Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2012, Article ID 912028, 7 pages
Mao-Qiang Man,1,2MelanieHupe,2Richard Sun,2George Man,2
Theodora M. Mauro,2andPeterM.Elias2
1The Center for Skin Physiology Research, Dalian Skin Disease Hospital, Liaoning 116021, China
2Dermatology Service, Veterans Affairs Medical Center and Department of Dermatology, University of California, San Francisco,
4150 Clement Street, San Francisco, CA 94121, USA
Correspondence should be addressed to Mao-Qiang Man, email@example.com
Received 24 July 2012; Revised 10 October 2012; Accepted 18 October 2012
Academic Editor: Wagner Vilegas
Copyright © 2012 Mao-Qiang Man et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Herbal medicines have been used in preventing and treating skin disorders for centuries. It has been demonstrated that systemic
administration of chrysanthemum extract exhibits anti-inflammatory properties. However, whether topical applications of
apigenin, a constituent of chrysanthemum extract, influence cutaneous inflammation is still unclear. In the present study, we
first tested whether topical applications of apigenin alleviate cutaneous inflammation in murine models of acute dermatitis. The
murine models of acute allergic contact dermatitis and acute irritant contact dermatitis were established by topical application
of oxazolone and phorbol 12-myristate 13-acetate (TPA), respectively. Inflammation was assessed in both dermatitis models by
measuring ear thickness. Additionally, the effect of apigenin on stratum corneum function in a murine subacute allergic contact
dermatitis model was assessed with an MPA5 physiology monitor. Our results demonstrate that topical applications of apigenin
with the vehicle treatment, topical apigenin treatment significantly reduced transepidermal water loss, lowered skin surface pH,
and increased stratum corneum hydration in a subacute murine allergic contact dermatitis model. Together, these results suggest
that topical application of apigenin could provide an alternative regimen for the treatment of dermatitis.
Increasing evidence demonstrates the beneficial effects of
herbal medicines in preventing and treating a variety of
disorders, including inflammatory dermatoses. Prior studies
have shown that topical applications of herbal extract
prevent acute irritant murine contact dermatitis  and that
oral administration of Cordyceps sinensis extract prevents
cutaneous damages from Streptococcus pyogenes infection
in an air pouch murine infection model . Likewise,
oral administration of Hainosankyuto reduces skin lesion
size and increased survival rate in a Streptococcus pyogenes
infected murine model . Similarly, oral administration of
the water extract of Astragalus membranaceus inhibits the
development of atopic dermatitis-like lesions in a murine
model . Moreover, topical herbal extracts protect skin
from UV radiation [5–7]. Additionally, Scutellaria bardata
exhibits a preventive effect on the development of skin
cancer . Furthermore, the therapeutic effects of some
herbal medicines on cutaneous inflammation have been well
studied in both animals and humans. For instance, previous
studies demonstrated that either topical or oral applica-
tions of herbal extracts inhibited both acute cutaneous
inflammation and atopic dermatitis in animal models [9–
12]. Study revealed that the majority of atopic dermatitis
patients accepted herbal medicines as an alternative treat-
ment approach . Clinically, oral administrations of
herbal medicines are effective in treating psoriasis, atopic
dermatitis, and glucocorticoid-induced dermatitis [14–17].
Chrysanthemum is a common herbal medicine. The
anti-inflammatory effects of chrysanthemum have been doc-
umented. For example, systemic administration of chrysan-
themum extract inhibits both acute and chronic irritant
2 Evidence-Based Complementary and Alternative Medicine
contact dermatitis in murine models . Topical applica-
tions of chrysanthemum extract alleviate diaper dermatitis
in infants and newborns with erythema venenatum [19,
20]. Improvement of certain cutaneous drug reactions also
has been reported with chrysanthemum . Apigenin is
an active constituent that is present in large quantities in
chrysanthemum extract [22, 23]. It has been shown that
apigenin exhibits preventive activity against UVB-induced
cyclooxygenase-2 (COX-2) expression in keratinocyte cul-
tures [24, 25]. In a murine model, an apigenin-enriched diet
attenuated the development of atopic dermatitis-like lesions
. Although one clinical study showed that an apigenin
containing cream inhibited cutaneous inflammation ,
the therapeutic effects of topical apigenin on cutaneous
inflammation and barrier function have previously not been
elucidated yet. In the present study, we evaluated the effects
of topical apigenin on both acute and subacute cutaneous
inflammation in murine models.
