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Received: 2 April 2019    Revised: 13 June 2019    Accepted: 28 June 2019

DOI: 10.1111/jocd.13086

ORIGINAL CONTRIBUTION

Anti‐skin aging properties of protocatechuic acid in vitro and in

vivo

Seoungwoo Shin PhD1  | Shin Hwan Cho PhD2 | Deokhoon Park PhD1 |

Eunsun Jung PhD1

1
Biospectrum Life Science Institute, Yongin,
Korea
2
Skincure Life Science Institute, Yongin,
Korea
Correspondence
Eunsun Jung, Biospectrum Life Science
Institute, U‐TOWER 18th FL, 767, Sinsu Ro,
Suji Gu, Yongin, Gyunggi Do, Korea.
Email: bioso@biospectrum.com
Funding information
The Ministry of Trade, industry and Energy,
Republic Korea., Grant/Award Number:
R0002895
Abstract
Background: Protocatechuic acid has reported containing antioxidant effects. However,
information on its other biological activities such as anti‐wrinkle properties is limited
Aims: The objective of this study was to evaluate an antioxidant, collagen synthesis,
MMP‐1 inhibition (in vitro), and anti‐wrinkle (in vivo) effects of protocatechuic acid
(PCA) as a potent ingredient for wrinkle‐care cosmetic.
Methods: Antioxidant effect was evaluated based on its scavenging activity for free
radicals (DPPH, ABTS+). To evaluate the anti‐skin aging potency of PCA, levels of
MMP‐1 and type I procollagen were measured using an ELISA kit in cultured human
dermal fibroblasts. To further investigate if PCA could increase collagen synthesis,
full‐thickness human skin explants were immunostained with an anti‐collagen I an‐
tibody. In an in vivo study, 22 female subjects were enrolled in a placebo‐controlled
trial. Facial wrinkle, especially crow’s feet around eyes, was treated with lotion‐con‐
taining 0.02% PCA for 8 weeks and compared with the placebo.
Results: In in vitro study, PCA showed high antioxidant activ ity. PCA also showed
potential to induce the synthesis of type I collagen in human dermal fibroblast and
skin explants. It inhibited MMP‐1 secretion from UVA‐irradiated human dermal fi‐
broblast. An in vivo study, treatment with lotion‐containing 0.02% PCA for 8 weeks
significantly reduced the percentage of all skin wrinkle parameters.
Conclusion: Based on the results of in vitro assays and in vivo skin testing in human
subjects, PCA shows potential in anti‐wrinkle or anti‐skin aging treatments.

KEYWORDS
antioxidant, anti‐wrinkle, collagen synthesis, protocatechuic acid, topical formulation

1 |  I NTRO D U C TI O N
Type I collagen is the primary factor contributing to maintenance of the
extracellular matrix (ECM) in the dermis. Reduced synthesis of type I
collagen is characteristic of aged skin with thin and atrophic dermis and
1
deep wrinkle. The quality and quantity of collagen are regulated by the
balance between its synthesis and breakdown. Several factors such as
transforming growth factor‐β (TGF‐β) and epidermal growth factor (EGF)
can stimulate type I collagen synthesis. The breakdown of collagen is
normally controlled by matrix metalloproteinases (MMPs). UV‐induced
excess reactive oxygen species (ROS) activate synthesis of MMP‐1 which
results in the breakdown of collagen, subsequently leading to photoaging.
Polyphenols are the most well‐known secondary metabolites
found in the fruits, vegetables, beverages, and cereals.2 They have
strong antioxidant properties through ROS and reactive nitrogen spe‐
cies (RNS) scavenging activities and show protective effect against

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978       SHIN et al.

