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Management of Atopic Dermatitis Via Oral and Topical Administration of Herbs in Murine Model: A Systematic Review

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Over the past few decades, complementary and alternative medicine (CAM) using herbs, or their active constituents have garnered substantial attention in the management of a chronic and relapsing inflammatory skin disorder called atopic dermatitis (AD), particularly in attenuating disease recurrence and maintaining long-term remission. In Eastern Asian countries including China, Korea and Taiwan, herbal medicine available in both topical and oral preparation plays a significant role in treating skin diseases like AD as they possibly confer high anti-inflammatory properties and immunomodulatory functions. Conventional murine models of AD have been employed in drug discovery to provide scientific evidence for conclusive and specific pharmacological effects elicited by the use of traditional herbs and their active constituents. Coupled with the goal to develop safe and effective novel therapeutic agents for AD, this systematic review consists of a summary of 103 articles on both orally and topically administered herbs and their active constituents in the murine model, whereby articles were screened and selected via a specialized framework known as PICO (Population, Intervention, Comparator and Outcome). The objectives of this review paper were to identify the efficacy of oral and topical administered herbs along with their active constituents in alleviating AD and the underlying mechanism of actions, as well as the animal models and choice of inducer agents used in these studies. The main outcome on the efficacy of the majority of the herbs and their active constituents illustrated suppression of Th2 response as well as improvements in the severity of AD lesions, suppression of Immunoglobulin E (IgE) concentration and mast cell infiltration. The majority of these studies used BALB/c mice followed by NC/Nga mice (commonly used gender–male; commonly used age group – 6–8 weeks). The most used agent in inducing AD was 2, 4-Dinitrochlorobenzene (DNCB), and the average induction period for both oral and topical administered herbs and their active constituents in AD experiments lasted between 3 and 4 weeks. In light of these findings, this review paper could potentially assist researchers in exploring the potential candidate herbs and their active constituents using murine model for the amelioration of AD.
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Management of Atopic Dermatitis Via
Oral and Topical Administration of
Herbs in Murine Model: A Systematic
Review
Vivi Nur Khalieda Mohd Kasim
1
, Siti Mahirah Noble
2
, Kong Yen Liew
1
, Ji Wei Tan
2
,
Daud Ahmad Israf
1
and Chau Ling Tham
1
*
1
Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia,
2
School of Science, Monash University Malaysia, Subang Jaya, Malaysia
Over the past few decades, complementary and alternative medicine (CAM) using herbs,
or their active constituents have garnered substantial attention in the management of a
chronic and relapsing inammatory skin disorder called atopic dermatitis (AD), particularly
in attenuating disease recurrence and maintaining long-term remission. In Eastern Asian
countries including China, Korea and Taiwan, herbal medicine available in both topical and
oral preparation plays a signicant role in treating skin diseases like AD as they possibly
confer high anti-inammatory properties and immunomodulatory functions. Conventional
murine models of AD have been employed in drug discovery to provide scientic evidence
for conclusive and specic pharmacological effects elicited by the use of traditional herbs
and their active constituents. Coupled with the goal to develop safe and effective novel
therapeutic agents for AD, this systematic review consists of a summary of 103 articles on
both orally and topically administered herbs and their active constituents in the murine
model, whereby articles were screened and selected via a specialized framework known
as PICO (Population, Intervention, Comparator and Outcome). The objectives of this
review paper were to identify the efcacy of oral and topical administered herbs along with
their active constituents in alleviating AD and the underlying mechanism of actions, as well
as the animal models and choice of inducer agents used in these studies. The main
outcome on the efcacy of the majority of the herbs and their active constituents illustrated
suppression of Th2 response as well as improvements in the severity of AD lesions,
suppression of Immunoglobulin E (IgE) concentration and mast cell inltration. The majority
of these studies used BALB/c mice followed by NC/Nga mice (commonly used
gendermale; commonly used age group 68 weeks). The most used agent in
inducing AD was 2, 4-Dinitrochlorobenzene (DNCB), and the average induction period
for both oral and topical administered herbs and their active constituents in AD
experiments lasted between 3 and 4 weeks. In light of these ndings, this review paper
could potentially assist researchers in exploring the potential candidate herbs and their
active constituents using murine model for the amelioration of AD.
Keywords: herbs, atopic dermatitis, topical, oral, murine model, IgE, Th2 cytokines, systematic review
Edited by:
Gokhan Zengin,
Selcuk University, Turkey
Reviewed by:
Abdelhakim Bouyahya,
Mohammed V University, Morocco
Sengul Uysal,
Erciyes University, Turkey
*Correspondence:
Chau Ling Tham
chauling@upm.edu.my
These authors have contributed
equally to this work and share rst
authorship
Specialty section:
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 29 September 2021
Accepted: 19 April 2022
Published: 24 May 2022
Citation:
Mohd Kasim VNK, Noble SM, Liew KY,
Tan JW, Israf DA and Tham CL (2022)
Management of Atopic Dermatitis Via
Oral and Topical Administration of
Herbs in Murine Model: A
Systematic Review.
Front. Pharmacol. 13:785782.
doi: 10.3389/fphar.2022.785782
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 7857821
SYSTEMATIC REVIEW
published: 24 May 2022
doi: 10.3389/fphar.2022.785782
INTRODUCTION
Atopic Dermatitis (AD) is a chronic skin inammatory disorder
affecting 20% of children and up to 10% of adults worldwide
(Laughter et al., 2021). Clinical manifestations of AD include
dryness, erythema, itchy skin, and histological ndings illustrate
spongiosis and inltration of inammatory cells around the
upper dermal layer (Han et al., 2016). Immune dysregulation
as well as a plethora of genetic and environmental factors
signicantly contribute to the multifactorial etiology and
complexed pathophysiology of a debilitating skin disorder like
AD. With regards to immune dysregulation, AD has long been
understood to predominantly express skewness towards a
systemic T-helper type 2 (Th2)-dominant immune response
(Renert-Yuval et al., 2021). With the expression of a Th2-
skewed immunity, AD patients tend to exhibit an increase in
cytokine expression, with interleukins 4 and 13 (IL-4 and IL-13)
being the two pivotal cytokines that orchestrate the pathogenesis
of this disease as well as elevated levels of high-afnity IgE
receptor known as Fc epsilon receptor I (FcεRI). Studies have
reported that the initiation of AD is closely associated with Th2
cytokines whereas the disease progression and chronicity are
correlated with a delayed surge of Th1 cytokines mainly
interferon- γ(IFN- γ) in the chronic phase, thus presenting
itself as a biphasic inammation (Grewe et al., 1998). Amongst
the many prevalent hallmarks of AD, it is often correlated with a
high level of circulating IgE and an elevated mast cells (MC)
count in AD skin lesions (An et al., 2020).
Originally deriving from the bone marrow, MCs are the only
terminally differentiated hematopoietic cells that express the c-Kit
tyrosine kinase receptor and its ligand stem cell factor (SCF), to
synergistically aid in mast cell proliferation and maturation in
peripheral tissues (Mekori et al., 1995). Extensive studies in the
literature have established the role of MCs as key contributors in the
development and propagation of IgE-mediated hypersensitivity
reactions as well as in innate and adaptive immune responses.
Additionally, MCs are eminently located around the blood and
lymphatic vessels, hair follicles and glandular structures of the skin.
Mast cells found in the skin could be easily distinguished from
mucosal MCs by their protease content as the former contains both
chymase and tryptase in their granules whereas only tryptase is
present in the latter (Stone et al., 2010). Upon exposure and
sensitization to an allergen, activated B cells undergo
differentiation into plasma cells to produce IgE, which readily
cross-links with an antigen via high-afnity IgE receptors (FcεRI)
on the MCs surface. This in turn stimulates IgE-mediated activation
of MCs whereby subsequent degranulation induces the release of
cytokines (i.e., IL-4, IL-5 and IL-13), preformed lipid mediators
namely leukotrienes and platelet activating factor (PAF) which could
further intensify the progression of AD (Kulka and Befus, 2003).
