Atopic Dermatitis-like Skin Lesions Research Articles

Artemisia anomala Herba Alleviates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice and the Production of Pro-Inflammatory Mediators in Tumor Necrosis Factor Alpha-/Interferon Gamma-Induced HaCaT Cells.

Artemisia anomala S. Moore is a perennial herbaceous plant classified as Asteraceae of the genus Artemisia. Many species of Artemisia have been used as medicinal materials. Artemisia anomala S. Moore has been widely used in China to treat inflammatory diseases. However, the mechanism of its action on the keratinocyte inflammatory response is poorly understood. Here, we investigated the anti-inflammatory reaction of Artemisia anomala S. Moore ethanol extract (EAA) using human keratinocyte (HaCaT) cells, which involved investigating the nuclear factor kappa B (NF-κB), signal transducer, and activator of transcription-1 (STAT-1), as well as mitogen-activated protein kinase (MAPK) signaling pathways and atopic dermatitis-like skin lesions in mice. We elucidated the anti-inflammatory effects of EAA on tumor necrosis factor-α/interferon-γ (TNF-α/IFN-γ)-treated human keratinocyte cells and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD)-like mice. The levels of chemokines and cytokines (IL-8, IL-6, TARC, and RANTES) were determined by an enzyme-linked immunosorbent assay. The NF-κB, STAT-1, and MAPK signaling pathways in HaCaT cells were analyzed by western blotting. Thickening of the mice dorsal and ear skin was measured and inflammatory cell infiltration was observed by hematoxylin and eosin staining. Results showed that EAA suppressed IL-8, IL-6, TARC, and RANTES production. EAA inhibited nuclear translocation of NFκB and STAT-1, as well as reduced the levels of phosphorylated ERK MAPKs. EAA improved AD-like skin lesions in DNCB-treated mice. These findings suggest that EAA possesses stronger anti-inflammatory properties and can be useful as a functional food or candidate agent for AD.

Effects of chloroform fraction of Fritillariae Thunbergii Bulbus on atopic symptoms in a DNCB-induced atopic dermatitis-like skin lesion model and in vitro models.

Ethnopharmacological relevanceFritillariae thunbergii Bulbus (FT), knowns as “Jeolpaemo (浙貝母)” in Korean traditional medicine, is a perennial plant belonging to the Liliaceae family and has been used to treat symptoms such as cough, sputum formation, and purulent pneumonia. Owing to its effects of lowering heat, removing sputum, and reducing swelling, the plant has also been used as an external prescription medicine to treat inflammation. Aim of the studyTo analyze the anti-inflammatory effects of FT-ethanol extract (FT-Et) and FT-chloroform fraction extract (FT-Cl) on 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD) in vivo and in vitro. Materials and methodsThe effect of FT-Et and FT-Cl on AD was observed using an AD-like skin lesion model induced by DNCB in vivo. HaCaT and RBL2H3 cells were used to determine the effects of FT-Et and FT-Cl in vitro. After inducing AD-like skin lesions in vivo, FT was topically applied to the skin lesion for 35 days. Epidermal thickness, dermal thickness, scratching behavior, infiltration of inflammatory cells, and expression of skin barrier proteins were measured. TARC, MDC, and IL-4 levels were analyzed using ELISA in HaCaT cells. Beta-hexosaminidase and IL-4 levels were measured in RBL2H3 cells. The expression of filaggrin (FLG), loricrin (LOR), involucrin (INV), and aquaporin-3(AQP-3) was measured by PCR. Phosphorylation of MAPKs was analyzed using Western blot technique. ResultsFT-Cl significantly reduced ear swelling, scratching behavior, SCORAD index, epidermal thickness, infiltration of inflammatory cells, and loss of skin barrier proteins. FT-Et inhibited the infiltration of mast cells and CD8+ cells and decreased the loss of skin barrier proteins. In TNF-α/IFN-γ-stimulated HaCaT cells, FT-Cl inhibited TRAC, MDC, and IL-4 expression and upregulated the expression of FLG, INV, and AQP-3, whereas FT-Et inhibited the expression of TRAC and MDC and increased the expression of FLG, INV, and AQP-3 at high concentrations. In RBL2H3, FT-Cl downregulated β-hexosaminidase and IL-4 expression. In addition, FT-Cl inhibited the phosphorylation of ERK and p-38 in HaCaT and RBL2H3 cells. ConclusionsCollectively, FT-Cl showed better effect than FT-Et in vivo and in vitro. These results suggest that a specific component present in FT-Cl acted against AD. Future research should focus on the analysis of components contained in FT-Cl and the anti-inflammatory effects of the active ingredient.

