collagen in a non-specificfashion, it is considered to impair the flexibility of collagenand greatly influence functions of skin and blood vessels.
In order to prevent the accumulation of AGEs, it isconsidered to be effective not only to improve exercising andeating habits on a daily basis but also to take food ingredientsthat prevent the generation of AGEs. It is also known thatanti-oxidant compounds, such as flavonoid, catechin andprocyanidin, which are included in vegetables and fruits,

Contact Address: Kazuhiro Maejima
Food Development Laboratories, Nippon Shinyaku Co., Ltd.
14 Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601- 8550, Japan
TEL: + 81- 75 -321- 9208 FAX: +81-75-321- 9028
e-Mail: k.maejima@po.nippon-shinyaku.co.jp
Co-authors: Ohno R, reiichi296@gmail.com ;Nagai R, nagai@agri.u-tokai.ac.jp ; Nakata S, clintexe@gmail.com

Glycative Stress Research 2018; 5 (2): 095- 103(c) Society for Glycative Stress Research_ 95 _

Effect of Mangosteen Extract on Skin Moisture and Arterial Stiffness

prevent Maillard reaction and inhibit formation of AGEs
in vitro 18-20). Prengkuan et al. evaluated antioxidant activity
in edible fruit extracts to inhibit Maillard reactions andreported that mangosteen pericarp extracts possessed highinhibitory activity 21). Mangosteen is a fruit tree cultivated inSoutheast Asia, such as Thailand, and is called the Queen of
Fruits 22). Mangosteen pericarp includes α-mangostin, one
representative xanthone and also a variety of polyphenol,such as anthocyanin, epicatechin and procyanidin B2 22- 24).
In the U.S., juice produced by squeezing the whole fruit,
including mangosteen pericarp and alcoholic extractsof mangosteen pericarp, are used as health foods 25, 26).
In particular, it has been reported that a water solublecomponent of mangosteen pericarp has a strong antioxidative effect 27). In Japan, therefore, mangosteen pericarp
extract has been more widely used as a raw material for
health food.
Until recently, it was confirmed that after healthy womenin their 30s and 40s took hot water extract of mangosteen
pericarp (WEM), a skin fluorescence value, an index of AGE
accumulation, became lower, and also serum pentosidine
concentrations decreased, compared to the values before
intake 28). In this study, therefore, it was verified that WEM
intake reduced glycative stress and influenced functions ofskin and blood vessels. The subjects in this research were
healthy females at 25 through 59 years of age. After they
took 200 mg of WEM or placebo per day for 12 weeks,
blood, skin function and vascular function tests were carriedout before intake and 4, 8 and 12 weeks after intake. To
evaluate the efficacy of WEM, a placebo-controlled doubleblinded randomized clinical trial was performed.

Clinical test food

Mangostin aqua (Nippon Shinyaku CO., LTD., Kyoto,
Japan) was used as WEM. After mangosteen pericarp was
scalded for 2 minutes, it was dried at 70℃ for 8 hours. The
dried mangosteen pericarp was extracted with hot water,
filtrated and concentrated. After 33% of solid weight dextrin
was added to the concentrated mangosteen, it was powderedusing a spray drying method. As a result, WEM containing
0.078% of rhodanthenone B was obtained. The clinical test
foods were gelatin capsule types of food containing 100
mg of WEM per capsule and placebo capsules containing
100mg of crystalline cellulose per capsule instead of WEM,
which apparently looked like the WEM ones ( Table 1 ). The
amount of intake per day was two capsules. Table 2 shows
the nutrient composition.
Table 1. Test food composition(Compound amount: mg/2 capsules)

Water extract of Mangosteen
Saflower oil
Bees wax

Glycerine fatty acid ester
Crystalline cellulose

WEM

Placebo

200

0

340

340

30

30

30

30

0

200

WEM

Placebo

5.5

5. 5

0.21

0. 21

0.40

0. 40

0.27

0. 28

0.87

0.66

WEM, water extract of mangosteen.