To date, the management of AD mainly focuses on the
restoration of a normal functional skin barrier as well as to
elicit anti-inammatory and immunosuppressing effects, in a
stepwise manner according to disease severity and symptoms
(Lebwohl et al., 2013). Currently, standard treatment regimens
for AD involve the use of moisturizing emollients, topical
corticosteroids (TCs) and topical calcineurin inhibitors (TCIs)
for mild-to-moderate AD; and the reliance on systemic
immunosuppressant drugs such as azathioprine and
mycophenolate mofetil or phototherapy, especially for more
severe AD cases (Akhavan and Rudikoff, 2008;Lee HJ et al.,
2016). However, studies have emphasized an increased risk of
unwanted side effects such as skin atrophy, telangiectasia,
acneiform eruptions and many more due to long-term usage
of TCs and TCIs. Consequently, to address an unmet need in
establishing a gold standardtreatment for AD, profound
interest lies in unravelling the development of a safe,
efcacious as well as cost-effective anti-atopic agents derived
from traditional herbs or natural sources (Choi JH et al., 2017;
Nygaard et al., 2017).
Recent studies are actively demonstrating the potential
pharmacological actions of traditional herbs and their active
constituents as they might possess anti-inammatory,
antibacterial, antifungal, immunosuppressive activities and many
more. Aloe vera (L.) Burm.f. is a plant widely prized in the medicinal,
skincare and beauty industry owing to its wound healing and
immunomodulatory properties. Based on a review carried out by
Sánchez et al. (2020), the Chinese, Ayurvedic and Arabian medicine
highly utilize Aloe vera (L.) Burm.f. as a treatment for constipation,
helminth infections, and eczema respectively. In studies performed
by Kim et al. (2010) and Finberg et al. (2015),theefcacy of a
medicinal plant like Aloe vera (L.) Burm.f. in treating AD could be
proven by its ability to modulate immunological responses in AD
when administered via oral and topical routes. Once known as folk
medicine, this stemless plant has gained a well-deserved reputation
in ameliorating AD due to its profound anti-inammatory
properties and effectiveness in wound healing (Zari and Zari,
2015). Moreover, local inhabitants have been using herbs as one
of the methods in managing diseases including skin related
problems. As evidently seen in Nigeria, residents in Kefare
known to utilize the leaves of Senna alata (L.) Roxb. as a
treatment for eczema by applying the herb extract to the affected
areas (Mowobi et al., 2016) and this herb was proven to elicit
dermatophytic activities due to its bioactive compounds (Oladeji
et al., 2020). As reported by Hennebelle et al. (2009),Senna alata (L.)
Roxb. was used not only as a topical treatment but also as an oral
medicament against skin diseases including eczema. In
consolidation, Senna alata (L.) Roxb. and Aloe vera (L.) Burm.f.
were administered via the two most common routes of drugs
administration, which further elucidates the primary focus of this
review on highlighting both oral and topical routes of
administration. A systematic review can therefore assist in
analyzing the recent and relevant data from studies investigating
the potential therapeutic effects of herbs and their active constituents
on AD via two common routes of drug administration namely oral
and topical. On top of that, an astonishing array of animal models
have been developed in the eld of skin diseases for drug discovery
particularly in mice whereby they develop spontaneous skin lesions
after prolonged exposure to various allergens and closely mimic the
features of human AD. Therefore, this systematic review consists of a
total of 103 in vivo studies of AD models that were being divided into
two categories with the rst section studying the oral administration
ofherbsandtheiractiveconstituents(n= 48) followed by the topical
route (n= 55). This review paper was commissioned:
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 7857822
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
i. to screen recent 6 years of publications (20142020) on oral
and topical administration of herbs and their active
constituents in murine models of AD
ii. to rene the suitable conditions for animal experimentation
on AD by identifying the choice of animal models and
inducer agents used
iii. to elucidate the presumed underlying mechanism of actions
of oral and topical administered herbs and their active
constituents as well as their efcacies
METHODS
Search Strategy
Relevant articles in the literature were identied through systematic
searches in two electronic databases, namely PubMed and
ScienceDirect. The search terms comprised of two components:
1) intervention or exposure to herb and 2) disease of interest, atopic
dermatitisor eczema.The Preferred Reporting Items for
Systematic Reviews and Meta-analysis (PRISMA) criteria were
followed in this study (Shamseer et al., 2015). PubMed thesaurus
and MeSH term were used and lter was activated to select full text
and publication year from 2014 to 2020. An additional lter on
species Other Animalwas also selected to focus on animal studies.
ScienceDirect search was generated by truncating a term with an
asterisk (*) as well as with the use of Boolean operators such as
ANDand ORto narrow the search to more manageable and
relevant articles. After the initial search, rene lter was used to
narrow down the articles to those published between 2014 and 2020.
Owing to the absence of an animal exclusion search lter on
ScienceDirect, manual searching was done to identify all relevant
animal studies. The detailed search strategies for the two databases
are presented in Table 1, where as the process and result of the
systematic search are displayed in Figure 1.Theow diagram was
created using an online tool that conforms to the PRISMA2020
Statement (Haddaway et al., 2021).
TABLE 1 | Respective search strategies applied for PubMed and Science Direct.
PubMed Science direct
Intervention (Herb* OR herbal medicineOR medicinal plantOR Traditional Chinese
MedicineOR Korean medicineOR kampo OR Ayurveda OR ethnobotany)
(Herb* OR herbal medicineOR medicinal plantOR Traditional Chinese
MedicineOR Korean medicineOR kampo OR Ayurveda OR
ethnobotany)
Disease of
interest
Atopic dermatitis OR eczema Atopic dermatitis OR eczema
Outcome
measures
Not included in the search term Not included in the search term
Filter 20142020 Full-text available Other animals 20142020 Research articles
FIGURE 1 | Flow chart illustrating the search strategy and study selection process from Pubmed and Science Direct according to the PRISMA statement.
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 7857823
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
Eligibility Criteria
The inclusion criteria are 1) herbs (extract, mixture and active
constituents from the herbs), 2) AD or eczema in murine model.
In contrast, the exclusion criteria are 1) review articles, 2) fungi,
microbiome, 3)in vitro studies, 4) acupuncture, 5) population-
based studies, 6) non-oral and non-topical route of herb
administrations, 7) clinical trials, 8) miscellaneous articles
(food chemistry, non-english, etc.) The eligibility criteria
according to the PICO approach (population, intervention,
comparator and, outcome) are as follows:
Population: murine model with no restriction on gender,
age and weight.
Interventions: herbal extracts, complex mixtures of herbs or
isolated active constituents from distinct parts of herbs.
Comparator: a group that received control drugs
(corticosteroids, calcineurin inhibitors or others).
Outcomes: severity of AD lesions, serum IgE levels,
inltration of mast cells, Th1 and Th2 cytokine
concentrations and other relevant parameters associated
with AD.
Study design: murine experimental research.
Study Appraisal and Selection
Study selection was conducted independently by two reviewers
(VK and SN) who searched the articles in PubMed and
ScienceDirect databases. Irrelevant duplicate articles were
crosschecked and removed by both authors and the remaining
articles were screened based on the titles and abstracts. The
relevant articles were further assessed to ensure that they
comply with the eligibility criteria. Any contradictions between
the authors were settled by consensus. Excluded articles were
recorded with reasons. Subsequently, eligible literature was
analyzed by the authors to extract the relevant information.