TA B L E 1   Formulation of PCA‐containing lotion and placebo lotion been elucidated. In this study, we investigated the anti‐skin aging prop‐
erties of PCA by evaluating its efficacy on DPPH, ABTS radicals, type I
Phase INCI name %W/W placebo %W/W test
procollagen synthesis, and MMP‐1 expression in vitro, ex vivo, and its
A Deionized water To 100 To 100
anti‐wrinkle effect in clinical study.
Glycerin 3.00 3.00
B Shea butter 3.00 3.00
2 | M ATE R I A L S A N D M E TH O DS
Cetearyl alcohol 2.00 2.00
Beeswax 2.00 2.00
2.1 | Materials
Cetearyl olivate (and) 2.00 2.00
Sorbitan olivate Dulbecco modified Eagle's medium (DMEM), penicillin‐strepto‐
Mineral oil 6.00 6.00 mycin, and fetal bovine serum (FBS) were purchased from Gibco‐
C Protocatechuic acid   0.02 BRL. Protocatechuic acid, L‐ascorbic acid, Trolox, 2,2′‐azi‐no‐bis
D 1,2‐Hexandiol 2.00 2.00 (3‐ehylbenzothiazoline‐6‐sulphonic acid) (ABTS), 1,1‐diphenyl‐2‐
Ethylhexylglycerin 0.10 0.10 picrylhydrazyl (DPPH), dimethyl sulfoxide (DMSO), and 3‐(4, 5‐di‐

Fragrance Q.S Q.S methylthiazol‐2yl)‐2, 5‐diphenyltetrazolium bromide (MTT) were

oxidative stress, indicating their potential use as key elements for
human health.3,4 Oxidative stress, the primary factor contributing to
skin aging, is provoked by increased production of ROS and decreased
antioxidant activity with increasing age. Therefore, natural antioxidants
5
have attracted increasing interest in cosmetic application. Plant poly‐
phenols such as (−)‐epigallocatechin‐3‐O‐gallate (EGCG), resveratrol,
and ferulic acid have been applied to cosmetics including sunscreens,
whitening, and anti‐aging products.6 Protocatechuic acid (PCA), nat‐
urally occurring phenolic acid, is widely found in plants and fruits, in‐
cluding plums (Prunus domestica L.), gooseberries (Ribes uvacrispa L.),
and rosemary (Rosmarinus officinalis L.). A variety of research on bio‐
logical and pharmacological properties of PCA has been performed.
According to previous studies, PCA is reported to have an antibacterial,
antioxidant, anticancer, and anti‐inflammatory effects on both in vitro
and in vivo.7-9 However, the effects of PCA on skin aging have not yet
obtained from Sigma. Human recombinant TGF‐β1 was purchased
from R&D Systems.
2.2 | The determination of antioxidant activity
The antioxidant activity of PCA was determined by measuring its
DPPH and ABTS radical scavenging activity, according to previously
described method.10,11 To measure DPPH scavenging activity, PCA
at various concentrations (1 ~ 200 μg/mL) was mixed with 0.2 mL
of DPPH (0.1 mM) solution, and then, the mixture was shaken and
left for 30 min at room temperature. The absorbance was recorded
at 540 nm by using a microplate reader (Gen5™, Bio‐Tek). To meas‐
ure ABTS radical scavenging activity, PCA at various concentrations
(1 ~ 200 μg/mL) was mixed to the ABTS working solution which
was prepared by reacting ABTS (7 mM) with potassium persulfate
(2.45 mM) in equal volume and keep them in darkness for overnight.
The absorbance was measured at 712 nm.

F I G U R E 1   Antioxidant properties of PCA. Radical scavenging activity was determined by using different concentrations (1‐200 μg/mL) of
PCA or vitamin C and trolox through DPPH (A) and ABTS+ (B) assays. Data are presented as mean ± standard deviation. #, P < .01 compared
with vehicle‐treated group (n = 5). These results were obtained from three independent experiments
SHIN et al. |
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incubated with an MTT solution (1 mg/mL) for 2 hours and media

2.3 | Cell line and cell culture
Human dermal fibroblasts (HDFs) from neonatal foreskin (American
Type Cell Collection) were maintained in DMEM containing 10% FBS
and 1% penicillin‐streptomycin at 37°C in a humid, 95% air/5% CO2.
was discarded. Then, DMSO was added to solubilize the formazan
crystal. After complete solubilization, the absorbance was measured
at 540 nm.