Table 2. Test food nutritional constitutes(Administration amount per day)

MethodSubjects

The subjects in this research were healthy Japanesewomen in their 20s to 50s who had subjective symptomsof sagging skin or dull skin. Interview-based inquiry was
conducted on the telephone for clinical test volunteer
registrants, when they were recruited. In order to select the
subjects, the following exclusion criteria were set as follows:
1) subjects who are currently taking medicine or supplements,
2) subjects who have a past medical history of critical
illnesses related to liver, kidney, heart, lung and blood, or
have a history of present illness, 3) subjects with skin diseases,
including atopic dermatitis, 4) subjects who are currently
participating in other human clinical studies or participatedin those kinds of studies within three months, 5) subjects
who are likely to change their life style (due to a night shift
or long-term travel) during the test and 6) subjects who are
considered to be inappropriate for this clinical test by thedoctor in charge.
During the clinical test, the subjects were required
to comply with the following precautions: 1) not keeping
irregular hours, including excessive drinking and eating orlack of sleep, 2) fasting from 4 hours before blood sampling
until the end of the test, 3) not changing their life style, 4)
being prohibited from exposing themselves to direct sunlightoutdoors and to expose their measurement site to ultraviolet
rays in everyday life, 5) not taking new health food and 6)
not changing the kinds of skincare products they use or how
to use them.

Energy (Kcal)
Protein (g)Lipid (g)Carbohydrate (g)Sodium (mg)

WEM, water extract of mangosteen.

Clinical study design

In order to design the human study, a placebo-controlled
double-blinded randomized clinical trial was implemented.
An assignment supervisor randomly divided 40 subjects,
who had been selected through a screening process, into twogroups, and determined one group as WEM group and theother one as the placebo group. The allocation assignment
list was sealed up tightly and kept until the list was unsealed.
Two capsules of the test food per day (200mg as WEM)
were taken for 12 weeks. Before intake (0 week), 4, 8 and 12
weeks after intake, measurement of evaluation items as well
as physician interviews were conducted. The subjects took
the capsules from February through April in 2016.

_ 96 _Glycative Stress Research

Evaluation items
Skin function index

As skin function indices, transepidermal water loss andhorny cell layer water moisture were measured. After themeasurement site of skin was cleaned and acclimated in atemperature and humidity controlled room (21℃ ± 1℃, 50%± 10%) for 20 minutes, the measurement was carried out.
Tewameter (TM-300; Courage-Khazaka, Köln, Germany)
was used to measure transepidermal water loss, whereas
Corneometer (CM825; Courage-Khazaka) was used tomeasure horny layer water moisture. In both cases, a sectionof skin in the apex of the cheekbones on the left side of theirface was measured.

Vascular function index

As vascular function indices, API (arterial pressureindex) as well as AVI (arterial velocity pulse index) were
measured 29). PASESA AVE -1500 (Shisei Datum, Tokyo,
Japan) was employed to measure a site of their right upperarm.

Serum pentosidine quantitative

After blood serum (0.2 mL) was hydrolyzed withhydrochloric acid (6 N HCl, 100℃, 24 hours), it wasevaporated and solidified under reduced pressure. Then it wasdissolved in 1 mL of distilled water. This solution was added
to an equilibrated cation exchange column (Strata-X-Cv
Polymeric Strong Cation, 30 mg/mL; Phenomenex, Torrance,
CA, USA) and cleaned with 3mL of 0.1 M HCl. Afterbeing eluted with 3mL of 7% ammonia, it was evaporated
and solidified under reduced pressure. This substance wasredissolved in a heptafluorobutyric acid (HFBA) solution
and filtrated with 0.20 μm. Then it was quantified using highperformance liquid chromatography (HPLC) 28).

(Sidak test) was used to measure the comparison between
before and after intake, whereas an unpaired t-test (two-sidedtest) was performed to measure a comparison between thetwo groups. The significance level was below 5%.

Ethical principles

This study was conducted in accordance with Declarationof Helsinki (the declaration was corrected at WMA Fortaleza
General Assembly in 2013) as well as ethical principles
concerning medical researches (notification of Ministryof Education, Culture, Sports, Science and Technology as
well as Ministry of Health, Labor and Welfare). In order tosecure the subjects’ human rights and security, and ensure
the reliability of examination data, this research was carriedout after being deliberated and approved by Oriental Ueno
Medical Examination Center Ethics Review Committee(2016-01-06), Nippon Shinyaku Co., Ltd. Research Ethics
Committee (No.A151005) and “Ethics Committee for
Human Subject Research” at Tokai University. Furthermore,this study was registered by University hospital Medical
Information Network-Clinical Trials Registry (UMIN-CTR)
and implemented (Registration No: UMIN000032310).