Data Extraction
Data from all articles that met the criteria were extracted. Basic
characteristics of the animals (age, gender and species) and
experimental procedures including the inducers, the usage of
barrier disruption tools, investigation sites and the control drugs
were tabulated. Experimental outcomes and proposed
mechanisms were listed systematically. This was followed by
the preparations and chemical analysis of the herbs and their
constituents.
Risk of Bias
Risk of Bias (RoB) assessment was performed using the
SYstematic Review Centre for Laboratory Animal
Experimentation (SYRCLE). The types of biases under RoB
assessment include selection bias (sequence generation,
baseline characteristics, allocation concealment), performance
bias (random housing, blinding), detection bias (random
outcome assessment, blinding), attrition bias (incomplete
outcome data), reporting bias (selective outcome reporting)
and other sources of bias. For each bias, there are different
domains which constitute the ten entries for RoB tool for
animal research. Each study was screened for all the entries
and jotted with yesfor a low risk of bias, nofor a high
risk of bias and unclearfor an unclear risk of bias as presented
in Figure 2.
RESULTS
Risk of Bias
Risk of Bias (RoB) tool for animal intervention research in this
sysmatic review is presented by SYRCLE (Hooijmans et al., 2014).
SYRCLE is a tool for assessing the risk of bias in animal studies
which consists of six types of bias. Under the selection bias, there
are three domains. First is sequence generation. Almost half of the
studies (45.54%) reported on the sequence generation that refers
to the random sequence of the animal especially on the grouping.
Second is baseline characteristics. Most studies (93.07%)
mentioned the age, gender and weight of the animal in the
methodology which proved that the experiments were started
with animals having similar characteristics before the induction
of AD. Third is allocation concealment. However, none of the
studies mentioned that the information on the allocation of the
animals were concealed from the investigators. Next,
performance bias that consists of random housing and
blinding were not reported in any studies. Under detection
bias there are random outcome assessment and blinding. Only
one study by Sur et al. (2017) reported random outcome
assessment where the investigators randomly picked the
animals before proceeding with the assessment. In only
15.84% of the studies, the outcome assessors were reported to
be blinded. Incomplete outcome data under attrition bias revealed
that 43.56% of the studies included all animals in the analysis.
Reporting bias refers to whether or not the published report
included all expected outcomes. All 103 studies reported expected
oucomes when comparing methods and results section which
dened as low risk of reporting bias. Other sources of bias such as
the inappropriate inuence of funders and the addition of new
animals to replace dropout data were not reported in any of the
studies. Nevertheless, these ndings were expected as a survey
disclosed that methodology and materials are poorly reported for
experiments using animals, and the users of SYRCLE also
mentioned that they had to judge a large number of entries as
unclear(Kilkenny et al., 2009;Hooijmans et al., 2014).
Oral Administration of Herbs and Their
Active Constituents
Basic Characteristics of the Included Studies
In this review, 48 studies on orally administered herbs and their
active constituents were analyzed with majority (n= 32) of them
being based in Korea, 13 in China and the remaining three articles
were from Japan, Taiwan and Pakistan, respectively. All the
articles included in this review were rigorously assessed and
screened according to a specialized search strategy known as
PICO. The choice of intervention used during the screening
process was herbwhich was being divided into three
categories based on their formulation namely, extract, mixture,
and compound. Most of the studies worked on the extracts (n=
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 7857824
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
20), followed by herb mixtures (n= 19) and compounds isolated
from herbs (n= 8) as shown in Supplementary Table S1. The
preparation steps of the herbs and their active constituents were
shown in Supplementary Table S2. In addition, only one study
focused on oil extracted from herb. None of the studies in this
review was reported to work on the same herb using same route of
administration. Two studies conducted by Tsang et al. (2016) and
Aslam et al.(2018) were identied to work on a mixture of herbs
named Pentaherbs and compound named Thymoquinone,
respectively, via both oral and topical routes of administration.
Drug Control
The efcacy and safety of these novel oral herbal agents in the
treatment of AD was corroborated with the use of well-
established treatment modalities against AD. The choice of
positive controls or comparison drugs in these studies varied
from dexamethasone (n= 18), prednisolone (n= 5) and four
individual studies by Ok et al. (2018) used terfenadine, Wu et al.
(2014) used quercetin, Chen et al. (2017) used cetirizine and
Aslam et al.(2018) used tacrolimus. However, 20 studies did not
include a positive control drug. Lastly, a study by Zheng et al.
(2019) was identied to use a total of three positive control drugs
namely dexamethasone, loratadine and montelukast.
Animal Models Used
Murine models were the choice of population (P) for all the
studies included in this review, to investigate the anti-AD effects
of both oral and topical herbal administrations in an in vivo
setting. Out of the 48 studies involving the oral route of herbal
administration, male murine models (n= 28) and female murine
models (n= 14) were used, however sex of the mice was not
mentioned in six of the remaining studies. Moreover, the animal
species also differed as 47 studies were identied to use mice of
various strains; with BALB/C mice (n= 31) being the most
popular strain, followed by NC/Nga mice (n= 14), C57BL/6J
mice (n= 1), IL-4/Luc/CNS-1 transgenic mice (n= 1) and
Sprague Dawley rats (n= 1). With reference to Table 2,
induction of AD-like skin lesions was mostly achieved by the
chemical exposure to 2, 4-Dinitrochlorobenzene (DNCB) as
stated in 20 studies followed by 2, 4-Dinitrouorobenzene
(DNFB) as mentioned in eight studies. Six studies used
Dermatophagoides farinae (DfE) and less than ve studies
used each of these inducers; uorescein isothiocyanate (FITC),
ovalbumin, oxazolone, phthalic anhydride (PA) and trimellitic
anhydride (TMA). Interestingly, ve studies were investigated to
use a combination of inducers namely acetone with DNFB, 2, 4, 6-
trinitro-1-chrolobenzene (TNCB) with ovalbumin and lastly, DfE
with DNCB. In addition, mice in six studies received treatment
with sodium dodecyl sulfate (SDS) to facilitate skin barrier
perturbation and surgical tape stripping was performed in
seven studies. Most of the studies administered the inducer on
areas which include dorsal skin, ear or a combination of both as
indicated in Table 2.
Topical Administration of Herbs
Basic Characteristics of the Included Studies
In this review, fty-ve studies were conducted across several East
and South Asian countries with majority (n= 43) of them being
based in Korea, seven in China, two in Japan, two in Taiwan and
one study was performed in Pakistan. With cross-reference to
Supplementary Table S3, the action of three different herbs
namely, Pyrus ussuriensis Maxim., Gardenia jasminoides J.Ellis
and Stellera chamaejasme L. were investigated repetitively in a few
studies, whereas the subsequent 53 studies worked on diverse
herbs of interest, in its extract (n= 32), mixture (n= 10) and
compound (n= 11) forms. Interestingly, two studies in this
review focused on studying the essential oil extracted from
herbs. The preparation steps of the herbs and their active
constituents were shown in Supplementary Table S4.
Drug Control
With close reference to Table 3, majority of the studies in this
review used the two primary classes of drugs commonly used
to treat AD as positive control drugs, which includes topical
FIGURE 2 | Assessment of the risk of bias (SYRCLE) for selected studies, presented as the percentages of the total.
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Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
TABLE 2 | Basic characteristics of the murine models and experimental procedures from studies involving oral treatments of herbs and their active constituents.
