Native Vietnamese Medicinal Plants with Anti-atopic Dermatitis Activity: A Systematic Review

Aims: Medicinal plants have always been highly valued as an accessible traditional treatment for atopic dermatitis in Vietnam. Accordingly, this review aims to assemble and discuss plants with validated anti-atopic dermatitis potency in the country, putting a great emphasis on the practice of phytomedicines and the development of plant-based products for dermatologic conditions. Existing concerns and future perspectives are included to ensure comprehensiveness of the overview. Methodology: This review is a systematic compilation of published in vitro studies, clinical trials and case studies on the effectiveness of single plant extracts in alleviating atopic dermatitis that can be found in Vietnam. Results: 39 publications presenting 31 plant species were collected in total. Preparation of plant extracts and route of administration varied slightly between the studies. Root and leaves are plant parts that were most commonly investigated (25.00% and 22.50%). Disease symptoms were mostly induced on NC/Nga mice (61.54%) using sensitizers like 2,4-dinitrochlorobenzene (28.57%), 1-fluoro-2,4-dinitrobenzene (25.71%) and Dermatophagoides farinae body extract (28.57%). Effects of plant extracts on epidermal/dermal thickness, IgE serum level, infiltration of Review Article Trang and Son; JOCAMR, 1(4): 1-24, 2016; Article no.JOCAMR.30578 2 immune cells and hyperproduction of inflammatory cytokines were intensively investigated in the collected studies. Conclusion: This review highlights the enormous potential of medicinal plants as an effective and easily accessible alternative therapy against atopic dermatitis. The use of these still needs to be further supported by scientific evidence and controlled by strict regulations to ensure good practice and stable development of phytomedicines.


Atopic Dermatitis
Atopic dermatitis (AD) or atopic eczema is a chronic inflammatory disease with high prevalence up to 20% in infants and 3% in adults with the hallmark of intense pruritic skin lesions [1]. AD is characterized by eczematous skin lesions, lichenification, xerosis, cutaneous hyperactivity and hyperkeratosis [2] manifested through acute, subacute and chronic AD [3] and causes serious frustration for patients in daily life due to its relapsing nature and associated risks of inducing atopic march development [2][3][4].
Predisposing factors of AD include genetic impairments and environmental factors that can provoke skin inflammation such as microorganism, irritants, allergens, climate, and intense psychological interactions [5,6]. The treatments of AD, thus, aim to alleviate pruritus intensity and restore skin barrier's function and integrity that are damaged through prolonged eczematous, xerotic and lichenlified condition. Unfortunately, existing AD managements are bound to certain concerns that could negatively affect patients' adherence to the treatment [7]: The use of corticosteroids as standard disease management associates with phobia of local side effects like skin atrophy, striae, steroid acne or increased hair growth and systemic side effects such as dwarfism, cataract or Cushing's syndrome [8][9][10][11]. Topical calcineurins inhibitors can cause immunosuppression or skin irritating effect, when other systemic therapies can lead to adverse events like headache, nausea, renal impairment or hypertension [12]. Considering these solid evidences, a serious demand for discovery and development of complementary approaches to AD has been imposed, promoting the practice of holistic methods and utilization of naturally derived materials to a great extent [13].

Vietnamese Medicinal Plants
In Vietnam, a tropical country blessed with a sheer abundance of flora, phytomedicines have been utilized and appreciated since antiquity to treat dermatological conditions. Regarding to atopic dermatitis, a great number of unconventional antidotes have been passed around for generations, using extracts from familiar herbs like common purslane, false daisy, candle bush, snake jasmine, and antique spurge to apply on eczema areas, or mixtures of medicinal plants decocted in daily diet. There are, however, only a relatively small number of plants whose effectiveness is confirmed by scientific methods; and still, they have not yet been assembled or systemized for the sake of good and common practice. The use of medicinal plants in Vietnam is furthermore advocated by the fact that Vietnamese participants had an exceptionally low frequency of using conventional AD managements (moisturizers, topical corticosteroids and systemic antibiotics) compared to counterparts from other Southeast Asian countries [14] while a large portion of participants showed their preference for AD herbal treatments. Another reason why plant extracts and plant-isolated phytocomponents deserve more attention is that they are widely used in over-the-counter products for AD thanks to their significant anti-inflammatory, antimicrobial and wound healing abilities. With aforementioned reasons, this review aims to summarize the literatures on medicinal plants in Vietnam with anti-AD potentials in an effort to define the role of phytomedicines in treatments for AD, as well as to create an archive of investigated plants and their bioactive compounds that will be useful for drugs discovery and development.

MATERIALS AND METHODS
Preliminary search for articles was carried out on various databases like PubMED, HerbMed, ResearchGate, Science Direct and Google Scholar using queries such as "atopic dermatitis or eczema or contact dermatitis", "plant extracts or medicinal plants", and "suppress" or its common synonyms (prevent, inhibit, reduce) or related terms (alleviate or attenuate or ameliorate or improve). All pertinent hits went through a blind assessment done by two individuals using criteria as follows: Vietnam's territory. Publications from Đỗ Tất Lợi (Những cây thuốc và vị thuốc Việt Nam [14]) and Võ Văn Chi (Từ điển cây thuốc Việt Nam [15]) were regarded as sources of reference.
• Exclusion criteria: -Articles examining efficacy of one single compound, and multi-compound or multiextract preparation.
-Articles whose full-texts were not available. -Articles whose contents were poorly presented. -Articles in other languages than English.
This review was synthesized in a narrative format using acceptable search hits, following the Animal Research: Reporting of in vivo Experiment (ARRIVE) Guidelines, and enriched with additional relevant information from other materials. No data pooling or meta-analysis were performed since data from obtained studies were not sufficiently homogenous in terms of methods, testing intervals and outcomes. For readability and informativeness, study design, dosage, route of administration, experimental animals, and results extracted from these studies on different medicinal plants were discussed in separated sections while adverse effects, active components or mechanism of action were appended if existent only.