2.1. Materials. Both 6–8-week-old female hairless mice
(hr/hr) and C57BL/6J mice were purchased from Charles
River Laboratories (Wilmington, MA, USA) and fed mouse
diet (Ralston-Purina Co., St Louis, MO, USA) and water ad
libitum. Apigenin powder was from Sigma Chemical Co. (St
Louis, MO, USA). Phorbol 12-myristate 13-acetate (TPA),
4-Ethoxymethylene-2-phenyloxazol-5-one (oxazolone), and
ethanol were purchased from Sigma Chemical Co. (St Louis,
2.2. Experimental Protocols and Functional Studies. All ani-
mal procedures were approved by the Animal Studies Sub-
committee (IACUC) of the San Francisco Veterans Admin-
istration Medical Center and performed in accordance with
their guidelines. For anti-inflammatory studies in irritant
contact dermatitis model, ear inflammation on C57BL/6J
mice was induced by a topical application of 15μL of 0.03%
TPA to both the inner and outer surfaces of both ears [28,
29]. 20μL of 0.1% (about 0.67mg/kg body weight) apigenin
in ethanol was applied to both surfaces of the right and 20μL
of ethanol alone was applied to both surfaces of the left ear at
45min and 2 hours following TPA treatment. Additionally,
the oxazolone-induced ear inflammation model (allergic
contact dermatitis model) was also used to assess the
anti-inflammatory effects of apigenin. C57BL/6J mice were
sensitized by topical application of 3% oxazolone to the
back once daily for two days. One week later, 15μL of 0.5%
oxazolone was applied to both the inner and outer surfaces
of both ears. 20μL of 0.1% apigenin or ethanol alone was
applied to both surfaces of the right or left ear at 45min
and 2 hours following oxazolone treatment. Ear thickness
was measured with a digital caliper (Mitutoyo, Tokyo, Japan)
before and 20 hours after the challenge with oxazolone or
TPA application. Under anesthesia (4% chlorohydrate, IP
injection) ear samples were taken with surgical scissors for
hematoxylin and eosin staining (H&E) staining of 5μm
paraffin-enabled sections .
Ear thickness (mm)
N = 9
N = 9
N = 10
N = 10
P < 0.02
P < 0.001
Figure 1: Topical apigenin reduces ear thickness in acute murine
dermatitis models. Acute irritant contact dermatitis and allergic
and Methods. 20μL of 0.1% apigenin in ethanol or ethanol alone
was applied to both surfaces of the right or left ear, respectively,
45min and 2 hours following TPA or oxazolone challenge. Ear
thickness was measured with a digital caliper (Mitutoyo, Tokyo,
Japan) before and 20 hours after challenge with oxazolone or TPA
application. The dotted line represented the normal ear thickness.
Numbers and significances are indicated in the figures.
For the subacute dermatitis model, 6–8-week-old female
hairless mice (hr/hr) with body weight of 28–30g were sen-
sitized by topical application of 3% oxazolone to the back
once daily for two days. One week later, 60μL of 0.01%
oxazolone was applied to both flanks of mice once every
other day for 4 applications. One group of oxazolone-treated
mice was topically treated with 60μL of 0.1% (about 2mg/kg
body weight) apigenin twice daily for 7 days. The other
group of oxazolone-treated mice was topically treated with
ethanol alone and served as the control. In the case that
oxazolone and apigenin or ethanol were applied on the
same day, apigenin and ethanol were applied one hour after
oxazolone application. On the 8th day, 18 hours after the last
apigenin or ethanol application, basal transepidermal water
loss (TEWL), stratum corneum hydration, and skin surface
pH were measured using their respective probes connected
to MPA5 (C&K, Cologne, Germany) as described earlier
2.3. Statistics. Data are expressed as the mean ± SEM.
GraphPad Prism 4 software (San Diego, CA, USA) was used
for all statistical analyses. Unpaired two-tailed Student’s t-
test with Welch’s correction was used to determine the statis-
tical significances when two groups were compared. One-
Way ANOVA with Tukey correction was used when three or
more groups were compared.