2.5 | Quantitative detection of type I collagen

2.4 | Measurement of cell viability
The effect of PCA on cell viability was determined by using MTT
assay. Cells were seeded onto 24‐well plates and maintained over‐
night. Serum‐free medium containing various concentrations of
PCA was treated for 48 hours. After treatment ends, the cells were
Levels of type I collagen were quantified by detecting the procolla‐
gen type I carboxy‐terminal peptide (PIP) using an ELISA kit (Takara,
Bio Inc Shiga). After treatment with PCA for 48 hours, culture super‐
natants were harvested for measuring PIP. The concentration of PIP
was evaluated by following the manufacturer's instructions.

F I G U R E 2   Anti‐skin aging effect of PCA in human dermal fibroblasts. Human dermal fibroblasts were cultured in 24‐well plates.
Human dermal fibroblasts were treated with PCA at indicated concentrations for 24 h at 37°C. A, Cell viability was measured by MTT
assay. B, Human dermal fibroblasts were treated with or without TGF‐β and/or PCA at indicated concentrations for 48 h at 37°C. Culture
supernatants were harvested and measured with a sandwich immunoassay kit. C, Human dermal fibroblasts were treated with different
concentration (20‐100 µg/mL) of PCA for 24 h after they were exposed to UVA. Culture supernatants were harvested and measured with
a sandwich immunoassay kit. Data are presented as mean ± standard deviation. #, P < .01 compared with the vehicle‐treated group (n = 3).
Results were confirmed by five independent experiments
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980       SHIN et al.
2.6 | UVA irradiation
The UVA source was an LZC‐UVA lamp (Luzchem), with a peak irradi‐
ance of 365 nm. UVA doses were measured using a UV‐340 UV light
meter (Lutron). Cells were washed and overlaid with PBS and then ex‐
2
posed to UVA irradiation (10 J/m ). The unexposed control sample was
covered with aluminum foil and then irradiated with same UVA doses.
After UVA irradiation, PBS was changed to DMEM containing the indi‐
cated concentration of test materials and incubated for 24 hours.
2.7 | MMP‐1 inhibition assay
The secretion of MMP‐1 in the culture supernatant was measured using
an ELISA kit (R&D systems) following the manufacturer's instructions.
2.8 | Ex vivo study
The ex vivo test was performed in Laboratoire BIO‐EC in compli‐
ance with the declaration of Helsinki and good laboratory practices
after obtaining informed consent from the patient. Eight human skin
explants were obtained from an abdominoplasty of a woman. The
diameter of each explant was 11 mm (±1). They were kept alive in
Laboratoire BIO‐EC’s Explant Medium (BEM®) at 37°C in a humid, 5%
CO2 for 12 hours. The PCA was solubilized with a carboxymethyl cel‐
lulose (CMC) gel at 0.02%. CMC gel with or without PCA was topically
applied to skin explants at days 0, 2, 3, and 4. At day 5, anti‐collagen
I antibody (Monosan) diluted in 1:400 in PBS containing 0.3% BSA
and 0.05% Tween‐20 applied for paraffinized section using Vectastain
avidin/biotin amplifier system (Vector). Expression of collagen I was
revealed by fluorescein isothiocyanate (FITC)‐linked anti‐rabbit IgG.
Propidium iodide (PI) was used to counterstain the nuclei. The image
was captured with Leica DMLB microscope, and image analysis was
performed by using Image J software, as described previously.12
2.9 | Clinical trial
To assess the anti‐wrinkle effects of PCA, randomized, double‐blind
clinical trial was performed by the Korea Dermatology Research
F I G U R E 3   Effects of PCA on collagen synthesis in skin explants. A, Collagen I was detected by immunostainings using specific
antibodies. Overexpression of collagen I was demonstrated in skin explants treated with or without PCA (0.02%). B, Quantification of
collagen expressions was performed using image analysis. Data are presented as mean ± standard deviation. #, P < .01 compared with the
vehicle‐treated group (n = 3). Results were confirmed by five independent experiments
Institute (KDRI) in Seongnam, Korea. Ethical approval for this study
was obtained from the Ethics Committee of KDRI, and the written
informed consent was obtained from all individual subjects before
the study. Twenty‐two healthy Korean women aged 35‐57  years
(45.32 ± 5.87 years) who had skin sagging and wrinkle in the crow's