RESULTS
A total number of 39 eligible studies referring to 31 medicinal plants were achieved following presented approach. These results were both described in details and assorted into Table 1 where scientific names, vernacular names and reported pharmacological activities of the plants could be acquired.

Alisma orientale (A. orientale)
Anti-inflammatory activity of A. orientale has been demonstrated in several studies: The plant extract inhibited contact dermatitis in mouse pinnae before sensitization with 2,4dinitrochlorobenzene(DNCB) [16] and notably suppressed ear swelling occurred in induction phase of picryl chloride-induced contact dermatitis (PC-CD) model in ICR mice [17]. However, it was over a decade after that A. orientale's effect against AD was examined more intensively. Reduction in dermatitis severity score (37.5%) and scratching behavior (32.1%) was noted in 2,4,6-trinitrochlorobenzene (TNCB)treated NC/Nga mice after oral administration of A. orientale extract in 5 weeks (200 mg/kg/d), although there was no decrease in serum Immunoglobulin E(IgE) level. The degree of hyperplasia and immune cells recruitment in inflamed skin sites were only moderately lowered. The content of alisol and its derivatives in A. orientale extract was concluded to be attributable for the plant's mitigating effects [18]. Anti-inflammatory, neuroprotective, immunosuppressive, anti-fungal and antiallergic activities [50] Alkaloids, limonoids, phenolic glycosides, dictamine, fraxinellone and skimmianine [50] Bark [50] Diospyros kaki Thunb.

Aloe vera (A. vera)
Orally administered A. vera extract (0.8 mg/kg) to mice with spontaneously induced AD showed positive effects that were achieved through suppression of IL-5 and IL-10 [19]. However, the increase of serum IgE level in extract-receiving mice contradicted a later study in which 96% gel was used. The gel improved DNCB-induced AD-like symptoms in BALB/C mice as ulceration and hyperkeratosis were lessened while reappearance of skin structures such as hair follicles or sweat glands were noted at the end of this 10-day treatment. It was then proposed that inhibition of T helper cell 2 (Th2) activation was possibly the mechanism behind A. vera gel's anti-AD activity via topical route [20].
Additionally, the effectiveness of A. vera as a treatment for other types of dermatitis was as well recorded, including seborrheic dermatitis [21] and diaper dermatitis [22]. There is, however a case in which A. vera was found to induce contact dermatitis, although the occurrence of allergic reactions linked to this plant is extremely low [23].

Angelicae dahurica (A. dahurica)
Efficacy of Anglicae dahuricae Radix ethanol extract in suppressing AD development was investigated topically at dose 10 mg/mouse using Dermatophagoides farinae body extract (DFE)induced AD model in NC/Nga mice. After 4 weeks of treatment, significant reductions in skin severity and dermal/epidermal thickness accompanied by lowered levels of histamine and IgE were recorded in immunized mice. In vitro investigations in this study revealed that the extract also markedly suppressed nitric oxide (NO) synthesis, as well as Thymus and Activation Regulated Chemokine (TARC) and monocyte-derived cells (MDC) mRNA expression in a dose-dependent manner. Presence of oxypeucedanin, oxypeucedanin hydrate, byakangelicin, nodakenin, imperatorin, and isoimperatorin in this extract, which could be attributable for its healing efficacy, was confirmed using HPLC [31].

Astragalus membranaceus (A. membranaceus)
Oral administration of lyophilized A. membranaceus dried root extract (100 mg/kg/day) was demonstrated to be effective in treating1-fluoro-2,4-dinitrobenzene (DNFB)induced dermatitis in NC/Nga mice [32]. Despite the failure to suppress IL-4 and serum IgE production, it significantly decreased skin lesions and ear swelling that was followed by hyperplasia and cells infiltration. However, the plant extract was seemingly more effective when being used as a topical treatment than oral intake. Application on skin using 1% A. membranaceous extract considerably reduced classic AD symptoms and histological features in DNCB-immunized BALB/C mice [33]. In contrast to the result of Lee et al. serum IgE level slightly declined as production of IL-4, -5, -6, and -13 was strongly inhibited, denoting A. membranaceus's inhibitory effect on Th2mediated pathway in AD development. TNF-ߙ level and nuclear factor kappa-light-chainenhancer of activated B cells (NF-ߢB) expression were also found to decline in extract-treated mice. Such decrease in inflammatory responses might be related to astragaloside IV, a saponin in A. membranaceus phytocomponents with the ability to inhibit NF-ߢB activation pathway and exert anti-inflammatory effect [34].

Boesenbergia pandurata (B. pandurata)
Ethanol extract of B. pandurata rhizome has proved to be an effective curative agent against dermatitis in a study where it was orally administered to oxazolone-treated hairless mice in 4 weeks. At both of investigated doses (50 mg/kg/day and 150 mg/kg/day), this extract successfully prevented the advance of AD, as shown by less damages in mice skin barrier, milder clinical manifestations, reduced epidermal/dermal thickness and a fewer amount of infiltrated immune cells. These changes were bound to numerous immunologic evidence like declined IgE concentration that occurred while the level of IgG2a was increased. Significant decreases in the amount of various Th2mediated molecules (IL-5, IL-13, IL-31, chemokine ligands CCL5, CCL11, CCL17, CCL22, and CCL24), as well as suppresses in IL-5, IL-13 and GATA-3 mRNA expression levels were also reported, concomitantly with the increase of T helper cell 1 (Th1)-and regulatory T cell (Treg)-mediated molecules (IL-12, T-bet, IL-10, Transforming Growth Factor beta (TGF-β), and Foxp3) in mouse spleen. B. pandurata has possibly reduced inflammatory responses in AD mice via the blockade of NF-ߢ B signaling pathway, as the lowered concentration of NF-ߢB1 and 2 mRNA indicated [35].

