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Efficacy and Safety of Enzyme-Modified Panax ginseng for Anti-Wrinkle Therapy in Healthy Skin: A Single-Center, Randomized, Double-Blind, Placebo-Controlled Study

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  • Biomedical Dermatology Research Institute

Abstract and Figures

Human skin undergoes changes during aging that result from the synergistic effects of intrinsic and extrinsic factors. These changes may culminate in wrinkle formation, a characteristic of aged skin. Panax ginseng and ginsenosides have promising properties in preventing skin aging. Our previous study demonstrated that enzyme-modified ginseng extract (EG) has inhibitory effects against UVB-induced skin aging. The purpose of the current study was to evaluate the preventive effects of EG on eye-wrinkle formation by applying EG cream in 23 randomized human subjects. Compared to the placebo, EG significantly reduced global photodamage score. In addition, total roughness (R1), smoothness depth (R4), and arithmetic roughness average (R5) were significantly decreased with use of EG. In a post-study questionnaire, subjects responded that EG efficiently absorbed into the skin and was more potent in moisturizing and softening skin than the placebo. No participants reported adverse reactions to treatment. In conclusion, EG sufficiently suppressed eye wrinkle formation by decreasing various roughness measures based on assessment with non-invasive devices. Therefore, our results indicate that EG is a promising anti-aging candidate that could be used as an ingredient in natural functional food and cosmetic products.
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Efficacy and Safety of Enzyme-Modified Panax ginseng
for Anti-Wrinkle Therapy in Healthy Skin:
A Single-Center, Randomized, Double-Blind,
Placebo-Controlled Study
Eunson Hwang,
1,
*Sang-Yong Park,
1,
*Hae Jo,
2
Don-Gil Lee,
1
Hee-Taek Kim,
3
Yong Min Kim,
3
Chang Shik Yin,
4
and Tae Hoo Yi
1,2
Abstract
Human skin undergoes changes during aging that result from the synergistic effects of intrinsic and extrinsic
factors that may culminate in wrinkle formation, a characteristic of aged skin. Panax ginseng and ginsenosides
have promising properties in preventing skin aging. Our previous study demonstrated that enzyme-modified
ginseng extract (EG) has inhibitory effects against ultraviolet B (UVB) radiation-induced skin aging. The purpose
of the current study was to evaluate the preventive effects of EG on eye-wrinkle formation by applying EG cream
in 23 randomized human subjects. Compared to the placebo, EG significantly reduced the global photo-damage
score. In addition, total roughness (R1), smoothness depth (R4), and arithmetic roughness average (R5) were
significantly decreased with use of EG. In a post-study questionnaire, subjects responded that EG was absorbed
efficiently into the skin and was more potent in moisturizing and softening skin than the placebo. No participants
reported adverse reactions to treatment. In conclusion, EG sufficiently suppressed eye wrinkle formation by
decreasing various roughness measures on the basis of assessment with non-invasive devices. Therefore, our
results indicate that EG is a promising anti-aging candidate that could be used as an ingredient in natural functional
food and cosmetic products.
Introduction
Human skin undergoes constant changes during
aging that result from the synergistic effects of both
intrinsic (genetic determinants) and extrinsic (environmental
influences) factors. While intrinsically aged skin appears thin
and finely wrinkled, extrinsically aged (photo-aged) skin is
characterized by deep and thick wrinkles.
1
To date, many
studies have investigated mechanisms of protecting against
extrinsic insult to human skin. These include studies of the
chemicals, toxins, reactive oxidative species (ROS), and ul-
traviolet radiation (UVR) implicated in the aging process,
with the ultimate goal of slowing the development of photo-
aged wrinkle formation. Among the extrinsic factors that
contribute to skin aging, UVR is thought to play the most
important role.
2
UVR activates the enzyme family of matrix
metalloproteinases (MMPs) that can degrade extracellular
matrix proteins.
3
Stimulated MMPs accelerate dermal colla-
gen degradation that causes skin thickening and coarse
wrinkle formation.
4
Furthermore, over time, repetitive ac-
tions of the facial musculature result in the development of
permanent facial lines.
5
Contraction of the orbicularis oculi
muscle, for example, forms eye wrinkles commonly called
crow’s feet.
Over the past two decades, interest in reversing the effects
of aging on skin has increased considerably.