Results

After researchers obtained approval from 40 volunteers
from 25 through 59 years of age, the study started with 20
subjects in the WEM group and 20 subjects in the placebogroup. Because two of them voluntarily quit, 19 subjects inthe WEM intake group and 19 subjects in the placebo group
actually participated in the research. The backgrounds ofthese subjects are shown in Table 3.
Table 3. Clinical characteristics

Safety index

As safety indicators, blood pressure/pulse, body weight/
body fat percentage/body mass index (BMI), a hematologic
test, a blood biochemical test and a urine test were conducted.
Blood pressure/pulse were measured using PASESA AVE1500, while body weight/body fat percentage/body massindex (BMI) were measured using DC-320 (Tanita, Tokyo,
Japan).
Hematologic examination items are shown as follows:
leucocyte count, erythrocyte count, hemoglobin, hematocrit,erythrocyte indices (MCV, MCH, MCHC) and blood platelet
count.
Biochemical examination of blood items are shown as
follows: total protein (TP), albumin (Alb), urea nitrogen (UN),creatinine (CRE), uric acid (UA), aspartate aminotransferase(AST), alanine aminotransferase (ALT), γ -glutamyltranspeptidase ( γ - GT), creatine kinase (CK), CRP
quantitative (CRP), total cholesterol (T-C), triglyceride(TG), LDL cholesterol (LDL-C), HDL cholesterol(HDL-C), sodium (Na), potassium (K), chloride (Cl), iron(Fe), fasting plasma glucose and HbA1c.

Statistical analysis

The results of the research were indicated with mean ±standard deviation. As examination methods, a multiple test

WEM (n =19)

Placebo (n =19)Age

43.1 ± 10.3

42.9 ± 10.2

Weight (kg)51.8 ± 6.8

51.6 ± 6.1

Height (cm)158.5 ± 5.0

156.0 ± 6.8

Values: means ± standard deviation. WEM, water extract of mangosteen.

Serum pentosidine concentration in the WEM group was
significantly greater than that of the placebo group before
intake (94.0 fmol /μL vs. 79.3 fmol /μL, p = 0.036). In the
WEM group, serum pentosidine concentration significantly
lowered 8 weeks after intake, compared with the level before
intake, whereas no significant change was determined in theplacebo group throughout the trial period, compared withthe level before intake ( Table 6 ). Meanwhile, no significant
difference in blood glucose level was identified between
before and after intakes as well as in the two groups
throughout the trial period. Although HbA1c of the WEM
group was significantly lower than that of placebo group 8
weeks after intake, no obvious change was observed between
the levels before and after intakes ( Table 6 ).

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Effect of Mangosteen Extract on Skin Moisture and Arterial Stiffness

Table 6. Hematologic testing

Parameter

Unit

Reference range Group

Pentosidine

fmol/μL–

Glucosemg/dL

70 – 109

HbA1c%

4.6 – 6.2

Total protein

g/dL

6.7 – 8.3

Albuming/dL

3.8 – 5.3

Urea nitrogenmg/dL

8 – 22Creatinine

mg/dL

0.47 – 0.79

Uric acidmg/dL

2.5 – 7.0

AST (GOT)