Broussonetia kazinoki (B. kazinoki)
The therapeutic effect of heartwood and leaves ethanol extract of B. kazinoki was examined using DFE-immunized NC/Nga mice model, both in dose of 10 mg/mouse for 4 weeks [36,37]. Following the treatment with the extract, thickening of dermis/epidermis, hyperkeratosis, hypertrophy, skin severity score and the number of infiltrated mast cells in dorsal skin markedly decreased, and so did IgE and IL-4 levels in the plasma. The extract's ability to interfere in TNF-ߙ /IFN-ߛ -induced production of AD related chemokines TARC, MDC and Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) might be the underlying mechanism for its activity.

Chrysanthemum indicum (C. indicum)
Anti-dermatitis effect of 1,3-butylene glycol from C. indicum flower extract was topically examined in two concentrations (5% and 30%) using NC/Nga mice with DNCB-induced AD [38]. After the treatment of highly concentrated extract, marked improvements in skin conditions were found along with lowered levels of serum immunoglobulins (IgE and IgG1) while histological changes like significantly decreased amounts of eosinophils and mast cells in dermis, hypertrophy, hyperkeratosis, and edema were noted. Serum levels of relevant mediators (IFN-γ and IL-4) were found decreased as well, concomitantly with the suppressed mRNA expression levels of IFN-ߛ, IL-4 and IL-13. Such evidence together confirmed C. indium as an anti-AD agent with restoring ability on Th1/Th2 ratio.

Cinnamomum cassia (C. cassia)
The daily topical treatment using C. cassia ethanol extract against DFE induced-AD in NC/Nga mice (400 ߤg/day) significantly improved skin condition with less signs of erythema, dryness, edema, scarring, hyperkeratosis and dermal recruitment of inflammatory cells after 23 days [39]. The extract furthermore suppressed the expression of TNF-ߙ and TARC while inhibiting serum IgE and histamine levels in a dose-dependent manner. The efficacy of extract from C. cassia produced by solid-state fermentation with Phellinus baumii (afCc/Pb) was found to be superior to that of mentioned C. cassia extract in a study of Shin et al. [40]. In DNFB-immunized mice treated with afCc/Pb for 8 times over duration of 2 weeks (100 g/mL), observable clinical features were less severe while immune responses were reduced up to 40%. It was also reported that afCc/Pb's effectiveness was probably owing to its inhibitory effects on matrix metalloproteinases-2, -9, -10 and IL-4, -32 expressions.
In spite of evidence for C. cassia's potential in treating AD, there are numerous cases in which it played the role of causative factors. Frequent exposure to C. cassia as flavoring agent might cause occupational allergic contact dermatitis, especially to people in bakery or confectionery industry while consumers of cinnamon-containing products might encounter stomatitis and perioral dermatitis [41][42][43][44][45][46][47]. It was thus remarkable that a safer anti-AD therapy with higher efficacy could be attained using solid-state fermentation with P. baumii to eliminate C. cassia's allergenic components, according to Shin et al. in the cited study.

Cudrania tricuspidata (C. tricuspidata)
Anti-AD activity of C. tricuspidata was confirmed using DFE-immunized NC/Nga mice model when oral administration of the plant extract markedly hindered alterations in skin conditions (60 mg/kg) over 50 days of the experiment [48]. Specifically, restoration of biophysical features was reflected through lowered Eczema Area and Severity Index (EASI) values while reductions of dermal/epidermal thickness and number of infiltrated cells showed significant histological improvements in inflamed skin sites. Such changes associated to the reduction of IgE, histamine and TARC mRNA in the plasma that were also accomplished thanks to C. tricuspidata extract.

Dictamnus dasycarpus (D. dasycarpus)
DNFB-induced dermatitis on BALB/c mice was a common model used to investigate the antiinflammatory and anti-allergic activity of D. dasycarpus extract [49,50]. In both studies of Han et al. and Kim et al., two doses 30 ߤg/ear and 300 ߤ g/ear were administered topically, when the higher dose was more efficacious in suppressing edema, dermal hyperplasia, spongiosis, IFN-γ/TNF-ߙ levels and intercellular adhesion molecule(ICAM)-1 immune-expression. In vitro investigations from those studies revealed the plant's wide range of regulatory effects, including on mast cells degranulation mediated by β-hexosaminidase and histamine, on phosphorylation of p38Mitogen-Activated Protein Kinases(MAPK), NF-ߢB p65 and Iߢ-Bߙ, not to mention on production of numerous mediators (IL-6, IL-8, monocyte chemoattractant protein (MCP)-1 and RANTES). It was also reported that D. dasycarpus possessed antipruritic and anti-allergic effects by deactivating release of histamine and serotonin in mast cells, making it a potential antagonizing agent against AD [51].

Diospyros kaki (D. kaki)
The extract obtained from steeping dried D. kaki leaves in boiling water was added into a moderate fat diet to reach 0.125% concentration and provided to mice with constant dose of 250 mg/kg during 8 weeks of treatment [52]. For extract-receiving mice, impeded AD progression reflected through skin clinical scores, less histopathological findings and lower scratching frequency were reported. Anti-dermatitis activity of this extract was clarified as production of many mediators including IgE, IL-4 and IL-13 were found suppressed, and furthermore supported by its strong anti-histamine and anti-allergic effects that were examined in this study as well. Additionally, the fact that the efficacy of astragalin, which was investigated all along, showed to be more potent than D. kaki leaf extract claimed the major role this compound played in skin healing process. Nonetheless, contribution of other constituents such as kaemferol should as well be regarded when the anti-AD activity of D. kaki comes into discussion.