6
Because skin
is damaged by the aging process itself and by extrinsic in-
sults like long-term or severe UVR, there is need for func-
tional food and cosmetic products that can delay facial
wrinkling. Studies of oriental herb extracts have provided
new insights into the effects of functional cosmetics on the
prevention of skin aging.
7
Panax ginseng is one promising
candidate that has been used as a botanical drug for several
thousand years. The biological activity of Panax ginseng is
imparted by its component ginsenosides. The major ginse-
nosides found in ginseng (Rb1, Rb2, Rc, Rd, Re, and Rg1)
1
Department of Oriental Medicinal Material and Processing, College of Life Science, Kyung Hee University Global Campus, Yongin,
Republic of Korea.
2
Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea.
3
College of Oriental Medicine, Semyung University, Jecheon, Korea.
4
Acupuncture and Meridian Science Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Korea.
*These authors contributed equally to this work.
REJUVENATION RESEARCH
Volume 18, Number 5, 2015
ªMary Ann Liebert, Inc.
DOI: 10.1089/rej.2015.1660
1
comprise about 80%, whereas the minor ginsenosides (F1,
F2, Rg3, Rh1, Rh2 compound Y, compound Mc, and
compound K) are absent or present in low concentrations.
8
Recent research has investigated the precise role of these
ginsenosides and ginseng extract in preventing skin ag-
ing.
9,10
For example, ginsenoside Rb1 has anti-aging ac-
tivities in skin that result from increased type I collagen
production and suppression of UV-induced apoptosis.
11,12
Kim et al. (2004) reported that topical treatment with
compound K increases the amount of hyaluronan in the skin
of hairless mice.
13
Ginsenoside Rg3 inhibits growth of hu-
man melanoma cells.
14
Lee et al. (2003) showed that gin-
senoside F1 protects human HaCaT keratinocytes from
UVB-induced apoptosis.
15
It has been reported that minor ginsenosides may function
more effectively than major ginsenosides because minor gin-
senosides are more easily absorbed into the bloodstream.
16
Therefore, minor ginsenosides may have potential as func-
tional food ingredients and drug candidates. Major ginseno-
sides can be transformed into minor ginsenosides through
hydrolysis of their sugar moieties. The minor ginsenoside F2 is
transformed by protopanaxadiol (PPD) derivatives that enzy-
matically hydrolyze two glucose molecules at C-3 and one
glucose molecule at C-20.
17
Our previous study demonstrated
that ginsenoside F2 has anti-cancer effects in breast cancer
stem cells and glioblastoma multiforme.
18
Recently, we also
reported that ginsenoside F2 prevents hair loss and simulta-
neously induces hair growth.
19,20
On the basis of the mounting
evidence of the anti-aging properties of ginseng and our pre-
vious findings that enzyme-modified ginseng extract (EG) has
inhibitory effects against UVB-induced skin aging in human
dermal fibroblasts and hairless mice,
10
we hypothesized that
topical application of EG may be beneficial to reduce clinical
signs of skin aging.
Materials and Methods
Preparation of enzyme-modified Panax ginseng cream
Enzyme-modified Panax ginseng (EG) was extracted as
previously described.
10
EG was produced using a patented
protocol (Korea patent no. 1014540660000). Briefly, the crude
enzyme was extracted from Aspergillus niger (KACC 40280),
which was isolated from the Nuruk for makgeolli, Korean
traditional wine. The active enzyme was purified by loading it
into an ion-exchage resin. Dried and ground ginseng (0.5 kg)
was incubated with the enzyme solution containing
ginsenoside-b-glucosidase and extracted from 5.0 liters of
ethanol. Ginseng was incubated with the enzyme at 50–60C
for 24 hr. After reaction, the enzyme was removed by ultra-
filtration (molecular weight cutoff [MWCO], 10,000 Da). The
solution was then filtered and concentrated. In addition, the
composition of EG had been analyzed and characterized pre-
viously by our research group.
10
Liquid chromatography
coupled with tandem mass spectrometry (LC-MS/MS) was
performed with an Agilent 6410 Triple Quad Tandem Mass
Spectrometer. The total ginsenosides content and two main
ginsenosides (Rb1 and Rg1) of EG were 214.24 lg/mg and
90.43 lg/mg, respectively. Ginsenoside F2 as an active com-
pound of EG was 45.51 lg/mg. EG and placebo formulations
were identical in color, fragrance, and packaging. The com-
position of formulations is shown in Table S1 (Supplementary
Data are available at www.liebertonline.com/rej/).