Age/Sex/Model
species
Induction of
AD-like skin
lesions
Barrier
disruption
Positive control
drug
Investigation site References
4w/M/BALB/c mouse DNCB N/A 1 mg/kg Dexamethasone Dorsal skin Lee JH et al. (2019)
5w/M/BALB/c mouse DNCB N/A 10 mg/kg Terfenadine Dorsal skin Ok et al. (2018)
5w/M/BALB/c mouse DNCB N/A 1 mg/kg Dexamethasone Dorsal skin and ear Yang et al. (2018)
5w/M/BALB/c mouse DNCB N/A 1 mg/kg Dexamethasone Dorsal skin and ear Zari and Zari, (2015)
5w/M/BALB/c mouse DNCB N/A N/A Dorsal skin Jung et al. (2014)
5w/M/BALB/c mouse DNCB N/A N/A Dorsal skin Park JH et al. (2019)
5w/M/BALB/c mouse DNFB N/A N/A Dorsal skin Kee et al. (2017)
5w/M/BALB/c mouse DNFB N/A N/A Dorsal skin Jeon et al. (2015)
6w/M/BALB/c mouse DNCB N/A N/A Dorsal skin Ku et al. (2017)
6w/M/BALB/c mouse DNCB N/A N/A Dorsal skin Kim SR et al. (2014)
67w/M/BALB/c mouse DfE N/A N/A Ear Makino et al. (2014)
12w/M/BALB/c mouse TMA N/A N/A Ear Sur et al. (2017)
M/BALB/c mouse DNCB N/A 30 mg/kg Prednisolone Dorsal skin and ear Song-lin et al. (2014)
4w/F/BALB/c mouse DNCB and HDM (house dust
mite)
Tape Dexamethasone (dose not
indicated)
Ear Bae et al. (2016)
5w/F/BALB/c mouse Ovalbumin Tape 1 mg/kg Dexamethasone Dorsal skin Kong et al. (2015)
6w/F/BALB/c mouse DNCB and DfE Tape N/A Ear Choi et al. (2014b)
6w/F/BALB/c mouse DNCB and DfE Tape 1 mg/kg Dexamethasone Ear Jeong et al. (2018)
6w/F/BALB/c mouse Ovalbumin Tape 1.3 mg/kg Cetirizine Dorsal skin Chen et al. (2017)
68w/F/BALB/c mouse DNCB N/A 10 mg/kg Prednisolone Dorsal skin Meng et al. (2019)
68w/F/BALB/c mouse DNCB N/A 2.5 mg/kg Dexamethasone Dorsal skin and ear Chen et al. (2020)
610w/BALB/c mouse FITC N/A N/A Ear Tao et al. (2017)
610w/BALB/c mouse FITC N/A 0.67 mg/kg Dexamethasone Ear Wang et al. (2017)
8w/F/BALB/c mouse DNCB N/A N/A Dorsal skin and ear Han et al. (2016)
8w/F/BALB/c mouse Acetone and DNFB N/A 0.039 mg/kg Dexamethasone Abdominal and dorsal
skin
Han et al. (2018)
8w/F/BALB/c mouse TNCB and ovalbumin N/A 1.6 mg/kg Quercetin Dorsal skin Wu et al. (2014)
8w/F/BALB/c mouse DNFB N/A 10 nM Dexamethasone Dorsal skin Moon et al. (2019)
8w/F/BALB/c mouse Oxazolone N/A 2.5 mg/ml Dexamethasone Dorsal skin and ear Tsang et al. (2016)
F/BALB/c mouse DNCB N/A 30 mg/kg Tacrolimus Ear Aslam et al. (2018)
5w/BALB/c mouse DNCB N/A N/A Abdominal and dorsal
skin
Zhanxue et al. (2018)
68w/BALB/c mouse FITC N/A 0.67 mg/kg Dexamethasone Abdominal skin and ear Xiao-Tong et al.
(2019)
BALB/c mouse FITC N/A 0.67 mg/kg Dexamethasone Abdominal skin and ear Zheng et al. (2019)
1.3 mg/kg Loratadine
1.3 mg/kg Montelukast
3w/M/NC/Nga mouse DfE 5% SDS N/A Dorsal skin Kim et al. (2020)
3w/M/NC/Nga mouse DNFB Tape and
5% SDS
N/A Dorsal skin Cha et al. (2016)
3w/M/NC/Nga mouse DfE Tape and
5% SDS
N/A Dorsal skin Cha HY et al. (2017)
5w/M/NC/Nga mouse DNCB N/A 3 mg/kg Prednisolone Dorsal skin Park et al. (2018)
6w/M/NC/Nga mouse DNCB N/A 3 mg/kg Dexamethasone Dorsal skin Park BK et al. (2014)
6w/M/NC/Nga mouse DNCB N/A 3 mg/kg Dexamethasone Dorsal skin Park et al. (2015)
6w/M/NC/Nga mouse DNFB N/A N/A Dorsal skin Lee et al. (2017)
6w/M/NC/Nga mouse DfE 4% SDS 5 mg/kg Dexamethasone Dorsal skin Kang et al. (2018)
68w/M/NC/Nga mouse DNCB N/A 3 mg/kg Dexamethasone Dorsal skin, face and ear Yan et al. (2019)
8w/M/NC/Nga mouse DfE 4% SDS 3 mg/kg Prednisolone Dorsal skin and ear Lim et al. (2014b)
8w/M/NC/Nga mouse DfE 4% SDS 3 mg/kg Prednisolone Dorsal skin and ear Lim et al. (2015)
M/NC/Nga mouse DNFB N/A N/A Abdominal and dorsal
skin
Han et al. (2014a)
M/NC/Nga mouse DNFB N/A 0.039 mg/kg Dexamethasone Abdominal and dorsal
skin
Han et al. (2014b)
5w/F/NC/Nga mouse DNCB N/A 5 mg/kg Dexamethasone Dorsal skin Cha KJ et al. (2017)
4w/M/C57BL/6J mouse DNFB N/A N/A Dorsal skin Park J et al. (2019)
8w/IL-4/Luc/CNS-1 transgenic
mouse
PA N/A N/A Ear Kwak et al. (2017)
4w/M&F Lee/SD rat DNCB N/A N/A Dorsal skin and ear Wan et al. (2016)
N/A, Not applicable.
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 7857826
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
TABLE 3 | Basic characteristics of the murine models and experimental procedures from studies involving topical treatments of herbs and their active constituents.
Age/Sex/
Model
species
Induction of AD-like skin
lesions
Barrier
disruption
Positive control
drug
Investigation site References
5w/M/BALB/c
mouse
DNCB N/A Betamethasone (% not indicated) Dorsal skin (thoracic area) Mechesso et al.
(2019)
6w/M/BALB/c
mouse
DNCB N/A N/A Dorsal skin Jung et al. (2015)
6w/M/BALB/c
mouse
DNCB N/A Tacrolimus (% not indicated) Dorsal skin Hong et al. (2019)
6w/M/BALB/c
mouse
DNCB 4% SDS 10 µM Dexamethasone Dorsal skin Choi et al. (2018)
6w/M/BALB/c
mouse
DNCB N/A 0.1% Tacrolimus Dorsal skin Ku et al. (2018)
810w/M/BALB/c
mouse
DNFB N/A N/A Both ears Osada-Oka et al.