Alnus sibirica Compounds Exhibiting Anti-Proliferative, Apoptosis-Inducing, and GSTP1 Demethylating Effects on Prostate Cancer Cells.

Alnus sibirica (AS) is distributed in Korea, Japan, China, and Russia and has reported anti-oxidant, anti-inflammatory, and reducing activities on atopic dermatitis-like skin lesions, along with other beneficial health properties. In the present study, we tried to prove the cancer-preventive activity against prostate cancer. The extracted and isolated compounds, oregonin (1), hirsutenone (2), and hirsutanonol (3), which were isolated from AS, were tested for anti-proliferative activity. To do this, we used the MTT assay; NF-κB inhibitory activity, using Western blotting; apoptosis-inducing activity using flow cytometry; DNA methylation activity, using methylation-specific polymerase chain reaction in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines. The compounds (1–3) showed potent anti-proliferative activity against both prostate cancer cell lines. Hirsutenone (2) exhibited the strongest NF-κB inhibitory and apoptosis-inducing activities compared with oregonin (1) and hirsutanonol (3). DNA methylation activity, which was assessed for hirsutenone (2), revealed a concentration-dependent enhancement of the unmethylated DNA content and a reduction in the methylated DNA content in both PC-3 and LNCaP cells. Overall, these findings suggest that hirsutenone (2), when isolated from AS, may be a potential agent for preventing the development or progression of prostate cancer.

Effects of Josamycin on Scratching Behavior in NC/Nga Mice with Atopic Dermatitis-Like Skin Lesions.

Our previous study showed that chronic skin colonization by Staphylococcus aureus exacerbated atopic dermatitis (AD) and that control of such skin colonization using antibiotic ointment might relieve AD-related skin inflammation. However, the role of S. aureus colonization in the pruritus accompanying AD was not elucidated. The aim of the present study was to evaluate the effect of topically applied josamycin, a macrolide antibiotic, on the scratching behavior of NC/Nga mice with AD-like skin lesions. Josamycin (0.1%) was topically administered to NC/Nga mice with AD-like skin lesions induced by a mite antigen, Dermatophagoides farinae extract, and the therapeutic effects of josamycin were assessed by measurement of the skin severity score, S. aureus colonization, scratching count, and interleukin (IL)-31 mRNA expression in the skin lesions. Topical treatment with josamycin ointment significantly suppressed the increase of the skin severity score in NC/Nga mice. This suppressive effect was associated with decreases in the S. aureus count on the lesioned skin, scratching behavior of mice and IL-31 mRNA expression in the lesions. The present results show that the severity of AD-like skin inflammation in NC/Nga mice is correlated with the level of S. aureus colonization and subsequent IL-31 production in the skin. Therefore, topical application of josamycin to AD lesions colonized by S. aureus would be beneficial for control of AD by eliminating superficially located S. aureus and by suppressing the IL-31-induced scratching behavior.

Suppressive effect of 1,4-anhydro-4-seleno-D-talitol (SeTal) on atopic dermatitis-like skin lesions in mice through regulation of inflammatory mediators