Subjects and study design
In this randomized, double-blind study, 23 healthy Ko-
rean women 30–65 years old presenting with crow’s feet
wrinkles were enrolled and 22 women were recruited as
participants. One out of the initial 23 enrolled subjects was
excluded from subsequent analysis because of agreement
withdrawal/treatment refusal (n=1). Baseline severity of
global photo-damage was scored from 2 to 6 using the Jung
score of facial skin photo-aging. Participants were requested
to abstain from the following for the duration of the trial: (1)
Exposure to sunlight; (2) lotion, creams, or other facial
products; (3) smoking or excessive alcohol consumption;
and (4) no use of cosmetics for at least 12 hr prior to as-
sessment. Participants were excluded if they reported any of
the following: (1) Use of topical anti-aging products in the
previous 3 months; (2) tretinoin use or superficial peels in
the previous 6 months; (3) topical steroidal ointment in the
previous months; (4) history of fillers, botulinum toxin,
medium-depth peel, ablative laser, or surgical lifting in the
previous 24 months; (5) pregnancy or breastfeeding; (6)
exposure to artificial UV radiation; (7) allergy to any in-
gredients in the cream; or (8) dermatological problems.
All participants provided written informed consent before
enrolling in the study. After completing the above-mentioned
enrollment process, the study coordinator randomly allocated
the subjects into each group on the basis of a computer-
generated random number table. The subjects and investigators
were blind to the group allocation throughout the study period.
The study was conducted in accordance with the guidelines for
study no. 2009-166 of the Korea Food & Drug Administration.
The trial started on August 23 and was completed November
17. The protocol was reviewed and approved by the Ethics
Committee (Oriental Hospital of Se-Myung University, Je-
cheon, South Korea) in August 2011. This study was carried
out in accordance with the Declaration of Helsinki (1964),
changed in Tokyo (2004) and Seoul (2008).
Treatment
All volunteers were instructed about application of the
formulation, and the crow’s feet wrinkle area was selected as
the testing area. Active formulation (EG) was applied on the
left or right eye area manifesting signs of crow’s feet, and the
placebo was applied on the other eye area, respectively, twice
daily (morning and night) for 12 weeks. Before application,
subjects were asked to wash their skin using the same mild
facial nickel-tested cleanser. Subjects were not allowed to use
any other cosmetic products during the treatment period.
Visual assessment
Patients were assessed at the investigating center at baseline
(week 0) and at weeks 4, 8, and 12. The primary efficacy end
point was the investigator’s assessment of global photo-
damage score (GPDS) at week 12. GPDS ranged from 0 to 7 as
follows: 0, none; 1, none/mild; 2, mild; 3, mild/moderate; 4,
moderate; 5, moderate/severe; 6, severe; and 7, very severe.
21
Photography
Photographs of the patients’ faces were taken at weeks 0,
4, 8, and 12 weeks under standardized conditions. Photo-
graphs were of the areas lateral to the right and left eyes. All
2 HWANG ET AL.
photographs were taken with subjects looking straight ahead
under constant lighting conditions with the same camera,
camera settings, and camera placement. A Nikon D200
camera was positioned on an SVK 35D tripod to the right of
the subject’s face and perpendicular to the area to be pho-
tographed, whereas an Olympus twin T28 Macroflash unit
was positioned with one flash head directly above the lens
pointed at the subject and the other directed away. Exposure
was controlled by adjusting the lens aperture with the flash
set on manual at full output.
Non-invasive measurements of the skin
All measurements were performed under standardized
conditions, i.e., room temperature of 22 2C and a relative
humidity level of 50% 10%. An acclimatization time of at
least 30 min was allowed before measurements started. To
obtain skin replicas, 1.0 cm of light-bodied silicone (SilfloR,
Flexico, Colchester, UK) was prepared from two compo-
nents mixed at a ratio of 1:1 under decompression (two
drops each of catalyst and thinner). The mixture was then
applied to the skin surface. After drying and hardening, the
replicas were subjected to further analysis. (Fig. 1). Image
files were analyzed using the program Skin Viscometer SV
600 (Courage & Khazaka, Cologne, Germany). Arbitrary
units (R1–R5) were assigned to each sample on the basis of
the furrow depth according to shadow size and brightness
due to inflection under illumination. Investigated roughness
parameters were R1 (skin roughness), R3 (average rough-
ness), and R5 (arithmetic average roughness). Skin rough-
ness (R1) was defined as the difference between the highest
crest and lowest furrow. Maximum roughness (R2) was the
largest value recorded. Depth of smoothness (R4) was also
recorded.
