Dermatitis Skin Lesions Research Articles

Siraitia grosvenorii Residual Extract Attenuates Atopic Dermatitis by Regulating Immune Dysfunction and Skin Barrier Abnormality.

Atopic dermatitis is a persistent inflammatory skin disorder. Siraitia grosvenorii fruits (monk fruit or nahangwa in Korean, NHG) are used as a natural sweetener and as a traditional medicine for the treatment of asthma and bronchitis. We evaluated the activity of S. grosvenorii residual extract (NHGR) on allergic inflammation of atopic dermatitis in a Dermatophagoides farinae mite antigen extract (DfE)-treated NC/Nga murine model and in vitro. Oral administration of NHGR significantly reduced epidermal hyperplasia and inflammatory cell infiltration in the skin lesions of DfE-induced atopic dermatitis, as well as the dermatitis severity score. NHGR reduced serum immunoglobulin E levels. Splenic concentrations of IFN-γ, interleukin (IL)-4, IL-5, and IL-13 were reduced by NHGR administration. Immunohistofluorescence staining showed that NHGR administration increased the protein levels of claudin-1, SIRT1, and filaggrin in atopic dermatitis skin lesions. In addition, NHGR inhibited the phosphorylation of mitogen-activated protein kinases and decreased filaggrin and chemokine protein expression in TNF-α/IFN-γ-induced human keratinocytes. Moreover, NHGR also inhibited histamine in mast cells. The quantitative analysis of NHGR revealed the presence of grosvenorine, kaempferitrin, and mogrosides. These results demonstrate that NHGR may be an efficient therapeutic agent for the treatment of atopic dermatitis.

A combination of Olea europaea leaf extract and Spirodela polyrhiza extract alleviates atopic dermatitis by modulating immune balance and skin barrier function in a 1-chloro-2,4-dinitrobenzene-induced murine model

BackgroundAtopic dermatitis is a chronic inflammatory skin disease in humans. Although Olea europaea leaf extract (OLE) and Spirodela polyrhiza extract (SPE) have been used to protect against skin damage, the effects of their combined administration on atopic dermatitis have yet to studied. PurposeIn this study, we evaluated the potential therapeutic effects of an OLE and SPE combination on the progression of atopic dermatitis and the possible mechanisms underlying these effects in 1-chloro-2,4-dinitrobenzene (DNCB)-treated NC/Nga mice. MethodsAtopic dermatitis was induced by topical application of 0.2% w/v DNCB prepared in an olive oil:acetone solution (1:3), and thereafter OLE, SPE and OLE + SPE were administered orally for 5 weeks. We determined atopic dermatitis symptoms, serum IgE levels, and levels of cytokine- and gene expression in the dorsal skin and splenocytes, and performed histological and immune cell subtype analyses. The expression of skin barrier-related proteins (filaggrin, sirtuin 1, and claudin 1) was also evaluated. ResultsThe OLE + SPE combination significantly ameliorated atopic dermatitis symptoms, including dermatitis scores, and reduced epidermal thickness and infiltration of different inflammatory cells in mice with DNCB-induced atopic dermatitis. It also significantly reduced the number of CD4+, CD8+, and CD4+/CD69+ T cells; immunoglobulin E-producing B cells (CD23+/B220+) in the axillary lymph nodes; CD3+ T-cell eosinophils (chemokine–chemokine receptor 3+/CD11b+) in the skin; and CD3+ T cells, immunoglobulin E-producing B cells (CD23+/B220+), and eosinophils in peripheral blood mononuclear cells. Additionally, the experimental combination lowered levels of serum immunoglobulin E and histamine, as well as Th2-mediated cytokines, and interleukin-4, -5, and -13, whereas it increased the levels of Th1-mediated cytokine interferon-γ in splenocytes. Furthermore, the preparation significantly restored expression of the skin barrier-related proteins filaggrin, sirtuin 1, and claudin 1, and also reduced the expression of the inflammatory cytokine interleukin-6 and chemokine–chemokine receptor 3, as well as the pruritus-related cytokine interleukin-31 and interleukin-31 receptor, in atopic dermatitis skin lesions. ConclusionTaken together, our findings indicate that administration of a combination of OLE and SPE can alleviate atopic dermatitis symptoms by regulating immune balance and skin barrier function and may be an effective therapeutic option for the treatment of atopic dermatitis.

Recognizing and treating five common dermatologic conditions seen in primary care.