Eriobotrya japonica (E. japonica)
E. japonica seed ethanol extract was found effective in suppressing immediate and latephasic hypersensitive responses caused by either oxazolone or DNFB in rats [53]. Ear swelling, TNF-ߙ overproduction and elevated histamine content in inflamed tissues were dramatically suppressed while simultaneously, lower Erythropoietin and myeloperoxidase activity level revealed that oxazolone/DNFBinduced accumulation of eosinophils and neutrophils was restrained by orally administered E. japonica extract. ߚ-sitosterol and ߚ-sitosterol glycoside-containing composition of the plant might have been responsible for described medicating effects, as stated by Sun et al.. In a later study, E. japonica seed ethanol extract not only exerted the same anti-dermatitis effect on DNFB-sensitized rats, but also correct the Th1/Th2 balance skewed to Th2 by inhibiting IgE and IL-4 overproduction and increasing Th1 cytokine IL-10 [54]. The experimenting period lasted in 8 days and dose of administration was 10 mL/rat. Presented anti-allergic and immunomodulatory activity altogether have well demonstrated E. japonica's curative effect against AD.

Glycyrrhiza glabra (G. glabra)
Gel formulations contained 1% and 2% G. glabra extract significantly alleviated erythema, oedema and pruritus after a 2-week treatment for patients with mild to moderate AD in a clinical trial [55]. The 2% gel was evidently more potent than 1% gel as it remarkably improved skin conditions after the first week of the treatment. Such healing effect of G. glabra could be explained by its high glycyrrhizinic acid content (20.3% in the extract and 19.6% in the formulation). In fact, glycyrrhizinic acid has been incorporated as a main anti-inflammatory component of several marketed topical products with clinically investigated efficacy against dermatitis [56][57][58][59][60], possibly thanks to its inhibitory effect on 11 βhydroxysteroid dehydrogenase [61].
There are actually numerous constituents other than glycyrrhizinic acid in the phytocomposition of G. glabra that make the plant a promising herbal remedy for AD. For instance, glycyrrhizin had strong anti-allergic activity expressing through the ability to reduce erythema and edema in albumin-sensitized rabbits via inhibition of prostaglandin E2 [62]. Glycyrrihzin, 18βglycyrrhetinic acid and liquiritigenin individually were able to ease itchiness and lower ovalbumininduced elevated IgE level [63]. Licochalcone E, a chalconoid among G. glabra's components, was also effective in reducing skin inflammation, as it decreased ear thickness and suppressed IL-12p40 expression through NF-ߢB downregulation in ozoxalone-treated mice [64].

Houttuynia cordata (H. cordata)
In order to verify and enhance the efficacy of H. cordata extract in managing dermatitis, a study was designed on hairless mice immunized with DNCB for 5 weeks using the plant extract of 2% in PBS, liposomal suspension and cubosomal suspension [65]. AD-like features including skin roughness and increased water loss in epidermis were significantly reduced, especially for cubosomal suspension-receiving group and followed by liposomal suspension-receiving group. The immunoregulatory effects of these extract-containing suspensions on IFN-ߛ , IL-4 and IgE were found in the same order of magnitude. As a result, such evidence did not only imply H. cordata's therapeutic effect, but also proved the superior effectiveness that could be achieved through utilization of lipid nanocarriers. It was accordingly believed that these suspensions have enhanced skin permeation of H. cordata extract so that its inhibitory effect against AD could be more fully manifested.

Hypericum perforatum (H. perforatum)
The efficacy of a hypericum cream with high content of hyperforin (1.5%) was evaluated in a randomized, placebo-controlled, double-blind, monocentric study on 21 human subjects suffering from mild to moderate AD [66]. SCORing Atopic Dermatitis (SCORAD) Index of patients who adhered to these twice-a-day treatments and the colonization of Staphylococcus aureus in inflamed areas have significantly reduced in cream-receiving group as compared to the placebo group. In spite of several adverse events noted during the trial, the superiority of this specific hypericum cream in treating AD was still approved for its hypericinand allergens-free properties. The study was however limited due to its small sample size, especially when 3 cases of exclusion have been noted along this 4-week treatment.

Illicium verum (I. verum)
I. verum ethanol extract significantly mitigated DFE-induced AD in NC/Nga mice as it was topically applied in an amount of 1000 ߤg/mouse. Over a treating period of 23 days, classic symptoms including severity score, ear swelling, hyperplasia and dermis recruitment of inflammatory cells were suppressed, accompanied by lowered levels of serum IgE, IL-6, ICAM-1 and histamine [67]. In this study and one another, the plant's in vitro immunomodulatory effects related to dermatitis pathogenesis were presented. These included inhibitions on production of related cytokines (IL-4, IL-1ߚ, TNF-ߙ), chemokines (TARC, RANTES, MDC), and vascular cell adhesion molecules (VCAM)-1. I. verum's capability to induce blockade of NF-ߢ B, signal transducer and activator of transcription 1 (STAT1), ERK/p38 MAPK, and Akt pathways furthermore clarified its Th2-related therapeutic mechanism against AD [68].

Kochia scoparia (K. scoparia)
Inhibitory effect against dermatitis of K. scoparia fruit extract was investigated along with other allergic reactions on ICR mice in a study of Matsuda et al. [69]. The extract was found to reduce ear swelling slightly in effector phase (500 mg/kg, p.o.), yet exhibited no effect in induction phase of PC-CD-induced dermatitis model. Momordin Ic, a compound derived from K. scoparia, showed even stronger ability to suppress ear swelling in this study (50 mg/kg, p.o.). In another study by Choi et al. [70], 1% K. scoparia extract was used to treat DNCBinduced dermatitis in BALB/C mice. AD-like symptoms were alleviated as less hyperplasia was found while epidermal and dermal thickness was markedly reduced (39.2% and 35.6%, respectively). Considerable decreases in the production of pro-inflammatory cytokines (IL-1ߚ, TNF-ߙ) and in the expression of MAPKs ERK1/2, p38, JNK and NF-ߢB in K. scoparia-treated mice was reported as well.
Momordin Ic isolated from K. scoparia extract might play a major role in curative effect of the plant in both studies. Its greater ability in reducing ear swelling compared to K. scoparia extract's suggested that it was among phytocomponents with strong bioactivity in the first article. As being referred to in the second one, momordin Ic was a pro-apoptotic compound whose mechanism is related to MAPK-mediated iNOs pathways and was effective in reducing inflammatory responses in dermatitis model.