Questionnaire study
At the completion of the 12-week study period, all par-
ticipants answered the following questions presented in a
questionnaire: ‘‘Have you noticed an improvement in your
skin moisture?’’, ‘‘Have you noticed an improvement in your
skin smoothness?’’, ‘‘Has your skin elasticity improved?’’,
‘‘Which product do you think has an anti-wrinkle effect?’’,
and ‘‘If there was an observed improvement, which do you
think is more effective in absorption?’’ The answers choices
were as follows: A, excellent; B, good; C, moderate; D, poor;
and F, bad.
Clinical assessment
Assessments were performed by the same two professional
investigators at weeks 0, 4, 8, and 12 and were performed
blinded to previous assessments. Right and left eyes were
graded separately. Adverse effects were also recorded, in-
cluding erythema, edema, scaling, itching, stinging, burning,
tightness, or prickling of the skin, which were graded as none,
mild, severe, or very severe. Evaluation was performed in the
same location and with the same lighting at each visit.
Statistical analysis
Statistical analysis was performed for those who com-
pleted the trial. SPSS software version 17.0 (SPSS Inc.,
Chicago, IL) was used for statistical analysis. Differences
between groups were evaluated with Student’s t-test, and
differences within groups were analyzed with analysis of co-
variance (ANCOVA). A pvalue <0.05 was considered to be
significant. Descriptive statistical analysis was performed
with the questionnaire assessments.
Results
Demographics of subjects
Twenty-three subjects (female) with average age of
46.87 6.50 years enrolled in the study. Because of protocol
noncompliance, one subject was withdrawn from the study.
As shown in Table 1, eye wrinkles of right and left sides
were assessed by GPDS before treatment with EG. The
average GPDS values for the right and left sides of subject
faces were 3.83 1.53 and 3.91 1.53, respectively. Before
the study began, 70% of participants complained of dry skin.
Sixty-five percent complained of thin crow’s feet and nor-
mal skin elasticity.
Analysis of EG effect on eye wrinkles in human skin
As shown in Table 2, we compared the severity of eye
wrinkles by measuring GPDS before and after 4, 8, and 12
weeks of treatment. Before treatment with EG or placebo,
baseline GPDS scores were 4.05 1.46 and 3.86 1.55, re-
spectively. After 4 weeks, GPDS values increased to
4.09 1.41 in the EG group and 3.91 1.54 in the placebo
FIG. 1. Study flowchart of the participants describing trial
progress.
EFFICACY AND SAFETY OF EG FOR ANTI-WRINKLE THERAPY 3
group. However, GPDS values decreased in the EG treat-
ment (3.77 1.51) at 12 weeks.
Images of eye wrinkle sites were measured at each time
point by an SV600 Visiometer. Before treatment with EG or
placebo, total skin roughness (R1) was 0.16 0.04 and
0.14 0.05 arbitrary unit (AU) for the right and left sides,
respectively. At weeks 4, 8, and 12, R1 values significantly
decreased by 0.03 0.03, 0.04 0.04, and 0.05 0.05 A.U,
respectively, in the EG group. However, no significant
changes were found at these time points in the placebo
group (Table 3). The baseline maximum roughness (R2) was
0.09 0.02 A.U in both EG and placebo groups. EG treat-
ment decreased R2 values by 0.08 0.02, 0.07 0.02, and
0.6 0.02 A.U. at 4, 8, and 12 weeks, respectively (Table 4).
Before treatment with EG or placebo, the average roughness
(R3) was the same in both groups at 0.06 0.02 A.U. After
12 weeks, R3 values decreased in both EG and placebo
treatment groups (Table 5). However, it was more effec-
tively improved in the EG group at 0.04 0.01 A.U. than in
the placebo group at 0.05 0.01 A.U. In total, EG was more
effective than placebo in decreasing R1, R2, and R3
roughness after 12 weeks.