U/L

10 – 40

ALT (GPT)U/L

5 – 45

γ-GT

U/L

< 45

CK

U/L

45 – 210

CRP

mg/dL

< 0.30T-C

mg/dL

130 – 219

TG

mg/dL

35 – 149

LDL-C

mg/dL

70 – 139

HDL-C

mg/dL

40 – 96

Sodium (Na)mEq/L

135 – 147

Potassium (K)mEq/L

3.6 – 5.0

Chloride (Cl)mEq/L

98 – 108

Serum Iron (Fe)μg/dL

40 – 170

0W

4W

WEM

94.0 ± 20.8*

94.0 ± 23.9

WEM

89 ± 688 ± 8

Placebo79.3 ± 20.9
89 ± 6

Placebo
WEM
WEM

Placebo

89 ± 687 ± 690 ± 790 ± 67.7 ± 0.4

7.4 ± 0.5 #7.5 ± 0.4

7.6 ± 0.4

12 ± 3

WEM

83.5 ± 19.7

5.3 ± 0.2 #4.6 ± 0.3

Placebo70.8 ± 19.8

5.2 ± 0.2

4.7 ± 0.3

WEM

80.7 ± 21.8 # # 97.2 ± 23.0

5.3 ± 0.2 #*7.7 ± 0.4

Placebo

90 ± 612W

5.2 ± 0.2 # #5.3 ± 0.2

Placebo

83.3 ± 26.8

8W

11 ± 35.3 ± 0.3

7.4 ± 0.3 #4.5 ± 0.2
4.4 ± 0.3
13 ± 412 ± 35.5 ± 0.2 #7.4 ± 0.5 #4.6 ± 0.2
4.5 ± 0.3
12 ± 411 ± 35.4 ± 0.3
7.5 ± 0.4
4.5 ± 0.2
4.5 ± 0.2
13 ± 312 ± 3

WEM

0.59 ± 0.07

0.61 ± 0.08

0.62 ± 0.09

0.64 ± 0.08 ##WEM

4.3 ± 0.9

4.5 ± 1.1

4.3 ± 0.8

4.4 ± 1.0

Placebo0.55 ± 0.09
4.0 ± 0.7

Placebo

21 ± 6

WEM

20 ± 5

Placebo

17 ± 4

WEM

17 ± 6

Placebo

21 ± 11

WEM

Placebo

24 ± 110.57 ± 0.09
4.0 ± 0.6
21 ± 620 ± 416 ± 615 ± 522 ± 1121 ± 1081 ± 20

0.58 ± 0.09
4.0 ± 0.5
20 ± 619 ± 316 ± 516 ± 422 ± 1220 ± 7 #85 ± 26

0.61 ± 0.09 # #4.1 ± 0.6
20 ± 621 ± 515 ± 416 ± 422 ± 1218 ± 6 # #86 ± 32*

WEM

101 ± 63

WEM

0.04 ± 0.03

0.05 ± 0.03

0.06 ± 0.10

0.05 ± 0.04

WEM

217 ± 39

205 ± 38 # #210 ± 40211 ± 33

Placebo
Placebo
Placebo
WEM

Placebo

105 ± 480.04 ± 0.02
232 ± 34
70 ± 3176 ± 33

104 ± 57

0.13 ± 0.28
222 ± 29
68 ± 2174 ± 37

WEM

118 ± 32

111 ± 29 #WEM

89 ± 1981 ± 19 #Placebo
Placebo

136 ± 3685 ± 17127 ± 3181 ± 19WEM

139 ± 1

141 ± 2 # #WEM

3.9 ± 0.2

4.2 ± 0.2 #Placebo
Placebo

140 ± 14.0 ± 0.4

141 ± 1 # #4.1 ± 0.4

100 ± 420.08 ± 0.10
225 ± 26
61 ± 2078 ± 33

126 ± 73

0.04 ± 0.02
226 ± 2871 ± 2173 ± 33

111 ± 31110 ± 27 #88 ± 2084 ± 17126 ± 3385 ± 17127 ± 3284 ± 17141 ± 1 # #141 ± 2 #4.0 ± 0.2

4.0 ± 0.2

141 ± 1 # #4.1 ± 0.4

141 ± 1 #4.0 ± 0.4

WEM

101 ± 2*104 ± 2 # #105 ± 2 # #104 ± 2 # #WEM

98 ± 41*94 ± 32

96 ± 35

91 ± 38

Placebo

103 ± 2

Placebo

70 ± 40104 ± 2 #80 ± 42105 ± 2 # #79 ± 38

105 ± 2 # #82 ± 44

Values: means ± standard deviation. * p < 0.05, ** p < 0.01: Comparison with the Placebo group by t-test. # p < 0.05, ## p < 0.01: Comparison with before
administration by Sidak. WEM, water extract of mangosteen.