Morus alba (M. alba)
The topical treatment for AD induced by DFE in NC/Nga mice using M. alba ethanol extract in an amount of 10mg/mouse showed strong potency. At the end of 4 experimenting weeks, both skin severity reflected through EASI scores and histological evidence like hyperplasia, keratosis, or infiltration of immune cells were found to be significantly subdued [71]. The extract was also accountable for lowered histamine and IgE levels found in mice plasma, as well as for noteworthy decreases in nitrite, prostaglandin E2 and TARC production that was examined in vitro in this same study.

Myristica fragrans (M. fragrans)
Orally administered M. fragrans extract greatly reduced total serum IgE level in DFE-treated NC/Nga mice (50 and 100 mg/kg/day), along with other AD-like symptoms such as increased transdermal epidermal water loss (TEWL), erythema, epidermal thickness and dermal infiltration of inflammatory cells. Throughout 6 weeks of the investigation, the extract exerted suppressing effect on the expression of IL-4 and IFN-ߛ in axillary lymph nodes, as well as IL-13 and TNF-ߙ mRNA in skin lesions. Furthermore, it was capable of balancing Th1/Th2 ratio by inhibiting DFE-induced downregulation of T-box transcription factor and upregulation of GATA-3. M. fragrans was then suggested as a potential AD treatment with nutritional values [72].
Chung et al.'s work in fact agreed with a previous study in which anti-AD activity of macelignan in M. fragrans was predicted. This compound contributed to M. fragrans's curing effect probably by its ability to suppress mRNA levels of pro-inflammatory cytokines including IL-4, IL-13 and TNF-ߙ [73]. Adversely, M. fragrans oil was found in two pharmaceutical products in Belgium that caused contact dermatitis, though it was not declared that the oil single-handedly or directly induced allergic response [74]. Nonetheless, M. fragrans was listed among other contact dermatitis-inducing spices, as eugenol and solid triglycerides of myristinic acid content in the plant composition were considered to be culpable [75].

Perilla frutescens (P. frutescens)
Aqueous extract of P. frutescens has proved its potency in suppressing allergic and inflammatory responses by preventing ear swelling in sensitization phase of oxazolone-induced dermatitis model in ICR mice (400ߤL/mouse, p.o) [76]. This outcome could hypothetically be explained by interference of the extract in Langerhans cells migration during hypersensitization owing to its inhibitory effect on TNF-ߙ production [77]. In another study using C57BL/6 mice with DNFB-induced AD, orally administered P. frutescens's extract has dramatically reduced mice ear epidermis thickness (35%), presence of eosinophils in local skin tissues (73.7%), and other dermatitis features such as scarring and eczema at the concentration of 100 ߤ g/mL [78]. The extract also restrained the overexpression of matrix metallopeptidase-9 and IL-31 while balanced out distorted ratio of Th1/Th2 through augmentation of T-bet activity. In addition, the suppressing effect of P. frutescens oils on DNFB-induced ear swelling was claimed, although it was not of great significance [79].
P. frutescens, a promising anti-AD herb around the kitchen, should be used via ingestion for its activity to exert however. In other words, repetitive contact with the plant materials may in fact lead to dermatitis in many cases [80,81]. The content of perillaldehyde in P. frutescense extract was to be blamed for its reported toxicity [82].

Platycodon grandiflorum (P. grandiflorum)
Consecutively published researches on the use of P. grandiflorum parts have yielded remarkable outcomes. These include dramatic decreases in DNCB-induced dermatitis-like skin perturbation, elevated IgE level in serum and recruitment of inflammatory cells in NC/Nga mice after oral administration of the plant root extract at varied doses (300 and 500 mg/kg/day [83]; 100 mg/kg/day [84]). Suppression of various Th2 cytokines and chemokines from both study (IL-1, -4, -6, -13, TNF-ߙ, IFN-ߛ, and TARC), as well as increased level of Th1 IL-10 in the second one were reported. In another study by Kim et al., the downregulation of Th2 IL-4, -5 and IgG1 together with upregulation of Th1 IL-12p40, IFN-ߛ and IgG2a were found to accompany the improvements of DNFB-aggravated skin [85]. Correspondingly, these studies have provided concrete evidence for the plant's ability to correct Th1/Th2 balance skewed to Th2 upon AD development. In a similar fashion, the protective activity of Lactobacillus planetarium-fermented P. grandiflorum against DNFB-induced dermatitis NC/Nga mice with optimal potency at dose 50 mg/kg/day was reported [86]. Root-derived saponins, especially platycodin D, were identified both in vivo and in vitro as bioactive components responsible for the plant's potent healing effect [87,88]. They might have exerted such activities via induction of hemeoxygenase-1 expression, simultaneously with inhibition on NF-ߢ B and STAT1.

Psidium guajava (P. guajava)
Topically applied P. guajava-containing cream considerably reduced AD clinical severity score and hypersensitive responses to DNCB including elevated dermis/epidermis thickness and infiltration of inflammatory cells in NC/Nga mice [89]. Along with these improvements were dosedependent reductions in the levels of serum IgE, TARC, and a wide range of involved cytokines (IL4, -5, -13, TNF-ߙand IFN-ߛ). Another notable result was the increased production of Tregmediated IL-10 that was responsible for restoration of skin condition. P. guajava's inhibitory effect on TARC and MDC production via blockade of NF-ߢ B and STAT1 activation, concomitant with Heme oxygenase 1(HO-1) upregulation, might be a plausible explanation for its therapeutic effect [90].