High values of smoothness depth (R4) indicate reduced skin
moisture. Baselines of R4 of EG and placebo were 0.080.03
and 0.06 0.02A.U, respectively. These R4 values were
comparably improved by EG and placebo to 0.05 0.01 and
0.05 0.02A.U., respectively, at 12 weeks. However, the
Table 1. GPDS Values in Week 0
GPDS
a
23456
Eye side
Right (%) 17 44 4 9 26
Left (%) 22 26 17 9 26
a
Global photo-damage score (GPDS): 2, mild; 3, mild/moderate;
4, moderate; 5, moderate/severe; 6, severe.
Table 2. GPDS Value Changes
EG Placebo
Arbitrary
units (average SD
p
value
a
p
value
b
GPDS
Baseline 4.05 1.46 3.86 1.55 0.691
After 4 weeks 4.09 1.41 3.91 1.54 1.000
1.000
Difference
c
0.05 0.21 0.05 0.21 0.064
pvalue
d
0.045* 0.045*
After 8 weeks 4.05 1.36 3.95 1.50 0.364
0.323
Difference
e
0.00 0.31 0.09 0.29 0.090
pvalue
d
0.066 0.063
After 12 weeks 3.77 1.51 3.91 1.38 0.162
0.048*
Difference
f
-0.27 0.55 0.05 0.49 0.157
pvalue
d
0.117 0.104
a
Compared between groups: pvalue by Student’s t-test.
b
Compared between groups: pvalue by ANCOVA (adjustment
with baseline).
c
After 4 weeks -baseline.
d
Compared within groups: pvalue by paired t-test.
e
After 8 weeks -baseline.
f
After 12 weeks -baseline.
*p<0.05, **p<0.01 by Student’s t-test for comparison with
placebo group.
EG, enzyme-modified ginseng extract; GPDS, global photo-
damage score; SD, standard deviation; ANCOVA, analysis of co-
variance.
Table 3. Skin Roughness (R1) Value Changes
EG Placebo
Arbitrary
units (average SD
p
value
a
p
value
b
Skin Roughness (R1)
Baseline 0.16 0.04 0.14 0.05 0.064
After 4 weeks 0.13 0.04 0.12 0.03 0.360 0.406
Difference
c
-0.03 0.03 -0.02 0.04 0.010
pvalue
d
0.006** 0.008**
After 8 weeks 0.12 0.03 0.12 0.03 0.754
0.047*
Difference
e
-0.04 0.04 -0.02 0.04 0.012
pvalue
d
0.008** 0.008**
After 12 weeks 0.11 0.02 0.11 0.03 0.127
0.036*
Difference
f
-0.05 0.05 -0.02 0.04 0.014
pvalue
d
0.011* 0.008**
a
Compared between groups: pvalue by Student’s t-test.
b
Compared between groups: pvalue by ANCOVA (adjustment
with baseline).
c
After 8 weeks -baseline.
d
Compared within groups: pvalue by paired t-test.
e
After 16 weeks -baseline.
f
After 24 weeks -baseline.
*p<0.05, **p<0.01 by Student’s t-test for comparison with
placebo group.
EG, enzyme-modified ginseng extract; GPDS, global photo-damage
score; SD, standard deviation; ANCOVA, analysis of co-variance.
Table 4. Maximum Roughness (R2) Value Changes
EG Placebo
Arbitrary units
(average SD)
p
value
a
p
value
b
Maximum roughness (R2)
Baseline 0.09 0.02 0.09 0.02 0.412
After 4 weeks 0.08 0.02 0.08 0.02 0.772
0.803
Difference
c
-0.01 0.02 -0.01 0.02 0.005**
pvalue
d
0.018* 0.018*
After 8 weeks 0.07 0.02 0.08 0.02 0.394
0.069
Difference
e
-0.02 0.02 -0.01 0.02 0.006**
pvalue
d
0.018* 0.021*
After 12
weeks
0.06 0.02 0.08 0.02 0.159
0.057Difference
f
-0.03 0.03 -0.01 0.02 0.007**
pvalue
d
0.026* 0.021*
a
Compared between groups: pvalue by Student’s t-test.
b
Compared between groups: pvalue by ANCOVA (adjustment
with baseline).
c
After 8 weeks -baseline.
d
Compared within groups: pvalue by paired t-test.
e
After 16 weeks -baseline.
f
After 24 weeks -baseline.