_ 98 _Glycative Stress Research

Transepidermal water losses in the cheek skin before
intake were 18.0 in WEM group and 16.9 in the placebogroup, which indicated no significant difference between thetwo groups (p = 0.468). Compared with the value obtained
before intake, the WEM group revealed −3.0 %, 4.5% and−5.3%, respectively, 4, 8 and 12 weeks after intake, whichwere lower than those of the placebo group, because theplacebo group showed 1.0 %, 9.9 % and 1.7%, respectively.
However, there was no significant difference between thetwo groups before and after intakes ( Fig. 1-A). On the other
hand, skin moisture content of the WEM and the placebogroups before intake were 56.8 and 56.4, respectively,
which revealed no significant difference between the twogroups ( p = 0.865). Compared with the value before intake,skin moisture content of the WEM and placebo groups
demonstrated 3.6%, −2.7% and 7.4%, respectively, whereas
those of the placebo group were −3.0 %, −8.4 % and −3.9 %respectively, 4, 8 and 12 weeks after intake. This result,
therefore, clarified that skin moisture content of the WEM
group was significantly greater than that of placebo group 8
and 12 weeks after intakes ( Fig. 1-B ).
API before intake were 23.0 and 22.2 in the WEM
group and the placebo group, respectively, which showed nosignificant difference between the two groups ( p = 0.674).
Compared with API before intake, API values of the WEM
group were −7.4%, −13.4% and −8.7%, respectively, while
those of the placebo group were 5.2%, 7.5% and 1.9 %,respectively. The result, therefore, clarified that API of the
WEM group was significantly lower than that of the placebogroup 8 weeks after intake and also lower, compared withthe level before intake ( Fig. 2-A). Meanwhile, the AVI of the
WEM and the placebo groups before intakes were 18.7 and

17.6, respectively, which indicated no significant difference

50

A

Corneometer (change ratio %)Tewameter (change ratio %)50

between the two groups (p = 0.540). Compared with thevalue before intakes, the AVI of the WEM group were
−14.9 %, −9.8% and −0.7%, while those of the placebogroup were − 0.7%, 5.2% and 9.9 %, respectively, 4, 8 and
12 weeks after intake. This result showed that the AVIof the WEM group was significantly lower 4 weeks after
intake than AVI before intake ( p = 0.010).
Concerning the subjects’ body weight, body fat percentage
and BMI, no significant difference associated with WEM
intake was determined between the two groups. Moreover,there was no change between before and after intakes,
except that the body fat percentage of WEM group was
significantly lower 4 weeks after intake than before intake( Table 4 ). Regarding systolic blood pressure, diastolic bloodpressure and pulse rate, no significant change was identified
in both the WEM and the placebo groups throughout the test
period ( Table 4 ). Meanwhile, the decrease of erythrocyte
count, 4 and 8 weeks after intakes as well as the decrease ofhemoglobin count 8 weeks after intake were determined in
the WEM group, compared with the levels before intake. In
terms of hemoglobin and hematocrit, MCV, MCH, MCHC
and platelet count, a significant difference between the twogroups was identified from the levels before intakes ( Table 5 ).
Furthermore, values of TP, CRE, γ -GT, T- C, LDL-C,
HDL-C, Na, K and Cl in WEM group changed after intake,compared with those before intake. However, they did notdeviate from reference values. CK of the WEM group was
lower than that of the placebo group 12 weeks after intake,but the value still fell within the reference range ( Table 6 ).
In addition, the result of urine tests fell within the reference
range. No adverse event that had a causal relationship with
WEM intake was observed.

0

- 50

- 100

B
＊
＊

0

＃＃
- 50

-100
0W

4W

8W

12W

0W

4W

8W

12W

Fig. 1. Values of percutaneous water transpiration quantity measured with Tewameter (A) and skin moisturemeasured with Corneometer (B).
Results of change ratio (%) of WEM group ( ● ) and Placebo group ( ○ ) are expressed as mean ±standard deviation.
* p<0.05: Comparison with the Placebo group by t-test. ＃＃p < 0.01: Comparison with before administration by Sidak.

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Effect of Mangosteen Extract on Skin Moisture and Arterial Stiffness

100

100

A
AVI (change ratio %)API (change ratio %)

50

0

＊
＃

- 50

- 100

B

50

0

＃

- 50

- 100
0W

4W

8W

12W

0W

4W

8W

12W

Fig. 2. Values of API (A) and AVI (B) measured with the PASESA.