Rehmannia glutinosa (R. glutinosa)
R. glutinosa's suppressing effect on progression of DFE-induced AD in NC/Nga was extensively examined in a study by Sung et al. [91]. Clinical manifestations assessed by EASI values and histological features such as dermal/epidermal thickening or inflammatory cells accumulation were significantly assuaged in mice treated topically with plant extract. Hyperexpression of involved cytokines (IL-4, TNF-ߙ ), chemokines (TARC, MDC, RANTES) and adhesion molecules (ICAM-1, VCAM-1) was restrained together with histamine level and in vitro production of TARC, MDC and RANTES. Nonetheless, elevation of serum IgE level in extract-treated mice was recorded as an unexpected result that can play a part in clarifying R. glutinosa's mechanism of action AD.

Rhus verniciflua (R. verniciflua)
Although systemic and contact dermatitis caused by urushiols produced in R. verniciflua has been reported with common occurrence [92][93][94], the plant still contains components that were effective in treating AD. In a study using C57BL/6 mice with DNFB-induced dermatitis, urushiolremoved R. verniciflua extract significantly reduced degrees of skin exacerbation, recruitment of mast cell in inflamed sites and ear swelling accompanied by increased vascular permeability (500 mg/kg) [95]. iNOS expression, cytokines (IL-6, TNF-ߙ ) production and macrophage activation via NF-ߢB pathway were inhibited as well. Such findings were presumably related to the presence of fisetin in R. verniciflua's phytocomposition, as similar immunomodulatory effects of the compound were reported in a previous work of Goh et al. [96].

Saussurea lappa (S. lappa)
In vitro ability to inhibit the production and mRNA expression of TARC, MDC, RANTES, and IL-8 of S. lappa extract gave a hint about its anti-AD potential that was confirmed in the same study [97]. DFE-induced disturbances in skin barrier such as hyperplasia, keratosis or recruitment of immune cells and clinical severity presented by EASI values were lowered in NC/Nga mice fed with the extract. S. lappa also acted as a hindrance to the production of histamine, TARC and IgE in these mice, which in turn revealed a plausible mechanism behind the plant's healing capability.

Schizandra chinensis (S. chinensis)
NC/Nga mice subjected to repetitive exposure of DNCB with aggravated skin condition, hyperplasia, and intense pruritus from degranulation of infiltrated mast cell have achieved significant recoveries after the topical treatment with S. chinensis extract (1%) [98]. As similar to IgE and IgM concentration in the blood, histamine level along with expression of histamine receptors H1R, H3R and H4R were markedly reduced. Hyperexpression of IL-4, IL-5 and FcεRIβ were found to decrease as well. Likewise, clinical and histopathological manifestations in DNFB-immunized mice were alleviated by topically applied S. chinensis fruit extract in a more recent study [99]. Such healing effect might be owing to suppressed production of TNF-ߙ, IFN-ߛ, IL-6 andMCP-1 that held crucial roles in elicitation of inflammatory responses.

Sophora flavescens (S. flavescens)
Topically administered S. flavescens extract (10 mg/mL) significantly assuaged immunological responses to DNFB in BALB/c mice including ear swelling, edema, hyperplasia, spongiosis, and infiltration of mononuclear cells [100]. In vitro suppressing effects of the extract on mast cell activity and the release of its mediatorshistamines and ߚ -hexosaminidase -were reported along. S. flavescens's healing capability was also justified in a former study. Specifically, clinical manifestations of AD, dermal leukocytes infiltration and elevated serum IgE level caused by DFE in NC/Nga mice were was notably lowered after topical treatment with the plant extract [101]. These studies together demonstrated S. flavescens' wide range of immunomodulatory ability as the overproduction of IgE, Th cytokines (TNF-ߙ and IFN-ߛ ) and chemokines (TARC/CCL17, MDC/CCL22, and CTACK/CCL27) were well restrained. Prenylated chalcone present in the plant's component with in vitro inhibitory ability on chemokines expression via a HO-1-involved pathway might have great contribution to the potency of S. flavescens [102].

Uncariae rhynchophylla (U. rhynchophylla)
U. rhynchophylla extract administered via oral route was markedly effective in reducing AD-like skin lesions and ear edema resulted from topical sensitization with DNFB in NC/Nga mice [103]. Histological examination of inflamed skin showed notable reductions in dermal/epidermal thickness and recruitment of inflammatory cells. However, these alterations did not associate with either IgE serum level or IL-4 production since no change in these two parameters was found. The efficacy of U. rhynchophylla was hence assumed to arise from modulatory effect on Th1 immune responses via inhibition of IFN-ߛproduction [104].