feet were chosen for this study. Lotion containing 0.02% PCA and pla‐
cebo lotion were applied on crow's feet area over an 8‐week period. All
lotion formulations were mixing several principle ingredients as given
in the Table 1. All volunteers applied the lotion containing 0.02% PCA
and placebo lotion on right and left periorbital areas, respectively, twice
a day for 8 weeks. The test and placebo lotion were blinded and coded
for left or right side of the periorbital areas as per subject randomiza‐
tion. Subjects were trained on application after baseline assessment.
Skin replicas of crow's feet were obtained at 0, 2, 4, and 8 weeks
and applied for evaluating the skin wrinkle parameter (R1, skin rough‐
ness; R2, maximum roughness; R3, average roughness; R4, smooth‐
ness depth; and R5, arithmetic average) using SKIN VISIOMETER®
SV 600 (Courage–Khazaka Electronic GmbH).13,14
2.10 | Statistical Analysis
All data are expressed as mean ± standard deviation (SD). Differences
between control and treatment groups were evaluated by Student's
t test using Statview software (Abacus Concepts). A P < .01 was con‐
sidered statistically significant.15
3 | R E S U LT S
3.1 | Antioxidant capacities of PCA
To determine the antioxidant capacities of PCA, DPPH and ABTS
radical scavenging assay were performed. Vitamin C (50 μg/mL) and
trolox (50 μg/mL) were used as positive control. PCA scavenged
free radical in a concentration dependent manner and showed 50%
DPPH and ABTS radicals at the concentration of 8.73  ±  0.47 and
7.63 ± 0.40 μg/mL, respectively (Figure 1A, 1B). These results indi‐
cate that PCA can be an antioxidant, which play the role in scaveng‐
ing oxidative stress.
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F I G U R E 4   Changes of skin wrinkle parameters in crow's feet following 8 consecutive weeks application of test product (mean ± SEM. *
P < .05, # P < .01 vs before treatment)
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982       SHIN et al.
3.2 | Anti‐skin aging effect of PCA in human dermal
fibroblasts
To confirm the anti‐aging effect of PCA, synthesis of type I col‐
lagen and level of MMP‐1 were examined in HDFs. Cell viability
was also examined to exclude cytotoxic concentration of PCA.
PCA did not show any cytotoxic effect on HDFs at concentration
up to 200 µg/mL compared to no‐treatment control (Figure 2A).
In type I collagen synthesis assay, PCA increased the production
of type I collagen, 50 µg/mL PCA results in 2.4‐fold increase
in collagen level compared to the control (Figure 2B). Previous
studies have shown that UVA irradiation can cause photoag‐
ing through induction of MMP‐1 activity, which subsequently
breaks the crosslinks in collagen, including those of the triple
helix structure.16 To determine whether PCA could reduce UVA‐
induced MMP‐1, level of MMP‐1 protein was examined. Results
confirmed that UVA irradiation increased the level of MMP‐1
protein while PCA inhibited the UVA‐induced MMP‐1(Figure 2C).
These results suggest that PCA has anti‐skin aging potency by
promoting type I procollagen synthesis and decreasing UVA‐in‐
duced MMP‐1 expression.
3.3 | Effect of PCA on type I collagen synthesis in
skin explants
To further investigate whether PCA could increase the collagen syn‐
thesis in ex vivo model, human skin explants were used. Full‐thick‐
ness human skin explant contains the complete structure of skin. It
has been considered as an appropriate model for safety and efficacy
evaluation of skin care products. As shown in Figure 3, PCA‐treated
explants showed the increase of the collagen level compared to their
corresponding untreated controls. At a concentration of 0.02%, PCA
resulted in 2.7‐fold increase in collagen synthesis. These data sug‐
gest that PCA can promote type I collagen synthesis in the ex vivo
model.
F I G U R E 5   Visual improvement of wrinkles in the crow's feet area with PCA application for 8 weeks. Skin wrinkle images of crow's feet
following 8 consecutive weeks of application of the test product (Subject No. 15)
3.4 | Clinical trial with healthy volunteers
The anti‐aging effect of PCA was also evaluated in clinical trials.
Twenty‐two women aged 35‐57 years who had skin sagging and wrin‐
kle in crow's feet were treated with the lotion containing 0.02% PCA
and placebo lotion over 8 weeks. The skin wrinkle parameters R1, R2,