*p<0.05, **p<0.01 by Student’s t-test for comparison with
placebo group.
EG, enzyme-modified ginseng extract; GPDS, global photo-damage
score; SD, standard deviation; ANCOVA, analysis of co-variance.
4 HWANG ET AL.
overall change in R4 was greater in the EG-treated group than
in the placebo group (Table 6). EG treatment decreased the
arithmetic roughness average (R5) value (down to 0.01
0.01 A.U.), whereas placebo did not (Table 7). Overall, EG
treatment resulted in statistically significant decreases in R1,
R4, and R5 values. Representative pictures of clinical results
are shown in Fig. 2.
Self-satisfaction assessment after treatment
Questionnaires are routinely used in clinical research to
assess indices of reliability and validity.
22
Responses to the
questionnaire are summarized in Fig. 3. Compared to placebo,
subjects responded that EG was more efficiently absorbed
into the skin. Subjects also responded that EG was more po-
tent in moisturizing and softening the skin than was the pla-
cebo. However, almost all participants noted no difference in
anti-photo-aging effects between the two products.
Safety results
No participants reported adverse reactions to treatment, in-
cluding erythema, edema, scaling, itching, stinging, burning,
tightness, or prickling of the skin.
Discussion
In this explorative clinical trial, the efficacy of EG as an
anti-wrinkle agent was assessed using a variety of techniques,
including clinical examination by investigators, instrumental
evaluation measured by skin replicas, and self-report–type
questionnaires. We found that EG has significant anti-wrinkle
effects over placebo when used topically in human subjects.
Our previous study demonstrated that major ginsenoside Rb1
can convert to minor ginsenoside F2 by enzymatic reaction.
We further found that EG, which is rich in ginsenoside F2,
attenuated UVB-induced skin damage in both human dermal
fibroblasts and in hairless mice. Specifically, histological
examination of mouse skin showed that EG treatment
Table 5. Average Roughness (R3) Value Changes
EG Placebo
Arbitrary units
(average SD)
p
value
a
p
value
b
Average roughness (R3)
Baseline 0.06 0.02 0.06 0.02 0.444
After 4 weeks 0.05 0.01 0.05 0.01 0.125
0.813
Difference
c
-0.01 0.01 -0.01 0.01 0.004**
pvalue
d
0.011* 0.014*
After 8 weeks 0.05 0.01 0.05 0.01 0.052
0.118
Difference
e
-0.01 0.01 -0.01 0.02 0.004**
pvalue
d
0.011* 0.015*
After 12
weeks
0.04 0.01 0.05 0.01 0.237
0.213Difference
f
-0.02 0.02 -0.01 0.01 0.005**
pvalue
d
0.017* 0.014*
a
Compared between groups: pvalue by Student’s t-test.
b
Compared between groups: pvalue by ANCOVA (adjustment
with baseline).
c
After 8 weeks -baseline.
d
Compared within groups: pvalue by paired t-test.
e
After 16 weeks -baseline.
f
After 24 weeks -baseline.
*p<0.05, **P<0.01 by Student’s t-test for comparison with
placebo group.
EG, enzyme-modified ginseng extract; GPDS, global photo-damage
score; SD, standard deviation; ANCOVA, analysis of co-variance.
Table 6. Smoothness Depth (R4) Value Changes
EG Placebo
Arbitrary units
(average SD)
p
value
a
p
value
b
Smoothness depth (R4)
Baseline 0.08 0.03 0.06 0.02 0.016
After 4 weeks 0.06 0.02 0.05 0.02 0.715
0.167
Difference
c
-0.02 0.02 -0.01 0.02 0.006**
pvalue
d
0.021* 0.020*
After 8 weeks 0.06 0.02 0.05 0.02 0.629
0.074
Difference
e
-0.02 0.03 -0.01 0.02 0.007**
pvalue
d
0.026* 0.023*
After 12
weeks
0.05 0.01 0.05 0.02 0.430
0.011*Difference
f
-0.03 0.03 -0.01 0.02 0.008**
pvalue
d
0.030* 0.024*
a
Compared between groups: pvalue by Student’s t-test.
b
Compared between groups: pvalue by ANCOVA (adjustment
with baseline).
c
After 8 weeks -baseline.
d
Compared within groups: pvalue by paired t-test.
e
After 16 weeks -baseline.
f
After 24 weeks -baseline.