BackgroundAtopic dermatitis (AD) is a multifactorial chronic inflammatory disease that affects ∼20 % of children and 3% of adults globally and is generally treated by the topical application of steroidal drugs that have undesirable side-effects. The development of alternative therapies is therefore an important objective. The present study investigated the effects of topical treatment with a novel water-soluble selenium-containing carbohydrate derivative (4-anhydro-4-seleno-D-tatitol, SeTal) on the symptoms and inflammatory parameters in an AD mouse model. MethodsMice were sensitized by applying 2,4-dinitrochlorobenzene (DNCB) to their dorsal skin on days 1–3, then further challenged on their ears and dorsal skin on days 14, 17, 20, 23, 26, and 29. SeTal (1 and 2%) or hydrocortisone (1%) was applied topically to the backs of the mice from days 14–29, and skin severity scores and scratching behavior determined on day 30. The mice were euthanized, and their ears and dorsal skin removed to quantify inflammatory parameters, edema, myeloperoxidase (MPO) activity, and AD-associated cytokines (tumor necrosis factor alpha (TNF-α), interleukins (IL)-18, and IL-33). ResultsDNCB treatment induced skin lesions and increased the scratching behavior, ear edema, MPO activity (ear and dorsal skin), and cytokine levels in dorsal skin. Topical application of SeTal improved inflammatory markers (cytokine levels and MPO activity), cutaneous severity scores, and scratching behavior. ConclusionThe efficacy of SeTal was satisfactory in the analyzed parameters, showing similar or better results than hydrocortisone. SeTal appears to be therapeutically advantageous for the treatment and control of AD.

Haplopine Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice and TNF-α/IFN-γ-Induced Inflammation in Human Keratinocyte.

This study aimed to investigate the anti-inflammatory, antioxidant, and anti-atopic dermatitis (AD) effects of haplopine, which is one of the active components in D. dasycarpus. Haplopine (12.5 and 25 μM) inhibited the mRNA expressions of inflammatory cytokines IL-6, TSLP, GM-CSF, and G-CSF and the protein expressions of IL-6 and GM-CSF in TNF-α/INF-γ-stimulated HaCaT cells. In H2O2-induced Jukat T cells, haplopine (25 and 50 μM) suppressed the productions of proinflammatory cytokines (IL-4, IL-13, and COX-2) and increased the mRNA and protein expressions of oxidative stress defense enzymes (SOD, CAT, and HO-1) in a concentration-dependent manner. In vivo, haplopine significantly attenuated the development of AD symptoms in 2,4-dinitrochlorobenzene (DNCB)-stimulated Balb/c mice, as evidenced by reduced clinical dermatitis scores, skin thickness measurements, mast cell infiltration, and serum IgE concentrations. These findings demonstrate that haplopine should be considered a novel anti-atopic agent with the potential to treat AD.

Wikstroemiaganpi Extract Improved Atopic Dermatitis-Like Skin Lesions via Suppression of Interleukin-4 in 2,4-Dinitrochlorobenzene-Induced SKH-1 Hairless Mice.

Plants of the genus Wikstroemia are used in Chinese traditional medicine to treat inflammatory diseases, such as arthritis, bronchitis, and pneumonia. The present study was designed to determine whether Wikstroemia ganpi (Siebold and Zucc.) Maxim. offers a potential means of treating 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in mice. Symptoms such as redness, edema, and keratinization in AD mice induced by DNCB were alleviated by the co-application of an ethanolic extract of W. ganpi for 2 weeks. The severity of skin barrier function damage was evaluated by measuring TEWL (transepidermal water loss). TEWLs of DNCB sensitized mouse dorsal skin were reduced by the application of a W. ganpi ethanolic extract, and skin hydration was increased. In addition, the infiltration of inflammatory cells into the dermis was significantly reduced, as were blood levels of IgE and IL-4, which play an important role in the expression of AD. The results of this experiment suggest that W. ganpi is a potential therapeutic agent for AD.