Vernonia amygdalina (V. amygdalina)
In vivo anti-AD activity of V. amygdalina aqueous and methanol extract was evaluated on TNCBtreated NC/Nga mice [105]. Both the extracts showed strong prophylactic and curative effects against observable clinical features such as scratching behavior, eczematous skin, ear thickening and filtration of inflammatory cells into ear dermis, as well as upregulation of serum IgE, cytokines (IFN-ߛ, TNF-ߙ, IL-5) and chemokines (MCP-1, eotaxin). Such anti-allergic effect might relate to ERK pathway of which V. amygdalina was previously reported as an inhibitor. Also described in this study was the case of a 17year-old patient who reported complete disappearance of itchiness in the second week and lowered EASI score on day 21 of the topical treatment with V. amygdalina. Furthermore, the plant extract also demonstrated healing effect in the case of chronic, severe and recalcitrant AD of a 5-year-old Congolese patient [106]. The patient reported an appreciable decrease in EASI and Dermatology Life Quality Index (DLQI) after a 3week adherence to topical application of 10% leaf extract twice a day. At day 40 of the treatment, hematologic and immunologic assays showed lowered level of leukocytes, erythrocyte sedimentation rate (ESR), white blood cells, total IgG, as well as serum total IgE. In another preliminary clinical trial, 25 school children diagnosed with mild to moderate AD were randomly assigned to 4 groups of different treatment including V. amygdalinawater extract (Vamex1), V. amygdalina alcohol extract (Vamex2), dexamethasone and vaseline [107]. After a 3-weeks interval, 69% children in Vamex1 and 71 % in Vamex2 group were completely cleared of AD symptoms while at the end of the trial, significant decreases in pruritus, serum IgE level and ESR were noted.
In all cited studies, the efficacy of V. amygdalina extracts in suppressing AD was only slightly inferior to that of positive controls while no adverse effects were reported in all cases. Although these were strong evidence for the plant's safety and efficacy, small sample size of the studies however made it insufficient to confirm V. amygdalina's anti-AD activity in human. Still, its effectiveness could be explained by a wide range of bioactive compounds with anti-inflammatory and anti-allergic activity, especially vernondalin, a terpenoids found in V. amygdalina leaf extract [105].

Vigna angularis (V. angularis)
The prophylactic and therapeutic effects of red bean (V. angularis) on AD was investigated by feeding NC/Nga mice with plant extract daily for 2 weeks prior to the induction using DNCB [108]. Similar to severity of eczematous skin, histopathological features including dermal/epidermal hyperplasia, hyperkeratosis and recruitment of polymorphonuclear cells and mast cells were lessened, showing significant improvements in extract-receiving mice. Furthermore, mRNA expression levels of IL-4, IFN-ߛ and TNF-ߙ in splenocytes was markedly reduced along with peripheral eosinophils ratio and serum IgE concentration. The treatment in dose of 250 mg/kg was superior to 50 mg/kg as it generated statistically significant results. Specific plant components with anti-AD activity, however, have not yet been figured out since the investigated extract was comprised of great portions of carbohydrate (37.09%) and crude fat (38.06%) with high polyphenols content. In a more recent study, oleanolic acid acetate isolated from V. angularis was found to be effective in suppressing development of DFE/DNCB-induced AD and DNFB-induced CD in BALB/c mice [104].

DISCUSSION
AD is a multifactorial dermatologic condition with high prevalence characterized by appearance of eczematous skin and intense pruritus [1]. Current AD managements such as emollients, corticosteroids, calcineurin inhibitors, antibiotics, antihistamines or phototherapies, in spite of their potency, are chained to serious concerns of drugs addition, adverse effects and high cost that make it unfavorable for patients to sufficiently comply with in the long term. It was furthermore reported that the popularity of these conventional managements was not widespread among Vietnamese respondents as only a small proportion of respondents used topical corticosteroids (11% to 25%) and systemic antibiotics (11%) for severe AD [109]. Surprisingly, the practice of complementary and alternative therapies for the disease was preferred by a comparably high portion of participants from Vietnam and Japan (both 27%) [109,110]. The exploitation of phytomedicines is not limited to direct topical or oral uses as medicines only: Plant extracts are still one among the main ingredients of well-known commercialized AD products, e.g. Aloe barbadensis, Butyrospermum parkii and Vitis vinifera, and so are numerous compounds isolated from plants such as bisabolol from German chamomile, glycyrrhetinic acid and licochalcone A from licorice [111]. Thereupon, a retrospective review where medicinal plants with anti-AD activity in Vietnam are assembled is of great importance. It is then especially useful for the purpose of providing detailed insights into current phytotherapy approaches whose development would create substantial impacts on the managements of AD.
In this review, a systematic search was performed and a total of 39 studies on 31 medicinal plants with validated anti-AD activity in Vietnam were compiled and reported with additional relevant details. Procured studies fall into 3 categories including research article (87.5%), clinical trial (7.5%) and case study (5.0%). Root and leaves are the most frequently employed plant parts that were subjected in 25.0% and 22.5% of obtained studies respectively, followed by barks, suits and seeds, each in 7.5%. Other investigations utilized extract from whole plant or special parts such as rhizome, corm, heartwood, and legume. Most of these herbal remedies were tested as unadulterated extracts (34 studies) while some others were incorporated into different topical carriers such as gel (A. vera, G. glabra), cream (H. perforatum, P. guajava) or suspensions (H. cordata). Nonetheless, the efficaciousness of such loaded carriers and of these plants alone were scarcely compared and thus, posing certain questions about the actual potency of contained extracts, the contribution of used vehicles in disease improvements and the plausible pharmacological interactions between testing components.
Albeit all extracts were tested on murine models of AD, disease inducers, specific strains of experimental animals, and methods of delivery differ greatly. Disease induction on experimental animals availed common haptens, namely DNCB (28,57%), DNFB (25,71%), DFE (28,57%), etc., to mimic AD-like symptoms including pruritus, development of eczematous skin lesions, epidermal/dermal thickening and infiltration of pro-inflammatory lymphocytes, accompanied by elevation of serum IgE level and a wide range of Th2 cytokines. The number of articles using NC/Nga mice occupied 61.54% and outweighed those that used other strains such as BALB/C, hairless mice and C57BL/6 for extract evaluation. As an explanation for this particular favor, NC/Nga mice can develop analogous clinical features and histology to those of afflicted patients, including the overproduction of IgE, spontaneously under conventional condition and thus, are very much valued in the delineation of eczema pathophysiology and treatment [112]. All investigated materials followed topical or oral route of administration, both of which either reflect how the plants are traditionally used or suggest a more proper usage for AD treatment. Nevertheless, while the diversity in testing approaches enables researchers to opt for the most suitable method, it also challenged the conduction of data pooling and thus, no metaanalysis was performed in this narrative-style systematic review.
The determination of herbal healing efficacy critically requires in-depth studies on AD cellular and molecular biomarkers. In order to identify AD subtypes of different phases and pathologies, to assess dose-response relationship between therapeutic agents and disease manifestations, as well as to clarify the pathways by which the condition was made to subdue, it is necessary to examine the level of markers such as immunoglobulins, inflammatory cytokines, adhesion molecules, and immune receptors together with corresponding lymphocytes and effector cells [113]. Overall, immune molecules and cells investigated in collected studies made up a greatly extensive list that disabled data compression and comparison; thus, only a few commonly examined markers are presented here as examples. Thickened epidermis and dermis with histopathological findings and infiltration of eosinophils and mast cells are first signs to be sought. The level of serum IgE formerly considered as a factor with pivotal role in AD development was examined in most articles. While most potential extracts successfully restored IgE level upon improving skin condition, some do not. These extracts, including A. orientale, A. membranaceus and U. rhynchophylla, emphasized that IgE hypersensitivity is not prerequisite for AD development and is only a hallmark of extrinsic type [2]. Inflammatory cytokines are other reliable markers since their production is simple to determine and well correlated to disease severity and extract activity. Assessment of specific cytokines is useful for determining the phase, on which an extract can act upon, as well as its healing pathway and potency [114]. In the acute phase, AD development is primarily driven by Th2-cytokines, notably IL-4, -5 and -13 that are responsible for inflammatory responses and intense pruritus. The shift to chronic phase occurs when naive T cells differentiate into Th1 cells under the influence of IL-12 produced by activated dendritic cells and triggers the secretion of IFN-gamma, which acts along with other Th17/Th22 cytokines and eventually leads to lichenification [114,115]. Additionally, in vitro studies were usually conducted to clarify the particular inflammation inhibitory pathways that investigated plant extracts have followed.