(2018)
5w/F/BALB/c
mouse
DNCB N/A 10 µM Dexamethasone Dorsal skin Lee J et al. (2016)
6w/F/BALB/c
mouse
DNCB and Oxazolone N/A N/A Dorsal skin, ears Lee et al. (2018)
6w/F/BALB/c
mouse
DNCB 4% SDS 10 µM Dexamethasone Dorsal skin Choi et al. (2016)
6w/F/BALB/c
mouse
DNCB 4% SDS 10 µM Dexamethasone Dorsal skin Choi YY et al. (2017b)
6w/F/BALB/c
mouse
DNCB and DfE Tape N/A Both ears Choi and Kim,
(2014a)
6w/F/BALB/c
mouse
Oxazolone N/A N/A Both ears Jo et al. (2018)
6w/SKH-1
hairless mouse
DNCB N/A Pimecrolimus (1% Elidel) Dorsal skin
6w/F/BALB/c
mouse
Oxazolone N/A N/A Both ears Jung et al. (2018)
6w/F/BALB/c
mouse
Oxazolone N/A N/A Both ears Lee S et al. (2019)
6w/SKH-1
hairless mouse
DNCB N/A N/A Dorsal skin
6w/F/BALB/c
mouse
DNCB 4% SDS N/A Dorsal skin An et al. (2020)
6w/F/BALB/c
mouse
DNCB N/A 10 µM Dexamethasone Dorsal skin Choi YY et al. (2017a)
6w/F/BALB/c
mouse
Oxazolone N/A N/A Dorsal skin, ears Jegal et al. (2017)
6w/F/SKH-1
hairless mouse
DNCB N/A N/A Dorsal skin, ears
7w/F/BALB/c
mouse
DNCB N/A Wu Dai ointment Dorsal skin Wu et al. (2020)
7w/F/BALB/c
mouse
DNCB N/A N/A Dorsal skin Lim et al. (2018)
7w/F/BALB/c
mouse
DNCB 4% SDS 0.1 and 0.5% Dexamethasone Dorsal skin Lee HJ et al. (2016)
8w/F/BALB/c
mouse
DNFB N/A 5 mg/kg Dexamethasone Dorsal skin Ryu et al. (2018)
8w/F/BALB/c
mouse
DNCB N/A N/A Dorsal skin, both ears Fang et al. (2015)
8w/F/BALB/c
mouse
DNCB N/A N/A Dorsal skin, ears Huang et al. (2019)
8w/F/BALB/c
mouse
Oxazolone N/A 2.5 mg/ml Dexamethasone Both ears Tsang et al. (2016)
F/BALB/c mouse DNCB N/A 1% Tacrolimus Both ears Aslam et al. (2018)
4w/M/NC/Nga
mouse
DfE N/A N/A Dorsal skin, ears Yang G et al. (2016)
6w/M/NC/Nga
mouse
DNCB N/A N/A Dorsal skin Yang HJ et al. (2017)
6w/M/NC/Nga
mouse
DNFB N/A N/A Dorsal and abdominal skin Han et al. (2014c)
Biostir-AD 4% SDS 0.1% Tacrolimus Dorsal skin Ngo et al. (2020)
(Continued on following page)
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Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
corticosteroids (n= 19) i.e., dexamethasone (n= 15),
hydrocortisone (n= 2), mometasone (n=1),
betamethasone (n= 1) and topical calcineurin inhibitors
(n= 16) i.e., tacrolimus (n= 14) and pimecrolimus (n=2).
However, 19 studies did not include a positive control drug and a
study by Wu et al. (2020) conrmed the therapeutic actions of the
herbal medicinal treatment against a pre-existing traditional Chinese
medicine known as Wu Dai ointment.
TABLE 3 | (Continued) Basic characteristics of the murine models and experimental procedures from studies involving topical treatments of herbs and their active
constituents.
Age/Sex/
Model
species
Induction of AD-like skin
lesions
Barrier
disruption
Positive control
drug
Investigation site References
6w/M/NC/Nga
mouse
6w/M/NC/Nga
mouse
DNCB N/A 0.1% Dexamethasone Dorsal skin Yang IJ et al. (2016)
6w/M/NC/Nga
mouse
DfE 4% SDS 0.1% Tacrolimus Dorsal skin, ears Sung and Kim,
(2018)
7w/M/NC/Nga
mouse
DNCB N/A 3 mg/kg Dexamethasone Dorsal skin Kim et al. (2015)
8w/M/NC/Nga
mouse
DfE 4% SDS 0.1% Tacrolimus Dorsal neck, ears Park et al. (2020)
8w/M/NC/Nga
mouse
DfE 4% SDS 0.1% Tacrolimus Dorsal skin, ears Park SH et al. (2019)
8w/M/NC/Nga
mouse
DfE 4% SDS 0.1% Tacrolimus Dorsal skin, both ears Sung et al. (2016)
8w/M/NC/Nga
mouse
DfE 4% SDS 0.1% Tacrolimus Dorsal skin, both ears Sung et al. (2014)
8w/M/NC/Nga
mouse
DfE 10% (w/v) SDS 0.1% Tacrolimus Dorsal skin, both ears Lee et al. (2014)
8w/M/NC/Nga
mouse
DfE 4% SDS 0.1% Tacrolimus Dorsal skin, both ears Lim et al. (2014a)
8w/M/NC/Nga
mouse
DfE N/A 0.1% Tacrolimus Upper dorsal skin, both
ears
Ha et al. (2014)
8w/M/NC/Nga
mouse
DfE N/A 0.1% Tacrolimus Upper dorsal skin, both
ears
Ha et al. (2015)
4w/F/NC/Nga
mouse
DNCB N/A 0.1% Dexamethasone Dorsal skin, ears Cho et al. (2019)
4w/F/NC/Nga
mouse
DNCB N/A 0.1% Dexamethasone Dorsal skin, ears Cho et al. (2018)
4w/F/NC/Nga
mouse
DNCB N/A 0.1% Tacrolimus Dorsal skin, face and both
ears
Kim H et al. (2014)
4w/F/NC/Nga
mouse
DNCB N/A N/A Dorsal skin Ham et al. (2019)
5w/F/NC/Nga
mouse
DfE N/A 0.1% Hydrocortisone Dorsal skin Park KH et al. (2014)
5w/F/SKH-1
hairless mouse
Oxazolone N/A 0.1% Hydrocortisone Dorsal skin Kang et al. (2017)
6w/F/SKH-1
hairless mouse
DNCB N/A Pimecrolimus (1% Elidel) Dorsal skin Lee et al. (2020)
6w/F/SKH-1
hairless mouse
DNCB N/A N/A Dorsal skin Jo et al. (2018)
4w/M/Kunming
mouse
DNCB N/A Dexamethasone and Paeonol cream (% not
indicated)
Dorsal skin, right ear Yang J et al. (2017)
8w/M/Kunming
mouse
DNCB N/A Dexamethasone acetate (contain 0.075%
dexamethasone)
Dorsal skin, right ear Fan et al. (2019)
8w/M/Kunming
mouse
DNCB N/A 0.025% Dexamethasone Dorsal skin, right ear Fan et al. (2018)
58w/F/ICR
mouse
DNCB N/A 0.1% Mometasone furoate cream Dorsal skin, right ear Wang et al. (2018)
8w/HR-1 mouse Phthalic anhydride N/A N/A Dorsal skin, ears Ho et al. (2018)
68w/F/C57BL/6
mouse
MC903 (vitamin D3
analogue)
N/A N/A Dorsal side of left ear Hou et al. (2019)
810w/M/NC/Tnd
mouse
N/A N/A N/A Dorsal skin Amagai et al. (2017)
N/A, Not applicable.
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Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
Animal Models Used
Murine models had been used in all the studies to investigate the
anti-AD effects of novel topical herbal administration in an in
vivo setting. Female mice were identied in 30 studies while male
mice were used in 25 studies, however, a few studies did not
disclose the gender of the mice. Categorically, the BALB/c mice
model (n= 25) was most extensively used among the included
studies, superseded by NC/Nga (n= 20), hairless mice (n= 6),
Kunming mice (n= 3), ICR mice (n= 1), HR-1 mice (n= 1),
C57BL/6 (n= 1) and NC/Tnd mice (n= 1). It is also noteworthy
that three individual studies conducted by Jegal et al. (2017),Jo
et al. (2018) and Lee JH et al. (2019), utilized two different mice
species namely BALB/c and SKH-1 hairless mice. According to
Erkes and Selvan (2014), variation in the type of mouse strains
could lead to a substantial difference in the immune stimulatory
ability of haptens used to induce AD, which in these three studies,
were DNCB and oxazolone. In order to evoke AD-like skin
lesions, repetitive cutaneous sensitization with house dust mite
allergen namely Dermatophagoides farinae (DfE) and chemical
induced irritation i.e., DNCB, DNFB, oxazolone, MC903 (a
synthetic derivative of vitamin D) and phthalic anhydride
were used in 12 and 42 studies, respectively.However, a study
by Amagai et al.(2017) on Alpinia intermedia Gagnep., differed
substantively from the rest as they used NC/Tnd mice, a sub-
strain of Nc/Nga developed from inbreeding to give spontaneous
itch and eczematous skin which resembles AD. Hence, no
induction agent was needed to elicit AD-like skin lesions in
this particular mouse strain. Besides, sodium dodecyl sulfate
(SDS) was applied to the AD lesions in 13 of the studies for
barrier disruption purposes, in which 12 received treatment with
4% (w/v) SDS, whereas only one study by Lee et al. (2014) applied
10% (w/v) SDS to mice skin. Mechanical skin injury by surgical
tape stripping was only performed in a single study by Choi and
Kim (2014a). On top of that, the majority of the studies in this
review focused on investigating the dorsal skin, ears, or a
combination of both as they were representative sites depicting
the histological features of AD-like skin lesions.