Effects of mineral complex material treatment on 2,4- dinitrochlorobenzene-induced atopic dermatitis like-skin lesions in mice model

BackgroundAtopic dermatitis (AD) is a chronic allergic inflammatory skin disease characterized by complex pathogenesis including skin barrier dysfunction, immune-redox disturbances, and pruritus. Prolonged topical treatment with medications such as corticosteroids, calcineurin inhibitors, and T-cell inhibitors may have some potential side-effects. To this end, many researchers have explored numerous alternative therapies using natural products and mineral compounds with antioxidant or immunomodulatory effects to minimize toxicity and adverse-effects. In the current study, we investigated the effects of mineral complex material (MCM) treatment on 2, 4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in SKH-1 hairless mice.MethodsAnimals were divided into four groups; normal control (NC), negative control treated with DNCB only (DNCB only), positive control treated with DNCB and tacrolimus ointment (PC) and experimental group treated with DNCB and MCM patch (MCM). Skin inflammation and lesion severity were investigated through analyses of skin parameters (barrier score and strength, moisture and trans-epidermal water loss level), histopathology, immunoglobulin E, and cytokines. In addition, reactive oxygen species (ROS), nitric oxide (NO), glutathione peroxidase (GPx), and catalase (CAT) levels were measured in both serum and skin lysate.ResultsOur results demonstrates that MCM patch improved the progression of AD-like skin lesions by significantly increasing skin barrier strength and decreasing trans-epidermal water loss. Additionally, dermal administration of MCM patch significantly reduced epidermal thickness, ROS, and NO levels in skin lysate. Furthermore, we found that MCM suppressed the levels of AD-involved (Th1 and Th2) cytokines such as IL-2, IFN-γ, and IL-4 in blood. In addition, the levels of other Th1, and Th2 and inflammatory cytokines such as IL-1β, TNF-α, IL-6, IL-12(p70) and IL-10 were found lowest in the MCM group than in the DNCB only and PC groups. Moreover, we found total serum IgE level significantly increased after DNCB treatment, but decreased in the PC and MCM groups.ConclusionTaken together, our findings suggest that MCM application may have beneficial effects either systemic or regional on DNCB-induced AD lesional skin via regulation of the skin barrier function and immune-redox response.

Impressic Acid Ameliorates Atopic Dermatitis-Like Skin Lesions by Inhibiting ERK1/2-Mediated Phosphorylation of NF-κB and STAT1.

Impressic acid (IPA), a lupane-type triterpenoid from Acanthopanax koreanum, has many pharmacological activities, including the attenuation of vascular endothelium dysfunction, cartilage destruction, and inflammatory diseases, but its influence on atopic dermatitis (AD)-like skin lesions is unknown. Therefore, we investigated the suppressive effect of IPA on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin symptoms in mice and the underlying mechanisms in cells. IPA attenuated the DNCB-induced increase in the serum concentrations of IgE and thymic stromal lymphopoietin (TSLP), and in the mRNA levels of thymus and activation regulated chemokine (TARC), macrophage derived chemokine (MDC), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in mice. Histopathological analysis showed that IPA reduced the epidermal/dermal thickness and inflammatory and mast cell infiltration of ear tissue. In addition, IPA attenuated the phosphorylation of NF-κB and IκBα, and the degradation of IκBα in ear lesions. Furthermore, IPA treatment suppressed TNF-α/IFN-γ-induced TARC expression by inhibiting the NF-κB activation in cells. Phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) and the signal transducer and activator of transcription 1 (STAT1), the upstream signaling proteins, was reduced by IPA treatment in HaCaT cells. In conclusion, IPA ameliorated AD-like skin symptoms by regulating cytokine and chemokine production and so has therapeutic potential for AD-like skin lesions.

Acupuncture ameliorates not only atopic dermatitis-like skin inflammation but also acute and chronic serotonergic itch possibly through blockade of 5-HT2 and 5-HT7 receptors in mice

Acupuncture has been known to be effective for atopic dermatitis, especially ameliorating itch; however, its mechanisms are still unclear. The aim of this study was to test the anti-itch effects of acupuncture and to investigate its possible mechanisms. Acupuncture was performed at Gok-Ji (LI11) acupoints just before the injection of pruritogens in the mouse cheek model of acute itch and of MC903-induced atopic dermatitis displaying serotonergic chronic itch. Acupuncture significantly reduced acute itch triggered by compound 48/80, chloroquine, or especially serotonin. It also markedly reduced scratching behaviors evoked by the serotonin 5-HT2 receptor agonist α-methylserotonin and selective 5-HT7 receptor agonist LP 44. In addition, acupuncture treatment at LI11 had the preventive and therapeutic effects on persistent itch as well as the robust skin inflammation with epidermal thickening in mice with MC903-induced atopic dermatitis. It also considerably reduced the increased expression of 5-HT2A, 5-HT2B and 5-HT7 receptors in atopic dermatitis-like skin lesions in mice treated with MC903. Taken together, these findings highlight that acupuncture significantly ameliorates not only skin inflammation, but also acute and chronic serotonergic itch, possibly through blockade of serotonin 5-HT2 and 5-HT7 receptors.