Similar
to other therapies, there are shortcomings in the usage of phytomedicines that make it sometimes unfavored by dermatologist and physician. They include firstly the safety of herbal medicines, a pivotal aspect often belied by the assumption that natural treatments do little or no harm to health. This is in fact a dangerous misconception as some among reported plants in this review are even notorious for their highly allergenic profiles such as A. vera, C. cassia, I. verum and R. verniciflua [116], and a few others would cause severe systemic side effects while being used excessively.
Extrinsic factors, e.g misidentification, mislabeling and contamination of plant materials can be also considered as threats other than the plant's toxicity itself. Secondly, the variety of plant components on one hand exerts a wide span of immunoregulatory activities, but riddles the identification of lead compounds on the other hand. This challenges not only the isolation and confirmation of single plant-derived compounds which is potential for drug discovery, but also the adulteration and adjustment to enhance herbal medicine's efficacy in pharmaceutical manufacture. Lastly, more explanatory and pragmatic studies should be conducted to determine whether they can as well work effectively on human. That is to say, when AD animal models are claimed to be highly relevant to human manifestations, the evaluation of these is used merely to underline the potential of plant extracts, but by no mean to draw final conclusions about their effectiveness and safety in real practice.
The assembly of potential Vietnamese medicinal plants that can be served as substitutes for immunosuppressive agents has highlighted the practice of herbalism among therapeutic approaches for AD. Thereupon, further research to evaluate and optimize the efficacy of herbal medicines on human are absolutely critical to pave the way for the development of new herbal medications. Efficaciousness of composite herbal medicines should be examined to unveil prominent synergistism occurred between various extracts that could be extremely beneficial in the combat against AD. Another important task is to identify the main phytoconstituents responsible for healing effect that can be sufficiently isolated and refined for commercial use. Additionally, the safety of phytomedicines must be ensured by the removal of hazardous components preceded by approved risk assessment processes. Among several options for such task is solid-state fermentation, a "low technology" system with claims of being able to simultaneously boost the phenolics content and bioavailability of plant extracts as reported in the previous section of this review [117,118]. It is finally important to bear in mind that AD is a complicated skin condition whose exact etiology is unknown and thus, integrative therapy of various managements including the treatment with phytomedicines, dietary intervention, indoor environmental control and psychological support definitely deserves special attention.
On top of this, the underachieving status of traditional medicines deployment in Vietnam is a serious concern arose from weak enforcement of an inadequate and outdated legal framework. Given that Vietnam has an approximate amount of 10,000 flora species with about 4,000 plants that can be used for medicinal purposes, it is an alarmingly contradicting fact that 80-85% herbal medicines circulating on national markets originated from China as reported in June 2016 [119]. The number of GACP-complied herbal medicines manufacturers only counted to 7 by January 2016 [120] when that of GMP-complied manufactures added up to merely 174 by December 2015 [121]. Presented situation undoubtedly demands improved legislations specific to quality control, documentation and intellectual property rights of traditional medicines, at best with reference to guidelines of international organizations (WHO [122], IUCN [123], IUPAC [124], etc.), to ultimately facilitate the research and development of natural-derived AD therapeutics.

CONCLUSION
The present review features Vietnamese medicinal plants with alleviating effects on AD, thanks to which the role of plant-based treatments for this specific dermatologic condition is once again emphasized. Through collected studies, phytomedicines are proven to possess wide ranges of anti-inflammatory activities via various pathways without exerting severe side effects over experimental periods. This should however reaffirm the need for further study to validate the efficaciousness of discussing plants in practice and the mechanisms behind that could lead to the introduction of novel dermatitis counteragents, which are considered as alternatives and complements to existing managements. Calls for the embracement of Vietnamese rich medicinal source and tight policies on standardization, documentation and preservation are let out additionally to ensure appropriate deployment of anti-AD herbal medicines in the future to come.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.