3.1. Topical Apigenin Inhibits Acute Cutaneous Inflammation
in Murine Contact Dermatitis Models. We first assessed
whether topical applications of apigenin inhibit acute irri-
tant contact dermatitis (AICD) and acute allergic contact
dermatitis (AACD) in murine dermatitis models. As seen
in Figure 1, ear thickness increased following either TPA or
completely normalized ear thickness in a murine AACD
model (0.186±0.003 fornormal; 0.189±0.003 foroxazolone
+ apigenin). Similarly, topical apigenin significantly reduced
Evidence-Based Complementary and Alternative Medicine3
Figure 2: Topical applications of apigenin reduce edema in acute murine dermatitis models. Acute irritant contact dermatitis and allergic
contact dermatitis models were established as described in Materials and Methods Ear samples for H&E staining were taken immediately
after measurements of ear thickness. (a) and (d) are normal ears. (b) and (c) are acute allergic contact dermatitis (AACD) treated with
vehicle and apigenin, respectively. (e) and (f) are acute irritant contact dermatitis (AICD) treated with vehicle and apigenin, respectively. A
remarkable reduction in ear thickness and edema were evident in apigenin-treated ear. The magnifications for all images are the same. Scale
bar = 50μm.
ear thickness in murine AICD model (0.485 ± 0.013 for
TPA + vehicle; 0.409 ± 0.016 for TPA + apigenin, P <
0.001) (Figure 1). The anti-inflammatory effects of apigenin
on acute cutaneous inflammation were further confirmed
by H&E staining (Figure 2). These results demonstrate that
topical apigenin inhibits acute cutaneous inflammation in
murine dermatitis models.
3.2. Topical Apigenin Lowers Transepidermal Water Loss in
a Subacute Murine Allergic Contact Dermatitis Model. Pre-
vious studies have demonstrated that apigenin attenuates
the development of atopic dermatitis-like lesions  and
that transepidermal water loss positively correlates with the
severity of subacute and chronic dermatitis [33, 34]. We next
determined whether topical apigenin influences transepider-
mal water loss in subacute cutaneous inflammation in a
murine model. As shown in Figure 3(a), repeated topical
oxazolone treatment markedly increased transepidermal
water loss as compared with vehicle-treated control (P <
0.001). Topical apigenin treatment dramatically prevented
the increase in transepidermal water loss induced by oxa-
zolonetreatment(P < 0.001versusoxazolone+vehicletreat-
ment). This result indicates that topical apigenin improves
epidermal permeability barrier function in murine subacute
It has been shown that subacute and chronic dermatitis
are characterized by lower stratum corneum hydration
and higher skin surface pH [30, 35]. Therefore, stratum
corneum hydration and skin surface pH were also evaluated
following vehicle and apigenin treatment in oxazolone-
treated mice. As reported previously , repeated oxa-
zolone applications significantly decreased stratum corneum
hydration (Figure 3(b)). Although the apigenin treatment
did not normalize stratum corneum hydration, a notably
higher stratum corneum hydration was observed following
apigenin treatment (Figure 3(b), P < 0.05 for oxazolone +
vehicle versus oxazolone + apigenin). In agreement with
prior findings , repeated oxazolone treatment caused a
significantincreaseinskinsurfacepH(Figure 3(c),P < 0.001
for normal versus oxazolone + vehicle). In comparison with
the vehicle treatment, a substantially lower skin surface pH
was apparent in apigenin-treated mice (Figure 3(c), P <
0.05 for oxazolone + vehicle versus oxazolone + apigenin;
unpaired Student’s t-test). These results suggest that topical
apigenin partially inhibits the changes of stratum corneum
hydration and skin surface pH induced by repeated oxa-
Together, these results demonstrate that topical apigenin
by repeated oxazolone applications.
It has been shown that topical applications of herbal extracts
inhibit cutaneous inflammation and improve both the
epidermal permeability barrier and the antimicrobial barrier
medicines have not yet been well defined. Recently, an active
ingredient, hesperidin, in orange peel has been shown to
improve the epidermal permeability barrier function .