Effect of 6,7-dimethoxy-2,2-dimethyl-2H-chromene (agerarin) on the recovery of filaggrin expression through targeting of Janus kinases in the inflammatory skin.

Filaggrin (FLG) is a structural component of the stratum corneum that is essential for maintaining the barrier function of the skin and for the formation of natural moisturizing factors. 6,7-Dimethoxy-2,2-dimethyl-2H-chromene (Agerarin) is a bioactive compound derived from Ageratum houstonianum, a plant that is used as a traditional medicine to treat skin diseases. This study aimed to evaluate the effect of agerarin on skin inflammation in a dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model. We found that the topical administration of agerarin ameliorates atopic dermatitis-like skin lesions. We also showed that agerarin restores the reduced filaggrin (FLG) expression in DNCB-applied skin sections. Moreover, agerarin decreased phosphorylation of JAK1 and JAK2 kinases to enhance FLG expression, which was reduced by TNFα+IFNγ and IL4+IL13 treatment, in HaCaT keratinocytes. These results demonstrate the feasibility of agerarin as a possible therapeutic against conditions of skin inflammation, such as atopic dermatitis, by improving the upregulation of FLG expression.

Effects of a pyroglutamyl pentapeptide isolated from fermented barley extract on atopic dermatitis-like skin lesions in hairless mouse.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic and eczematous skin lesions. The skin of AD patients is generally in a dried condition. Therefore, it is important for AD patients to manage skin moisturization. In this study, we examined the effects of orally administered fermented barley extract P (FBEP), which is prepared from a supernatant of barley shochu distillery by-product, on stratum corneum (SC) hydration and transepidermal water loss (TEWL) in AD-like lesions induced in hairless mice using 2,4,6-trinitrochlorobenzene. Oral administration of FBEP increased SC hydration and decreased TEWL in the dorsal skin of this mouse model. Further fractionation of FBEP showed that a pyroglutamyl pentapeptide, pEQPFP comprising all -L-form amino acids, is responsible for these activities. These results suggested that this pyroglutamyl pentapeptide may serve as a modality for the treatment of AD.

Poly-γ-Glutamate microneedles as transdermal immunomodulators for ameliorating atopic dermatitis-like skin lesions in Nc/Nga mice

Atopic dermatitis (AD), a common, relapsing, inflammatory disorder of the skin, is associated with T helper type 2 (Th2)-biased immune responses. Despite the efficacy of existing drugs for AD treatment, their safety and side effects cause concern. The present study describes the use of dissolvable poly-γ-glutamate (γ-PGA) microneedles (MNs) with immunomodulatory effects for effectively relieving AD-like symptoms in Nc/Nga mice. γ-PGA MNs can easily penetrate the epidermis and release γ-PGA into the dendritic cell–rich dermis to interact with dendritic cells for modulating immune responses. Transdermal administration of high-molecular-weight (HMW, 1100 kDa) γ-PGA MNs significantly reduced clinical dermatitis scores, epidermal thickness, and mast cell infiltration in mice by downregulating immunoglobulin (Ig)E and IgG1 levels (Th2-associated antibodies) compared with the AD control group. However, low-molecular-weight (200–400 kDa) γ-PGA MNs ameliorated AD-like skin lesions less effectively than HMW γ-PGA MNs, thus indicating that the MW of γ-PGA may affect its immunomodulatory properties. Notably, the mouse skin quickly recovered its barrier function within 4 h after MN application. No weight loss or abnormality was observed in the MN-treated mice during the 8-week treatment period. These results suggest that the γ-PGA MNs represent an innovative, safe, and reliable therapeutic strategy for AD management. Statement of SignificanceThis study is the first to explore the feasibility of using poly-γ-glutamate (γ-PGA) microneedles (MNs) as transdermal immunomodulators for improving atopic dermatitis (AD) symptoms and to evaluate their immunomodulatory effect in mice with spontaneously developed AD. Transdermal administration of γ-PGA MNs enables the γ-PGA to localize in the skin for activation of dermal dendritic cells, thus modulating immune responses. We demonstrate that high-molecular-weight γ-PGA MNs can be retained in the skin for at least 6 days and effectively suppress AD-like skin lesions in mice by reducing infiltration of mast cells and downregulating Th2-associated antibody production (IgE and IgG1). The developed MN device has the potential to replace conventional therapy and to become an innovative treatment strategy for AD.