*p<0.05, **p<0.01 by Student’s t-test for comparison with
placebo group.
EG, enzyme-modified ginseng extract; GPDS, global photo-damage
score; SD, standard deviation; ANCOVA, analysis of co-variance.
Table 7. Arithmetic Average (R5) Value Changes
EG Placebo
Arbitrary units
(average SD)
p
value
a
p
value
b
Arithmetic average (R5)
Baseline 0.03 0.01 0.02 0.01 0.011
After 4 weeks 0.02 0.01 0.02 0.01 0.068
0.330
Difference
c
-0.01 0.01 -0.01 0.01 0.003**
pvalue
d
0.007** 0.011*
After 8 weeks 0.02 0.01 0.02 0.01 0.621
0.034*
Difference
e
-0.01 0.01 0.00 0.01 0.003**
pvalue
d
0.010** 0.010*
After 12
weeks
0.02 0.01 0.02 0.01 0.480
0.038*Difference
f
-0.01 0.01 -0.01 0.01 0.003**
pvalue
d
0.011* 0.011*
a
Compared between groups: pvalue by Student’s t-test.
b
Compared between groups: pvalue by ANCOVA (adjustment
with baseline).
c
After 8 weeks -baseline.
d
Compared within groups: pvalue by paired t-test.
e
After 16 weeks -baseline.
f
After 24 weeks -baseline.
*p<0.05, **p<0.01 by Student’s t-test for comparison with
placebo group.
EG, enzyme-modified ginseng extract; GPDS, global photo-damage
score; SD, standard deviation; ANCOVA, analysis of co-variance.
EFFICACY AND SAFETY OF EG FOR ANTI-WRINKLE THERAPY 5
FIG. 2. Representative pictures of before and after the treatment.
6 HWANG ET AL.
successfully reversed skin thickening and loose compaction
of collagen fibers following UVB irradiation. Furthermore,
photo-aging–related molecules such as MMP-1, procollagen
type I, transforming growth factor-b1 (TGF–b1), and elastin
were shown to be decreased by treatment with EG.
10
Global photo-damage scores of eye wrinkles were dimin-
ished by treatment with EG. Crow’s feet wrinkles in the EG
treatment group appeared thinner and dimmer in photographs
compared with placebo. These results suggest that topical
application of EG may have anti-wrinkle effects. Because
measurement using non-invasive devices permits evaluation
of correlations between hydration and roughness, many in-
vestigators use these instruments to assess anti-wrinkle effi-
cacy.
23
Our results showed that skin roughness values (R1 and
R5), determined by analysis of photographs collected by the
SV600 Visiometer, were significantly decreased by EG ap-
plication. Because we did not explore histological changes or
molecular mechanisms of the treatment with EG in this study,
FIG. 2. (Continued).
FIG. 3. Questionnaires following a 12-week treatment with enzyme-modified ginseng extract (EG) and placebo. The
answers choices were as follows: A, excellent; B, good; C, moderate; D, poor; and F, bad.
EFFICACY AND SAFETY OF EG FOR ANTI-WRINKLE THERAPY 7
further research is needed to determine whether EG can also
protect against human skin aging at the molecular level.
The weather conditions under which this study was per-
formed add an additional variable for consideration. The
change from fall to winter in South Korea (i.e., September to
February) is marked by dryer (average humidity, 62.3%) and
colder (average temperature, 6.9C) weather (Korea Meteor-
ological Administration). Because sweat evaporates quickly in
cold, dry air, moisture is lost through the skin. In colder
weather, additional water loss occurs as a result of increased
urine and respiration.
24
Even though our clinical trial was
conducted in drier weather conditions (i.e., from August 23 to
November 17), we still noticed significant improvements in
skin moisture by EG treatment. This finding was corroborated
by the questionnaires in which volunteers in the EG group
noted more potent moisturizing effects of treatment compared
to the placebo group. In a previous study, we demonstrated that
increased epidermal hydration caused by EG treatment pro-
tected against UVB-induced dryness in mouse dorsal skin.
10
Taken together, these results suggest that EG may play a role in
repairing dry skin by increasing skin moisture. Our findings
suggest the need for further studies that investigate the precise
mechanisms by which EG hydrates the skin.
There is a growing trend for natural products to be used in
functional foods.