In the present study, we first demonstrated that topical
applications of apigenin, an extract from chrysanthemum,
inhibit both acute irritant and acute allergic dermatitis in
murine models. Although the exact mechanisms by which
4 Evidence-Based Complementary and Alternative Medicine
Vehicle (n = 24)
Apigenin (n = 24)
P = 0.0011
P = 0.0132
Stratum hydration (au)
Vehicle (n = 24)
Apigenin (n = 24)
P = 0.0212
Skin surface (pH)
Vehicle (n = 24)
Apigenin (n = 24)
model was established as described in Materials and Methods. On the 8th day, basal transepidermal water loss, skin surface pH, and
stratum corneum (SC) hydration were assessed with an MPA5 (CK electronic GmbH, Cologne, Germany) connected to TM 300, pH905,
and Corneometer 825. Two readings were taken from each mouse for basal TEWL, hydration, as well as pH. (a) indicates a reduction in
transepidermal water loss following apigenin treatment; (b) shows apigenin induced an increase in stratum corneum hydration; (c) exhibits
a lower skin surface pH after apigenin treatment. Numbers and significances are indicated in the figures.
apigenin inhibits acute cutaneous inflammation are not
clear, several potential mechanisms could be involved. It is
well known that matrix metalloproteinase-1 is involved
in cutaneous inflammation [36, 37]. It has been reported
that apigenin inhibits matrix metalloproteinase-1 expression
induced by 12-O-tetradecanoylphorbol 13-acetate in dermal
fibroblasts . Secondly, in addition to inhibiting TNF-
alpha gene expression induced by lipopolysaccharide ,
apigenin also inhibits TNF-alpha secretion in vitro .
Similarly, oral administrations of apigenin reduce the high
serum TNF-alpha levels induced by romurtide in mice .
Thirdly, apigenin inhibits the expression of inflammation-
related molecules, such as intercellular adhesion molecule-
1, vascular cell adhesion molecule-1, and E-selectin, induced
by TNF-alpha and IL-1alpha [42, 43]. Studies suggest
that inhibition of inflammation by apigenin is via nuclear
factor (NF)-κB and MAPKs pathways [44, 45]. All these
anti-inflammatory effects induced by apigenin are likely
attributed to its antioxidant properties. Apigenin is a well-
known antioxidant [46, 47]. Studies have demonstrated that
antioxidants such as quercetin (Que) and cromolyn inhibit
release of inflammatory mediators including histamine,
leukotrienes, IL-6, IL-8, and TNF release from mast cells
in vitro . In vivo studies reveal that vitamin E, an anti-
oxidant, improves atopic dermatitis-like inflammation .
Therefore, the anti-inflammatory effect of apigenin could be
due to its antioxidant effects.
Previous studies revealed that stratum corneum func-
tion, especially transepidermal water loss, positively corre-
lates with the severity of atopic dermatitis [50, 51]. And inhi-
bition of cutaneous inflammation could decrease transepi-
dermal water loss [52, 53]. In the present study, the
effect of apigenin on subacute dermatitis was evaluated by
assessing transepidermal water loss, a parameter of epi-
dermal permeability barrier function. A significantly lower
level of transepidermal water loss was observed in apigenin-
treated mice. This improvement of transepidermal water
loss could be attributable to both the anti-inflammatory
and the antioxidant properties of apigenin. Thus, apigenin-
induced improvement of transepidermal water loss in the
murine subacute dermatitis model is at least partially due
to the inhibition of cutaneous inflammation. In addition,
apigenin exhibits antioxidant properties [54, 55]. It has
been shown that both systemic and topical administration
of antioxidants lower transepidermal water loss [56–59].
Hence, the apigenin-induced improvement in epidermal
Evidence-Based Complementary and Alternative Medicine5
permeability barrier homeostasis could result from its
It is worth noting that apigenin is a relatively safe agent.
Singh et al. reported that 50mg/kg body weight of apigenin
caused no changes in serum biomarkers (alanine amino
transferase, aspartate amino transferase, and alkaline phos-
phatase) of hepatotoxicity at 48 hours after intraperitoneal
injection in Swiss mice . Likewise, no sign of illness
was observed in mice after 10 days of single intraperitoneal
apigenin at dosage of 10mg/kg body weight significantly
inhibits cytokines such as TNF, IL-1 and IL-6 expression in
vivo . In the present, our results indicated that a lower
dermatoses and topical applications of apigenin at dosage of
dermatitis. Taken together, these results strongly suggest that
apigenin is a safe and effective anti-inflammatory agent,
especially for topical use.
acute inflammation and subacute dermatitis as indicated by
improved epidermal permeability barrier function. There-
fore, apigenin could be useful in treating acute and subacute
Conflict of Interests
All authors have no conflict of interests.
This work was partially supported by Grants AR19089, PEM;
AR051930, TM from the National Institutes of Health. The
authors are grateful to Dr. Shunpeng Song for his useful
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