Chijabyukpi-Tang Inhibits Pro-Inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-α/IFN-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice.

Chijabyukpi-tang (CBT) is an oriental herbal formula consisting of three herbs (Gardeniae Fructus (Gardenia jasminoides J.Ellis.), Phellodendri Cortex (Phellodendron amurense Rupr.), Glycyrrhizae Radix (Glycyrrhiza uralensis Fisch. ex DC.) at the ratio of 2: 2: 1. CBT has traditionally been used to treat eczema with inflammation in Northeast Asia. The components of CBT have been shown to have anti-inflammatory and anti-oxidant properties, but the exact role and mechanism of CBT on atopic dermatitis (AD) remain unclear. In this study, we investigated the anti-inflammatory effect and mechanism of CBT in the HaCaT human keratinocyte cell line and investigated the anti-atopic effect in mice models of atopic dermatitis-like skin lesions. In the tumor necrosis factor alpha (TNF)-α/interferon (IFN)-γ-stimulated HaCaT cells, CBT inhibited the production of pro-inflammatory cytokines and chemokines and elevated the nuclear translocation of NF-E2 p45 related factors 2 (Nrf2) and subsequent production of heme oxygenase-1 (HO-1). CBT improved the symptoms of atopic dermatitis-like lesions in 2,4-dinitrochlorobenzene (DNCB)-treated mice by suppressing the levels of serum immunoglobulin E (IgE), and various pro-inflammatory cytokines and chemokines. The improvement effect of CBT on atopic dermatitis-like lesions can be predicted to be due to increased Nrf2 and HO-1 gene expression. These results suggest that CBT is an herbal medicine with the potential for use as a therapeutic agent for inflammatory skin diseases such as atopic dermatitis.

P-coumaric acid, an active ingredient of Panax ginseng, ameliolates atopic dermatitis-like skin lesions through inhibition of thymic stromal lymphopoietin in mice

BackgroundAtopic dermatitis (AD) is associated with chronic skin inflammatory reactions. p-coumaric acid (pCA) is an active ingredient of Panax ginseng Meyer (Araliaceae). MethodsHere, we estimated an anti-AD effect of pCA on activated mast cells, activated splenocytes, and a mouse model of AD. Cytokines levels were measured by ELISA and protein activation was analyzed by Western blotting. 2,4-dinitrofluorobenzene (DNFB) was used to induce AD-like skin lesions. ResultsThe treatment with pCA suppressed the productions and mRNA expressions of thymic stromal lymphopoietin (TSLP), TNF-ɑ, IL-6, and IL-1β in HMC-1 cells. pCA downregulated the expressions of RIP2 and caspase-1, phosphorylated-(p)p38/pJNK/pERK, and pIKKβ/pIkBɑ/NF-κB in HMC-1 cells. pCA also decreased the productions of TSLP, TNF-ɑ, IL-6, IL-4, and IFN-γ in the supernatant of stimulated splenic cells. Comparing to DNFB-sensitized control group, pCA-treated group alleviated pathological changes of AD-like lesions. pCA decreased the proteins and mRNA expressions levels of TSLP, IL-6, and IL-4 in the skin lesions. Caspase-1 activation was also downregulated by pCA treatment in the AD-like lesions. The serum levels of histamine, IgE, TSLP, TNF-ɑ, IL-6, and IL-4 were suppressed following treatment with pCA. ConclusionThis study suggests that pCA has the potential to improve AD by suppressing TSLP as well as inflammatory cytokines via blocking of caspase-1/NF-κB signal cascade.