25
This trend is rooted in a desire for cos-
metic and food industries to be more environmentally
friendly. Natural products frequently result in fewer side ef-
fects than chemical-based products and also tend to cause less
harm to the earth. However, they are also typically more ex-
pensive. Ginseng is expensive, because it is fastidious to grow
and has a very long growth period (up to 6 years). Although
ginsenosides, especially minor ginsenosides, are protective
against various skin disorders,
26
they account for only 0.4%–
1% of total ginseng, making them difficult to use as ingredi-
ents of functional foods and cosmetics. Therefore, it will be
important to mass-produce minor ginsenosides, which have
varying bioavailability, using crude enzymes. Enzymatically
modified F2-rich ginseng is advantageous in this regard be-
cause it is both environmentally friendly and applicable for
mass production. The processing of EG relies on crude en-
zymes rather than chemical synthesis, and thus it is an easy,
cost-effective candidate ingredient.
In conclusion, this clinical study demonstrated that EG can
reduce wrinkles in the skin around the eyes. First, subjects in
the EG group showed decreased GPDS eye wrinkle scores
after 12 weeks. Second, skin roughness, a precursor to wrinkle
formation, was reduced by topical application of EG. Third, in
spite of low humidity in the environment, the moisturizing
effects of EG were remarkable. These findings suggest that
EG is a good candidate as an ingredient of natural functional
foods and cosmetics used for anti-aging.
Acknowledgments
This research was supported by the Korea Institute of
Planning and Evaluation for Technology in Food, Agri-
culture, Forestry and Fisheries (iPET, 810006-03-3-SB110),
Republic of Korea.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Tae-Hoo Yi
Department of Oriental Medicinal Materials & Processing
College of Life Science
Kyung Hee University
1732 Deokyoungdaero
Giheung-gu
Yongin-si, Gyeonggi-do, 446-701
Republic of Korea
E-mail: drhoo@khu.ac.kr
Received: January 12, 2015
Accepted: April 11, 2015
EFFICACY AND SAFETY OF EG FOR ANTI-WRINKLE THERAPY 9
... In addition to the downregulation of MMP-1 expression induced by ultraviolet light via AP-1 transactivation and its effects on skin elasticity and wrinkle formation [24], a photoprotective effect was also reported in a clinical trial using an enzyme-modified Panax ginseng extract prepared after the incubation of Panax ginseng ethanol extract with a ginsenosideβ-glucosidase [115]. After topical applications in 22 female volunteers, twice daily for 12 weeks, the formulation promoted several skin benefits, such as inhibitory effects against UVB-induced skin aging, evidenced by a reduction in the global photodamage score, total roughness, smoothness depth, and roughness average, with no adverse reactions during treatments [115]. ...
... In addition to the downregulation of MMP-1 expression induced by ultraviolet light via AP-1 transactivation and its effects on skin elasticity and wrinkle formation [24], a photoprotective effect was also reported in a clinical trial using an enzyme-modified Panax ginseng extract prepared after the incubation of Panax ginseng ethanol extract with a ginsenosideβ-glucosidase [115]. After topical applications in 22 female volunteers, twice daily for 12 weeks, the formulation promoted several skin benefits, such as inhibitory effects against UVB-induced skin aging, evidenced by a reduction in the global photodamage score, total roughness, smoothness depth, and roughness average, with no adverse reactions during treatments [115]. These protective properties were attributed to the presence of ginsenosides Rg1 and F2 (Figure 7). ...
... Skin photoprotection has been also reported to ginsenoside Rb1 and compound K, a metabolite of ginsenoside Rb1 (Figure 7) [116,117], indicating that Panax ginseng is a rich source of several active compounds with skin anti-aging properties. These photoprotective compounds act by different mechanisms of action, including the inhibition of UV-induced DNA damage via the induction or upregulation of the nucleotide excision repair complex and the reduction of the expression, secretion, and activity of the MMP-1, MMP-2, MMP-9, and MAPKs signaling pathway [115,116,118]. Recently, the ginsenoside Rg3 (Figure 7) was reported to attenuate skin disorders by a new mechanism of action, downregulating the murine double minute 2 and hypoxia-inducible factor 1α signaling pathways [119], whereas a ginseng plant extract induced photoprotection in NIH-3T3 cells via the activation of the protein kinase B signaling pathway [120]. ...
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