Skin conditions are one of the most common chief complaints encountered in the primary care setting. Primary care providers (PCPs) may not have not received enough exposure and education on dermatologic conditions. Of all skin conditions, atopic dermatitis, acne vulgaris, cellulitis/abscess, verruca vulgaris, and benign skin lesions are typically the most common to present in the primary care setting. PCPs must be well educated on these topics and confident in their diagnostic and management skills. This article reviews the five most common skin conditions encountered in primary care so that PCPs can reduce the number of referrals to dermatology for conditions that can easily be managed by PCPs.

Selective JAK1 Inhibitors for the Treatment of Atopic Dermatitis: Focus on Upadacitinib and Abrocitinib

Atopic dermatitis is a common, chronic, immune-mediated disease associated with several comorbidities. Elevated levels of T helper (Th)2, Th22, and also some Th1 and Th17 cytokines are found in atopic dermatitis skin lesions. Similar to psoriasis, there is a tendency towards increased use of more targeted therapies. However, there are still several unmet needs in the treatment of atopic dermatitis concerning long-term efficacy, tolerability, safety, route of administration, and cost. The increased knowledge of atopic dermatitis pathogenesis and the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways hasallowed the development of new compounds to inhibit this intracellular signaling pathway implicated in atopic dermatitis-related immune responses. Currently, JAK inhibitors are an important focus of therapeutic research for atopic dermatitis. Upadacitinib and abrocitinib are oral small molecules that inhibit the JAK/STAT pathway by selectively blocking JAK1. Data from phase II and III trials are encouraging, revealing that JAK1 inhibitors are effective and well-tolerated agents for moderate-to-severe atopic dermatitis. Selective JAK1 inhibitors may represent an important therapeutic option to be included in the treatment algorithm of atopic dermatitis, owing to oral administration and a favorable safety and tolerability profile. In this article, we review the current evidence on the efficacy and safety of oral selective JAK1 inhibitors for the treatment of atopic dermatitis.

APRIL expression is upregulated in atopic dermatitis skin lesions and at sites of antigen driven allergic skin inflammation in mice

Atopic dermatitis (AD) is the most common inflammatory skin disease. It is characterized by a defective skin barrier and a Th2 dominated skin inflammation. The TNF family member a proliferation-inducing ligand (APRIL) and its receptors transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) are expressed by immune cells and epithelial cells including keratinocytes. We demonstrate that APRIL expression is upregulated in the epidermis of skin lesions from patients with AD as well as in mouse skin undergoing allergic inflammation elicited by epicutaneous (EC) sensitization with the antigen ovalbumin. We show that APRIL from OVA sensitized mouse skin causes keratinocytes to upregulate the expression of IL-6, an inflammatory cytokine implicated in AD pathogenesis. These results suggest a role for APRIL in allergic skin inflammation and a potential role for APRIL blockade in treating AD.

Prevalence of Skin Diseases among Primary School Children in Three Semi Urban Communities in Rivers State, Nigeria: A Community Based Study

Background: Skin diseases are common among children in the developing countries in Sub Saharan Africa where there is low level of hygiene, overcrowding and warm humid climates. However, there are no known community based studies on the prevalence of skin diseases among primary school children in Rivers State, Nigeria. This study aimed to determine the prevalence and types of skin diseases among primary school children in three semi urban communities in ObioAkpor LGA in Rivers State, Nigeria.
 Materials and Methods: This descriptive, cross sectional study was conducted in five public primary schools in three semi urban communities in ObioAkpor LGA over a three months period from September to November 2017. Five hundred and twenty four children were recruited for the study from the selected schools. Interviewer administered questionnaire was used to obtain information on socio-demographics and a team of investigators examined each child for evidence of skin diseases.
 Results: There were 263 (50.2%) males and 261 (49.8%) females, with male to female ratio of 1.01: 1. Their ages ranged between 5 to 16 years, with a mean age of 9.5±2.22 years. The prevalence of skin lesions among the children was 35.3% (185/524). Skin infections, inflammatory dermatitis and other skin lesions accounted for 39.5%, 14.1% and 46.5% respectively of the skin diseases. The most prevalent specific skin disease found was Dermatophyte infection in 50 (27.0%) children, followed by Xerosis 21 (11.4%). Tinea capitis was the most common (52.1%) skin infection. The commonest inflammatory dermatitis found was Seborrheic dermatitis 53.8%. Age had no significant influence on the prevalence of skin infections (p=0.711).
 Conclusion: The prevalence of skin diseases was high among primary school children in the semi urban communities in ObioAkpor LGA and Dermatophyte infection accounted for more than a quarter of the skin diseases found. Maybe regular inspection of the skin of primary school children by health professionals and teachers should be done in order to reduce the spread of infectious skin diseases within the schools.