Free fatty acid receptor 4 (FFA4) activation ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis by increasing regulatory T cells in mice.

High dose intake of docosahexaenoic acid showed beneficial effects on atopic dermatitis in patients and was found to increase regulatory T cells in mice, but its molecular target has not been identified. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor sensing polyunsaturated long-chain fatty acids including docosahexaenoic acid. In the present study, we examined whether FFA4 acted as a therapeutic target of docosahexaenoic acid for treating atopic dermatitis. Experimental atopic dermatitis was induced in mice by 2,4-dinitrochlorobenzene (DNCB) sensitization on day 0, followed by repeated DNCB challenges from D7 to D48. The mice were treated with a selective agonist compound A (30 mg· kg−1· d−1, ip) from D19 to D48, and sacrificed on D49. We found that DNCB-induced atopic dermatitis-like skin lesions, i.e. hypertrophy and mast cell infiltration in skin tissues, as well as markedly elevated serum IgE levels. Administration of compound A significantly suppressed the atopic responses in ears and lymph nodes, such as hypertrophy and mast cell infiltration in the ears, enlarged sizes of lymph nodes, and elevated serum IgE and levels of cytokines IL-4, IL-13, IL-17, and IFN-γ in ear tissue. The therapeutic effects of compound A were abolished by FFA4 knockout. Similarly, increased CD4+Foxp3+ regulatory T-cell population in lymph nodes was observed in wide-type mice treated with compound A, but not seen in FFA4-deficient mice. In conclusion, we demonstrate that activation of FFA4 ameliorates atopic dermatitis by increasing CD4+Foxp3+ regulatory T cells, suggesting FFA4 as a therapeutic target for atopic dermatitis.

FFA2 Activation Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice.

Gut microbiota produce dietary metabolites such as short-chain fatty acids, which exhibit anti-inflammatory effects. Free fatty acid receptor 2 (FFA2, formerly known as GPR43) is a specific receptor for short-chain fatty acids, such as acetate that regulates inflammatory responses. However, the therapeutic potential of FFA2 agonists for treatment of atopic dermatitis has not been investigated. We investigated the efficacy of the FFA2 agonist, 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), for treatment of atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB). Long-term application of DNCB to the ears of mice resulted in significantly increased IgE in the serum, and induced atopic dermatitis-like skin lesions, characterized by mast cell accumulation and skin tissue hypertrophy. Treatment with 4-CMTB (10 mg/kg, i.p.) significantly suppressed DNCB-induced changes in IgE levels, ear skin hypertrophy, and mast cell accumulation. Treatment with 4-CMTB reduced DNCB-induced increases in Th2 cytokine (IL-4 and IL-13) levels in the ears, but did not alter Th1 or Th17 cytokine (IFN-γ and IL-17) levels. Furthermore, 4-CMTB blocked DNCB-induced lymph node enlargement. In conclusion, activation of FFA2 ameliorated DNCB-induced atopic dermatitis, which suggested that FFA2 is a therapeutic target for atopic dermatitis.

Enzyme-treated date plum leave extract ameliorates atopic dermatitis-like skin lesion in hairless mice