Results of change ratio (%) of WEM group ( ● ) and Placebo group ( ○ ) are expressed as mean ±standard deviation.
* p < 0.05: Comparison with the Placebo group by t-test. ＃p < 0.05: Comparison with before administration by Sidak. API,
Arterial Pressure Index; AVI, Arterial Velocity pulse Index.

Table 4. Physical testing

Body
composition

Bloodpressure

Pulse rate

Parameter

Unit

Weightkg

Body fat

%

MBI

kg/m2

Systolic

mmHg

Diastolic

mmHg

bpm

Group

0W

4W

8W

12W

WEM

51.8 ± 6.7

51.9 ± 6.8

52.1 ± 6.7

52.1 ± 6.9

Placebo51.6 ± 6.1

51.9 ± 6.4

52.1 ± 6.4

51.8 ± 6.4

WEM29.2 ± 5.4

28.7 ± 5.5 #28.9 ± 5.5

28.9 ± 5.1

Placebo29.7 ± 5.2

30.4 ± 4.6

30.3 ± 4.7

30.1 ± 4.4

WEM20.6 ± 2.7

20.7 ± 2.7

20.8 ± 2.7

20.7 ± 2.7

Placebo21.2 ± 2.4

21.4 ± 2.5

21.4 ± 2.4

21.3 ± 2.4

WEM

110 ± 12105 ± 13107 ± 12108 ± 13

Placebo

108 ± 18

106 ± 17113 ± 21108 ± 17WEM

67 ± 1063 ± 1068 ± 967 ± 10

Placebo

63 ± 1163 ± 1169 ± 1267 ± 10WEM

63 ± 963 ± 968 ± 965 ± 10

Placebo

66 ± 969 ± 971 ± 1368 ± 8

Values: means ± standard deviation. # p < 0.05: Comparison with before administration by Sidak. WEM, water extract of mangosteen; BMI, body mass index.

_ 10 0 _Glycative Stress Research

Table 5. Hematologic testing

Parameter

Unit

Reference range

Leukocyte count/μL

3500 – 9100

Erythrocyte count10 4/μL

376 – 500

Hemoglobin

g/dL

12.3 – 15.2

Hematocrit%

33.4 – 44.9

MCV

fL

79 – 100MCH

pg

26.3 – 34.3

MCHC

%

30.7 – 36.6

10 4/μL

13.0 – 36.9

Platelet count

Group

0W

4W

8W

12W

WEM

5958 ± 1245

5568 ± 1818

5826 ± 1505

5658 ± 1060

Placebo6132 ± 1812

6053 ± 2001

6026 ± 1707

5984 ± 1605

WEM

452 ± 28447 ± 28 #441 ± 26 #440 ± 29

Placebo453 ± 22443 ± 18443 ± 23443 ± 21WEM

13.6 ± 0.7*

13.5 ± 0.8**

13.3 ± 0.6 # **13.3 ± 0.9 *Placebo12.7 ± 1.5

12.4 ± 1.3

12.3 ± 1.3

12.4 ± 1.4

WEM42.1 ± 1.9*

41.3 ± 2.3*

40.7 ± 1.9 # # *41.2 ± 2.4

Placebo40.1 ± 3.5

39.1 ± 3.1

38.9 ± 3.1 #39.4 ± 3.4 #WEM

93 ± 5*93 ± 4 *93 ± 4 *94 ± 4 *Placebo

89 ± 788 ± 788 ± 789 ± 7

WEM

30.1 ± 1.4**

30.2 ± 1.4 **30.1 ± 1.4 **30.3 ± 1.5 **Placebo28.1 ± 2.9

28.0 ± 2.9

27.9 ± 2.9

28.0 ± 2.8

WEM32.3 ± 0.6*

32.7 ± 0.5 **32.6 ± 0.5 **32.3 ± 0.7 *Placebo31.6 ± 1.2

31.7 ± 1.1

31.7 ± 1.0

31.5 ± 1.2

WEM23.6 ± 3.7**

23.2 ± 3.8 **23.7 ± 3.6**

24.0 ± 4.3 *Placebo30.2 ± 6.4

29.2 ± 6.9

28.7 ± 6.9

29.1 ± 7.2

Values: means ± standard deviation. * p < 0.05, ** p < 0.01: Comparison with the Placebo group by t-test. # p < 0.05, ## p < 0.01: Comparison with before
administration by Sidak. WEM, water extract of mangosteen.