DISCUSSION
Over the past few decades, there has been a tremendous surge in
the publics shifting interest towards the reliance on natural
herbal remedies as alternative therapeutic options to
conventional Western allopathic medicine to treat AD.
Essentially, plant-based or herbal medicine are natural
products consisting portions of plants or unpuried plant
extracts that possess potential bioactive compounds offering a
myriad of medicinal and nutritive values possibly working
synergistically, to affect multiple targets that contribute to the
pathogenesis of AD. To date, the cornerstone of AD management
commonly involves therapeutic intervention with emollients,
TCs, TCIs and systemic immunosuppressants, especially for
more severe AD cases (Carr, 2013;Nygaard et al., 2017).
Nonetheless, inter-individual drug response variability and the
potential risk of adverse effects from long-term use such as skin
atrophy, tachyphylaxis and telangiectasia, are the key rationale
behind a shifting interest towards herbal drug development with
lesser side effects (Thomsen 2014;Montes-Torres et al., 2015).
With that goal in mind, this systematic review was drawn from
103 studies evaluating the efcacy of novel herbs and their active
constituents, synthesized from various preparations including
crude extracts, compounds isolated from the herbs or mixtures
of different herbs applied via oral and topical administration in in
vivo murine AD models.
The use of murine models is needed to aid in drug discovery
and testing of novel treatments as they are capable of mimicking
different aspects of the pathophysiology of human AD. Mice
models of AD are generally classied into three categories: 1)
mice induced by epicutaneous sensitization with allergens, 2)
spontaneous mice models and 3) genetically modied mice that
either over-express a transgene or lack of selective endogenous
genes. In this review paper, the majority of the studies used
allergen-induced AD models, which are relatively more
convenient as the usage of exogenous allergens permits dose-
and time-controlled induction (Kim et al., 2019). Also, out of 48
oral and 55 topical herbs administration studies involving AD in
murine models, the majority used BALB/c mice strain (oral: n=
31, topical: n= 25), followed by NC/Nga (oral: n= 14, topical: n=
20). BALB/c mice have been widely known to trigger a Th2-
dominant immune response, therefore, propagating the
development of AD (Lee et al., 2010). On the other hand, NC/
Nga mice were investigated to develop approximately 50% of
spontaneous AD-like skin lesions when they are kept in
conventional housing with uncontrolled air but remain normal
and healthy under specic pathogen-free (SPF) conditions.
However, this particular mouse model requires repeated
applications of a hapten to fully develop AD (Shiohara et al.,
2004).
Gender considerations remain an important facet in in vivo
pharmacology studies as a substantial body of literature supports
the notion that male mice are highly preferred in comparison to
female due to the ease of handling, less variation in results and
cost-effectiveness. Studies on orally administered herbs in this
review correspond to this notion as male mice (n= 28) and female
mice (n= 14) were used. Contrastingly, this was not constant with
studies involving topical herb administration as female mice were
found to lead the number with n= 30 and male (n= 25).
However, this gap was not of signicant difference and male
mice are indeed more favourable in AD research. According to
Wald and Wu (2010), female murine models confer a 4-day
oestrous cycle which therefore accounts for the use of a larger
number of animals as compared to males in order to keep their
cycle in synchrony, and this in turn makes it less economical.
Additionally, the uctuation of hormones across their oestrus
cycle results in behavioural variability in female mice as seen in
the production of a female sex hormone called oestrogen which
was reported to negatively regulate the wound healing process of
AD-like skin lesions (Mukai et al., 2016). Taken together,
researchers more typically eliminate the use of female murine
models on the presupposition that they elicit intrinsic variation as
compared to males, which could possibly interfere with the
efcacy of herbs of interest in ameliorating AD. It was also
brought to attention that a range between 6 and 8 weeks were
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Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
the most commonly used murine age groups across the studies in
this review, involving oral (n= 24) and topical (n= 43) herb
administration. In murine, the maturation of T cells was at
8 weeks of age, which is crucial for the production of T-cell-
dependent antibodies (Holladay and Smialowicz, 2000;Jackson
et al., 2017).
A vast array of inducer agents was utilized across the studies
on orally and topically administered herbs with the majority of
them involving the use of DNCB (n= 52) either individually or in
combination with DfE or Biostir-AD ointment (Choi and Kim,
2014a;Choi et al., 2014b;Bae et al., 2016;Jeong et al., 2018) and
oxazolone (Jegal et al., 2017;Lee et al., 2018;Jo et al., 2019).
DNCB exposure can create covalent conjugates with skin proteins
to undergo further processing and presented to T cells for
activation. Besides, repeated exposure to DNCB permits the
accumulation of macrophages at the sensitization site, hence
exemplifying an allergic inammatory response as seen in AD
(Yan et al., 2019). In fact, Ku et al. (2018) mentioned that
morphological changes in the skin lesions of DNCB-sensitized
mice revealed some of the major histopathological ndings
associated with human AD such as thickened epidermis,
massive inltration of CD4
+
T-cells producing pro-
inammatory cytokines as well as increased inltration of
inammatory cells i.e., mast cells and eosinophils. Apart from
DNCB, several other chemical compounds were also used to
induce AD-like lesions in topical application of herb section of
this review, including DNFB (n= 3), oxazolone (n= 6), repetitive
cutaneous sensitization with DfE ointment (n= 12), MC903 (n=
1), and phthalic anhydride (n= 1). As we dived into the induction
period, it was noticeable that the average duration of exposure to
an inducer lasted between 3 and 4 weeks, with the shortest being a
week. However, in a study conducted by Jung et al. (2015), DNCB
exposure lasted for approximately 8 weeks (~55 days). DNFB (n=
8), DfE (n= 6) and FITC (n= 4) are among other inducers that
were mentioned in this orally administered herb section of this
review. In terms of duration, FITC marked the shortest period of
AD induction with only 3 days then the mice were sacriced. This
is because the induction was only for the initial stage of AD and
the articles from Tao et al. (2017) and Wang et al. (2017) did not
mention any data on dermatitis score, serum IgE level and mast
cell count which are the hallmarks of AD hence it was difcult to
assess the AD severity. On the other hand, DfE recorded the
longest period of AD induction which is 8 weeks.
Interestingly, nine out of 14 studies on topically administered
herbs and their active constituents and ve out of six studies on
orally administered herbs and their active constituents were
subjected to repeated application of DfE, subsequently after
barrier disruption with a chemical substance mainly known as
sodium dodecyl sulfate (SDS). SDS functions to facilitate the
development of AD-like skin lesions by eliminating the lipid
lamella of the stratum corneum. With reference to
Supplementary Tables S1, S3, the oral and topical application
of herbs and their active constituents was found to ameliorate AD
symptoms via restoration of the skin barrier function (Cha et al.,
2016;Yang JH et al., 2016;Cha HY et al., 2017;Cha KJ et al., 2017;
Kang et al., 2018;Lee et al., 2018;Zhanxue et al., 2018;Cho et al.,
2019;Jo et al., 2019;Park J et al., 2019;Park JH et al., 2019).