Objective: To evaluate the effect of different extracts of Diospyros lotus leaves in atopic dermatitis Methods: Diospyros lotus leaves were extracted in ethanol and treated with or without hydrochloric acid or α-rhamnosidase to obtain three different extracts-ethanol, acid-hydrolyzed, and enzyme-hydrolyzed leaf extracts of date plum. The myricitrin content in all samples was measured using HPLC analysis. In vitro antioxidant and anti-inflammatory activities of the extracts were determined by measuring DPPH radical scavenging activities and nitric oxide production in RAW264.7 cells, respectively. Seven- week-old male hairless mice were used to evaluate the anti-atopic dermatitis effects of three extracts in vivo. Splenocytes and mast cells were used to further determine the anti-atopic dermatitis effects of the major compound in the ethanol leaf extract. Results: Enzyme-hydrolyzed leaf extract showed significant in vitro antioxidant and anti-inflammatory activities, and attenuated atopic dermatitis-like skin symptoms and clinical signs more significantly than ethanol and acid-hydrolyzed leaf extracts in 1-fluoro-2,4- dinitrobenzene and house dust mite antigen-treated hairless mice. Enzyme-hydrolyzed leaf extract also suppressed the serum level of immunoglobulin E, interleukin (IL)-4, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, thymic stromal lymphopoietin, and thymus and activation-regulated chemokine in mice with atopic dermatitis. Furthermore, histological analysis revealed that enzyme- hydrolyzed leaf extract suppressed the increased epidermal thickness, dermal infiltration of inflammatory cells, and infiltration and degranulation of mast cells more markedly than the other two extracts in atopic dermatitis-like skin lesions. In addition, this extract effectively inhibited the production of IFN-γ, IL-4,and thymus and activation-regulated chemokine compared with the other two extracts in concanavalin A-stimulated splenocytes. Myricitrin, a major compound of enzyme-hydrolyzed leaf extract, suppressed atopic dermatitis biomarkers in stimulated mouse splenocytes and HMC-1 human mast cells. Conclusions: These results suggest that enzyme-hydrolyzed leaf extract might be a potential candidate to treat atopic dermatitis.

Therapeutic Effects of Saline Groundwater Solution Baths on Atopic Dermatitis: A Pilot Study.

Background Saline groundwater, collected from the east coast of Korea, has been shown to have protective effects against 2,4-dinitrochlorobenzene- (DNCB-) induced atopic dermatitis-like skin lesions in the murine model. Objectives To determine the effects of saline groundwater solution baths as a treatment of mild-to-moderate atopic dermatitis. Methods Twenty-four subjects with mild-to-moderate atopic dermatitis were instructed to take a bath in saline groundwater solution for 20 minutes per day for two weeks. Evaluations were performed at baseline and week 2, including SCORing Atopic Dermatitis (SCORAD) index, corneometry, transepidermal water loss, visual analogue scale for pruritus, and collection of adverse events. Results Subjects showed significant improvement with respect to the SCORAD index, skin hydration, transepidermal water loss, and pruritus at week 2 when compared with the baseline. Conclusion Baths in saline groundwater solution may be an alternative therapeutic strategy for treating atopic dermatitis.

Therapeutic Effects of Chinese Herbal Formula (PTQX) on NC/Nga Mice with Atopic Dermatitis-Like Skin Lesions.

Atopic dermatitis (AD), also known as atopic eczema, is a chronic pruritic inflammatory skin disease. The available systemic therapies for atopic dermatitis are inadequate. Objective. This study aimed to evaluate the effects of the Chinese herbal formula Pei Tu Qing Xin (PTQX) on dermatitis severity and ear swelling, immunomodulation, and the infiltration of mast cells in a mouse model of 1-chloro-2,4-dinitrobenzene- (DNCB-) induced AD. Methods. AD-like symptoms were induced by DNCB in NC/Nga mice. Skin lesions, dermatitis, ear swelling, and scratching behaviour were evaluated. Changes in the T-helper type 1 (Th1), Th2, Th17, and regulatory T (Treg) subtypes and immunoregulation in the spleen and lymph nodes were detected by flow cytometry. Results. Histopathological and immunohistochemical analyses demonstrated that PTQX decreased the DNCB-mediated induction of mast cells and infiltration of inflammatory cells in the ear and dorsal skin. PTQX also reduced the DNCB-induced increase in the serum immunoglobulin E level, pruritus, and dermatitis (red, flaky areas) on the dorsal skin. Furthermore, PTQX regulated the balance between the populations of Th1, Th2, Th17, and Treg cells (particularly the latter two) in the lymph nodes. Conclusions. Our results suggest that the Chinese herbal formula PTQX can alleviate symptoms of AD, such as epithelial damage, redness, swelling, and pruritus, and potentially be used to treat this condition.