Discussion

Serum pentosidine concentrations of the WEM group
significantly decreased 8 weeks after intake, compared withthe value obtained before intake. This result correspondedwith the previous report 28). However, serum pentosidine
concentrations of both WEM and placebo groups increased
12 weeks after intake. Since there is not enough information
for healthy people’s variation factors for pentosidine
concentration in blood, the cause for the change in pentosidine
concentration 12 weeks after intake is unknown.
Because moisture content of skin of WEM group was
significantly higher than that of placebo group 8 and 12 weeks
after intakes, it was considered that WEM intake improved
the water retention function of skin. Pentosidine, one type ofAGE, forms cross-links between collagen molecules in thedermis in a nonspecific manner 17). It is, therefore, consideredthat improvement of glycative stress reduces production ofcross-links between collagen molecules, enhances turnoverof skin and leads to the improvement of three-dimensional
structures of skin collagen. Moreover, it has been reported
that N ε- (carboxymethyl) lysine (CML), a type of AGE,
induces apoptosis of fibroblasts, which secretes hyaluronan
contributing to water retention capacity of the skin 30, 31). It
was, therefore, considered that the reduction of glycative
stress could improve functions of dermal fibroblasts.
API reflects arterial stiffness of brachial artery in themeasurement site 29). Since due to the intake of WEM, APIvalue of the WEM group was lower than that of the placebogroup 8 weeks after intakes (Fig.2-A), and it was consideredthat the ingestion of WEM enhanced arterial softness.
According to Reddy GK’s report, glycation of rabbit tendons
increased their stiffness 32). This was because pentosidine
was formed in collagen 32). However, considering that WEM
intakes decreased serum pentosidine concentration, there
is also a possibility that stiffness of arterial collagen could
be improved by taking WEM. The result indicated that AVI
value reflected the function of vascular endothelium 33, 34).
Moreover, it was reported that AGEs elicited inflammation
through RAGE (Receptor of AGEs) and impaired blood vessels
by suppressing NO (nitric oxide) 35, 36). An epidemiologicalstudy reported a relationship between API value as well as
AVI value and the risk of arteriosclerosis that could happen
in the future 37). According to the result shown in Fig. 2-B,
the function of vascular endothelium was improved in the
WEM group. It is, therefore, expected that reduction of
AGE accumulation by taking WEM will alleviate vascular
injury through RAGE and lead to reduction of the risk ofarteriosclerosis that might occur in the future.
Saito et al. clarified that pentosidine concentration inbone collagen was related to stiffness of bone 38). On theother hand, Arai et al. reported a correlation between serum
concentrations of pentosidine and schizophrenia 39). Thus,by monitoring levels of AGEs on a daily basis, there is apossibility that we can recognize the changes in our healthconditions that we cannot notice through regular healthcheck-ups. It is, therefore, expected that inhibition of AGE
production associated with our lifestyle will greatly contributeto mental health as well as physical health in our everyday lifeand reduce the risk of becoming ill in the future.

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Effect of Mangosteen Extract on Skin Moisture and Arterial Stiffness

Conclusion

It was suggested that ingestion of WEM may reduce
glycative stress, improve moisture content of skin andcontribute to retention of skin moisture. Furthermore, it wassuggested that the ingestion of WEM not only improves
flexibility of blood vessels but also may reduce the risk ofarteriosclerosis that could occur in the future. It is, therefore,
considered that since the intake of WEM decreases glycative
stress, as a secure health food, WEM will play a key role in
reducing risks of the future illness.

Declaration of Conflict of Interest

The clinical test of this research was sponsored by Nippon
Shinyaku Co., Ltd., and was conducted in TES Holdings.
Meanwhile, Nippon Shinyaku Co., Ltd., invested on researchfunding of the quantitative analysis of serum pentosidine andit was carried out at Tokai University.

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