Breakdown in the architecture of the stratum corneum in
response to barrier disruption methods with either SDS or
tape stripping, further permits the entry of allergens across the
skin to interact with local antigen-presenting cells and immune
effector cells. Previous research in the literature illustrated that
repetitive application of DfE is capable of contributing to the
onset and development of AD via the activation of
inammasomes in the epidermal keratinocytes (Jin et al.,
2016). Restoration of an intact skin barrier in AD serves as a
valuable therapeutic target since it acts as the rst line of defence
from various microbes and environmental allergens, as well as
decreases in trans-epidermal water loss (TEWL). Subsequently,
we found out that two studies of oral herbs and their active
constituentsadministration and 13 studies using topical herbs
and their active constituentsadministration were shown to
decrease TEWL, whereas ve studies on orally treated herbs
and their active constituents and seven studies on topically
treated herbs and their active constituents showed increased
levels of epidermal barrier proteins such as laggrin,
involucrin and loricrin.
Until recently, the etiology of AD could possibly be accounted
by two opposing hypotheses brought up by Silverberg and
Silverberg (2015). The outside-inhypothesis supports the
notion impairments in the epidermal barrier are solely
responsible for the onset of inammatory lesions in AD and
an essential structural protein laggrin, possesses a fundamental
role in maintaining skin barrier integrity, skin hydration and pH
by minimizing water loss (Li, 2014;Malik et al., 2017). In contrast,
there are some who propose the inside-outhypothesis in which
a dysregulated immune response is the key event that propagates
the inammatory cascade in AD and skin barrier disruption is an
epiphenomenon (Boguniewicz and Leung, 2011;Silverberg and
Silverberg, 2015). In this review, 102 studies could be accounted
by the outside-in theory as murine models were introduced to the
experimental allergens repeatedly in order to disrupt epidermal
barrier integrity. Additionally, 12 studies in this review reported
that oral and topical herbs and their active constituents
administration elicited an increase in levels of epidermal
barrier proteins such as laggrin, involucrin and loricrin.
Hence, it allows us to justify that orally and topically
administered herbs and their active constituents confers the
potential to accelerate barrier recovery by up-regulating the
expression of such vital structural proteins of the skin.
To fully comprehend the origins of AD, a molecular link has
been well-documented between the elevated serum IgE levels and
marked inltration of mast cells. During AD inammation, an
allergen penetrates through the skin and gets readily bound to
MCs by cross-linking to the high-afnity IgE receptor, FcεRI,
expressed on their cell surface (Brown et al., 2008;Amin, 2012).
Upon the activation of MCs, degranulation occurs within
seconds, leading to the subsequent release of preformed
secretory granules containing biologically active inammatory
mediators and proteins including histamine (cutaneous inductor
of itch), PGs and leukotrienes, as well as serine proteases i.e. mast-
cell chymase and tryptase (Kawakami et al., 2009;Siebenhaar
et al., 2018). Among the 48 studies on orally administered herbs
and their active constituents, 37 of them were reported to
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Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
measure serum IgE levels and 22 studies measured the number of
MCs and reported congruent decrease. Decreased levels in both of
these crucial parameters suggest that the oral route of herbs and
their active constituentsadministration is capable of alleviating
the allergic responses. On the other hand, across the 45 studies
investigating IgE levels as an outcome parameter for topically
administered herbs and their active constituents, it was found that
39 of these studies measured serum IgE and six studies
investigated plasma IgE levels. Fortunately, serum or blood IgE
levels successfully decreased after treatment with topical herbs
and their active constituents in all 45 studies. However, it is
important to note that total serum IgE may not reect accurate
levels of systemic IgE since raised concentrations are present in
many patients who have no evidence of allergy. As a result,
accurate measures of allergen-specic IgE could assist in dening
the bona de mechanism of novel topically applied herbal drugs
in immunity (Qiu et al., 2020). In addition, from the studies
involving topical route of administration, 39 herbs and their
active constituents were found to signicantly decrease the extent
of mast cell inltration into the skin. Moreover, it seems that the
reduction of MCs inltration can be associated with a decrease in
MCs degranulation as well as down-regulation of IL-4 and IL-13
cytokines secretion. Therefore, this implies that MCs may serve as
a key contributing factor to the suppression of Th2 cytokines in
AD-like skin lesions via topical herbs and their active
constituentsadministration.
The extensive array of mediators secreted from FcεRI-
mediated mast cell degranulation can ultimately promote
inammation, resulting in the appearance of macroscopic and
microscopic skin lesions which are associated with AD. The
severity of AD-like skin lesions could be investigated
macroscopically according to the acronym widely known as
SCORAD (SCORing Atopic Dermatitis) index. This scoring
system serves as a clinical tool to assess the extent and severity
of eczema by evaluating the common characteristic skin
symptoms of AD including 1) erythema, 2), erosion, 3)
dryness and 4) lichenication. In our review, dermatitis
severity was measured in 26 studies using oral administration
of herbs in which all 26 herbs and their active constituents were
able to reduce the dermatitis severity score. The same results were
obtained for treatment with topical herbs and their active
constituents as the dermatitis severity score was found to
decrease in 19 studies. On top of that, there was a study
performed by Aslam et al.(2018), investigating on a single
compound named thymoquinone, which used both routes of
drug administration. Results from this study illustrated that both
routes were able to alleviate the dermatitis severity score in
murine models of AD. However, more in-depth studies need
to be performed to thoroughly compare the efcacy of
thymoquinone via different routes of administration before
denitive conclusions can be drawn.
The immunological hallmark of AD is characterized by a
predominant expression of Th2-inammatory cytokines
(i.e., IL-4, IL-5 and IL-13) in the acute phase followed by a
prolonged activation of Th1-type cytokines (i.e., IFN-γand TNF-
α) in the chronic phase of AD (Brunner et al., 2017;Choi et al.,
2014b). As demonstrated in Supplementary Table S1, 19 studies
showed a simultaneous decrease in both Th1 and Th2 cytokines
after treatment with orally administered herbs and their active
constituents. Apart from that, 11 articles were found to study the
Th2 cytokines independently and results showed a reduction in
the level of cytokines. Without much anticipation, four studies
measured the cytokines released from both types of helper T cells
reported an unpredictable nding as orally administered herbs
and their active constituents decreased the level of Th2 cytokines
but contrastingly, induced an increase in the level of Th1
cytokines (Wu et al., 2014;Kong et al., 2015;Wan et al., 2016;
Han et al., 2018). A substantial body of literature have suggested
that an aberrant Th2-immune response plays a key proximal role
in the pathogenesis of AD, hence the two vital Th2 cytokines, IL-4
and IL-13 were investigated in 38 and 32 studies of topical
administration of herb and their active constituents,
respectively. Besides, another Th2-mediated cytokine, IL-5 was
measured in 11 studies. In all the studies mentioned above, topical
application of herbs and their active constituents resulted in a
marked reduction of IL-4, IL-5 and IL-13 expression. To address
the classical Th1/Th2 paradigm in AD, TNF-αand IFN-γlevels
were investigated as representative Th1 cytokines in 24 and 16
studies, respectively. Across all these studies, topical herbal
application induced a decrease in TNF-αand IFN-γlevels,
however, this was not achieved in a study by Yang HJ et al.
(2017) whereby an unexpected asynchronism in both Th1
cytokines was reported after treatment. This nding could be
accounted by the Th1/Th2 imbalancein the immunological
hallmark of AD, in which Th1 responses are capable of
antagonizing the development of Th2 cells, hence producing a
contrasting effect in the levels of both types of cytokines
(Herberth et al., 2010). On the other hand, extremely low and
undetected levels of IFN-γwere reported by Yang J et al. (2017),
possibly due to a Th2-driven inammation whereby IL-4 was able
to truncate the key Th1 cytokines namely IFN-γ(Brunner et al.,
2017).