R3, R4, and R5 were evaluated at 0, 2, 4, and 8  weeks using SKIN
VISIOMETER SV 600®. Results showed that the means of the wrin‐
kle parameter in PCA lotion‐treated area were significantly decreased
over an 8 weeks period compared to 0 weeks. In addition, the means
of the wrinkle parameter in PCA lotion‐treated area were lower than
placebo‐treated area (P < .05; Figures 4 and 5). These findings suggest
that PCA can exert anti‐wrinkle effect in human trials.
4 | D I S CU S S I O N
Protocatechuic acid (PCA) is a phenolic compound with high anti‐
oxidant capacity. It is considered as an active compound from plant
extract which possess antioxidant, anti‐inflammatory, antiprolifera‐
tive, and protective effect on neurodegenerative, diabetic, cancer,
and hepatic disease model.7-9,17 Action mechanism of PCA has been
elucidated in diverse model, but its effects on skin aging are insuf‐
ficient. The result of this paper suggests PCA has a cosmeceutical
effect via its antioxidant and anti‐skin aging activities.
Extrinsic and intrinsic (chronological) factors induce skin aging
through a complex biological process that lead to cumulative struc‐
tural and physiological alterations with wrinkling, sagging, laxity, and
roughness.18,19 Decreased collagen synthesis and increased MMP
activity contribute to low collagen levels in aged skin. Ultraviolet
(UV) irradiation accelerates extrinsic skin aging via activation of
MMPs responsible for the breakdown of collagen. 20 In addition,
it induces production of ROS, which mediates harmful effects on
the skin such as skin wrinkling in photoaging through induction of
MMPs. 21,22 Thus, strategies to reduce the ROS generation may be
SHIN et al.
effective in preventing skin aging. Antioxidants can ameliorate the
harmful effect of ROS on the skin through free radical scavenging
activity. The results of the present study showed that PCA has free
radical scavenging activity at low concentration (Figure 1).
MMPs are produced by epidermal keratinocytes and dermal fibro‐
blasts in reaction to various stimuli such as UV, cigarette smoke, urban
pollutants, and thermal stress.23 It mediates the breakdown of the
different components of the ECM including collagen, elastin, and fi‐
bronectin and contributes to a connective tissue damage in aged skin.
MMP‐1 is a major member of the collagenase subfamily of MMPs and
degrades fibrillar collagen including collagen type I and III.24 Inhibition
of MMP‐1 is an attractive target for the development of anti‐aging
agents. In the present study, PCA showed inhibitory effect on UVA‐
induced MMP‐1 production in human dermal fibroblasts (Figure 2C).
Loss of collagen in the dermis is the primary cause of wrinkles. 25
We confirmed the effect of PCA on collagen synthesis using both in
vitro and ex vivo models. Type I collagen was assessed in human der‐
mal fibroblasts and skin explants. PCA significantly increased type I
collagen contents, compared with nontreated control both in vitro
and ex vivo models (Figures 2B and 3). To confirm whether the PCA
has an anti‐aging effect on human skin, we performed clinical trial
concerning skin wrinkling. Our analysis of the crow's feet wrinkle
showed that topical application of PCA lotion over an eight‐week
period significantly improve wrinkling compared to placebo group
(Figures 4 and 5). This could be due to the ability of PCA to stimu‐
late collagen synthesis and quench free radicals, thereby protecting
collagen from degradation. Further investigations are needed to elu‐
cidate the molecular mechanisms involved in its biological activity.
Our findings indicate that PCA has potential to scavenge free
radicals and increase synthesis of type I collagen. It also inhibits UV‐
induced MMP‐1 production. Furthermore, PCA shows anti‐wrinkle
effect in vivo. Taken together, these findings suggest that PCA can
be applied for anti‐skin aging agent in cosmeceuticals.
5 | CO N C LU S I O N S
Based on result of in vitro, ex vivo assessments and clinical trial,
PCA shows potential usefulness of anti‐wrinkle and anti‐skin aging
treatment.
AC K N OW L E D G M E N T S
This study was supported by a grant (R0002895) from the Ministry
of Trade, Industry and Energy, Republic Korea.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
ORCID
Seoungwoo Shin  https://orcid.org/0000-0001-5354-7286
|
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