Recent progress in molecular biology has provided insights
into the potential role of nuclear factor kappa B (NF-κB)
transcription factor family in the progression and maintenance
of AD (Tanaka et al., 2007). Studies have illustrated that
activation of the NF-κB pathway is accountable for the
regulation and chronicity of inammatory skin diseases like
AD. NF-κB participates in the differentiation of T cells into
various subsets comprising of Th1, Th2 and Th17. Moreover,
NF-κB functions to increase the expression and transcription of
numerous cytokines, growth factors and chemokines such as IL-
1β, IL-6 and IL-8, which are highly linked to the inammatory
cascade in AD (Tak and Firestein, 2001;Liu et al., 2017). In this
review, 10 articles on orally administered herbs and their active
constituents managed to inhibit the NF-κB pathway and similar
results were recorded from 10 articles on topically administered
herbs and their active constituents. Apart from NF-κB pathway,
the phosphorylation of mitogen-activated protein kinases
(MAPKs) signalling pathway is closely associated with the
production of pro-inammatory mediators which could trigger
and exacerbate AD. Owing to the importance of MAPK signalling
molecules i.e. ERK, JNK and p38, in the activation, proliferation,
migration and degranulation of immune cells involved in AD,
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 78578211
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
therefore pharmacological inhibition of this pathway may serve as
an attractive strategy for the treatment of allergic disorders
(Huang et al., 2019). Inhibition of MAPK activation were seen
in eight articles after administration of herbs and their active
constituents via oral route whereas 11 studies illustrated an
inhibition of MAPK phosphorylation after administration of
herbs and their active constituents topically, as illustrated by a
decrease in ERK, JNK and p38 protein kinases. As such, these
ndings propose that both NF-κB and MAPK signalling pathway
serve as the potential avenues of investigative research in the
development of a new therapeutic agent to treat AD.
Throughout this systematic review, we found that serum IgE,
inltration of mast cells and the levels of Th1 and Th2 cytokines
were evaluated the most in 82, 62 and 53 studies respectively.
These three biomarkers are interrelated in the pathogenesis of AD
as depicted in Figure 3. In brief, allergen penetration stimulates
T cells to secrete cytokines (IL-4, IL-5, IL-13, IFN-γ,etc.). The
released cytokines in turn trigger nearby B cells to produce IgE
which then bind to the high afnity receptor IgE, FcεRI on MCs.
The synthesis and release of inammatory mediators and
cytokines can be induced by IgE-dependent mechanism
(Williams and Galli, 2000:Kulka and Befus, 2003). The
mechanism of action of these herbs and their active
constituents may involve the inhibition of 1) binding of IgE to
the FcεRI, 2) the release of mediators and cytokines from MCs, or
3) synthesis of IgE from B cells. Although the exact mechanism
was not mentioned in each of these studies, the biomarkers of AD
related to these three parameters were found to be alleviated.
However, it may be difcult to compare the data from different
studies as various investigators used different experimental
approaches to assess the outcome of AD such as ELISA,
histological analysis and dermatitis severity. Reports may also
vary considerably depending on the methodological details
provided that could potentially lead to risk of bias. Generally,
most studies included in this systematic review did not describe
their methodologies precisely which could lead to an
underestimation or overestimation of the ndings. Thus, it is
suggested that animal experiments should be properly designed
and carried out well with transparency in every step especially
blinding in performance and assessment to avoid any bias. Data
should be reported entirely and reasons for any dropout data
should also be provided. With all the data gathered from 103
studies evaluating the efcacies of oral and topical administered
herbs along with their active constituents in alleviating AD and
the underlying mechanism of actions using various animal
models and inducers, it is hoped that this systematic review
will aid in the evidence-based selection of animal models for AD
in the future.
CONCLUSION
This systematic review has summarized 103 articles into several
aspects based on PICO; in which the most common population
(P) or choice of animal model used was BALB/C mice (n=56),
due to the fact that they lean towards a Th2-dominated immune
response which, therefore, suit the disease of interest, AD. As for
the intervention (I), this review consisted of both oral and topical
administration routes of herbs and their active constituents in
AD-like murine models and the most common positive control
(C) drug chosen among these studies was the topical
corticosteroid known as dexamethasone (n= 34). A
substantially large number of these studies (n= 75) were
conducted in Korea and none of the studies analysed the
same herb and only two articles by Aslam et al. (2018) and
Tsang et al. (2016) were understood to compare the different
routes of administrations of the same herb mixture and
compound. Findings from these two studies showed that both
oral and topical routes of herb and their active constituents
administration were able to alleviate AD, however, the authors
did not make a distinct comparison as to which route was more
effective than the other. The common outcome (O) parameters
of AD assessed amongst these studies include the histological
ndings of AD-like skin lesions, serum IgE levels, mast cell count
and Th1/Th2 cytokines. Generally, both oral and topical
administration of herbs and their active constituents elicited
the potential to decrease the AD parameters mentioned above.
Besides, large attention was also drawn towards the production
and expression of Th2 cytokines in these studies. Upon
tabulation of the vast array of ndings, a myriad of results
obtained from majority of the oral and topical studies
demonstrated that herb extracts, mixtures and compounds
isolated from herbs could markedly suppress IgE levels and
MCs inltration or degranulation. Theoretically, upon
successful inhibition of IgE-mediated activation of MCs, they
therefore hinder the subsequent degranulation and secretion of
pro-inammatory cytokines and preformed mediators. Taken
together, these ndings allow us to propose that the anti-AD
effects could be attained by down-regulation of IgE-mediated
MCs activation in in vivo models. Therewithal, MAPK and NF-
κB pathways are worth to dive into for future research
endeavours as the inhibition of these signalling pathways have
been recognized as a potential therapeutic candidate against AD.
It is also important to note that majority of the studies included
in this systematic review mentioned about compliance with
animal welfare as well as conict of interest statement among
FIGURE 3 | The mechanism of actions of orally and topically
administered herbs and their active constituents in murine model of AD.
Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 78578212
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
the authors. However, most studies did not distinctly elaborate
on examiner blinding, sample size calculation and animal
allocation. As a result, there is ample room for
methodological improvement in these studies as the authors
could declare these aspects in order to circumvent an unclear risk
of bias. Therefore, future research should implement these
crucial details to enhance the quality of studies.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in
the article/Supplementary Material, further inquiries can be
directed to the corresponding author.
AUTHOR CONTRIBUTIONS
VM and SN contributed to the conceptualization, investigation,
analysis and writing of the manuscript; KL, DI, and JT provided
important information and reviewed the manuscript; CT
conceived the idea, reviewed the manuscript and signicantly
rened the manuscript; all authors contributed to the nal
version of the manuscript.
FUNDING
This project was supported by Universiti Putra Malaysia under
Geran Putra Berimpak (UPM/800-3/3/1/GPB/9657600). VK was
a recipient of Universiti Putra Malaysia Graduate Research
Assistantship (GRA). KL was a recipient of Universiti Putra
Malaysia Graduate Research Assistantship (GRA) and Special
Graduate Research Allowance Scheme (SGRA).
ACKNOWLEDGMENTS
The authors would like to thank the members of Cell Signaling
Lab, Faculty of Medicine and Health Sciences, Universiti Putra
Malaysia for providing technical support for this study. The
authors wish to express sincere gratitude to Chan Yee Han for
her guidance, advice and support through all the stages of writing
this systematic review.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fphar.2022.785782/
full#supplementary-material
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Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 78578217
Mohd Kasim et al. Medicinal Plants in Atopic Dermatitis
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