ILC2 activation by keratinocyte-derived IL-25 drives IL-13 production at sites of allergic skin inflammation

BackgroundAtopic dermatitis skin lesions demonstrate increased expression of IL-25 by keratinocytes and increased numbers of type 2 innate lymphoid cells (ILC2s) that express high levels of IL-25 receptor (IL-25R). IL-13 is expressed in atopic dermatitis skin lesions and plays an important role in pathogenesis of the disease.ObjectiveOur aim was to determine the role of IL-25 and ILC2s in a mouse model of antigen-driven allergic skin inflammation.MethodsWild-type mice; mice that express an Il13-driven enhanced green fluorescent protein; and mice that lack IL-25R, IL-25 in keratinocytes, or IL-13 or IL-25R in ILC2s were subjected to acute or chronic epicutaneous sensitization with ovalbumin. Sensitized skin was examined by histology for epidermal thickening. Cellular infiltrates were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was quantitated by RT quantitative PCR.ResultIn both acute and chronic antigen-driven allergic skin inflammation, signaling by keratinocyte-derived IL-25 in ILC2s is important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, and cutaneous expression of Il13 and the IL-13–dependent TH2-cell–attracting chemokines Cc17 and Ccl22. ILCs are the major source of IL-13 in acutely sensitized mouse skin, whereas T cells are its major source in chronically sensitized mouse skin.ConclusionILC2 activation by IL-25 is essential for IL-13 expression at sites of allergic skin inflammation.

Subcutaneous injection of recombinant heat shock protein 70 ameliorates atopic dermatitis skin lesions in a mouse model.

Atopic dermatitis (AD) is a chronic inflammatory skin disease and sometimes is a tough challenge for physicians. We previously reported that in Th2 environment, the production and secretion of thymic stromal lymphopoietin (TSLP) from human keratinocytes was inhibited by recombinant heat shock protein 70 (rHSP70). The present study assessed the therapeutic effectiveness of rHSP70 in a mouse model of AD. An experimental model of AD was reproduced by systemic sensitization and local epicutaneous challenge with ovalbumin (OVA). Treatment of rHSP70 was performed by subcutaneous administration. The levels of OVA-specific IgE, as well as cytokines, were detected by ELISA. Skin samples from patch areas were also taken for histologic examination. Injection of rHSP70 improved the histologic picture by reducing the thickness of epidermis and allergic inflammation. Skin sonography revealed rHSP70 ameliorated skin remodeling. rHSP70 also significantly decreased the protein expression of TSLP of skin from patch areas. Furthermore, in ex vivo studies also showed group of rHSP70 treatment decreased IL-13, RANTES, MIP-1β and increased IFN-γ secreted from splenocytes stimulated with OVA. The rHSP70 intervention in the mouse model of AD reduced the skin expression of TSLP and attenuated the clinical appearance of OVA-induced AD mice. The effect was achieved by suppressed Th2 immune response in injected skin tissue and enhanced systemic Th1 immune response. These results suggest that rHSP70 have potential as a promising protein for the treatment of AD.

A Natural Compound Mixture Containing Arctigenin, Hederagenin, and Baicalein Alleviates Atopic Dermatitis in Mice by Regulating HPA Axis and Immune Activity.

Forsythiae Fructus, Lonicerae Flos, and Scutellariae Radix are medicinal herbs that possess anti-inflammatory and anti-atopic effects. Hence, we investigated the effects of a mixture (ADM), containing arctigenin, hederagenin, and baicalein, which are the main compound from these herbs on atopic dermatitis (AD) skin lesions and the underlying molecular mechanisms. ADM was topically applied to dorsal skin lesions of 2,4-dinitrochlorobenzene- (DNCB-) induced ICR mice, and the expressions of proinflammatory mediators and HPA axis hormones were investigated. The topical application of 0.5% ADM significantly reduced the DNCB-induced symptoms of AD in ICR mice. Histological analysis showed that ADM exerted antiatopic effects by reducing the epidermal thickness and mast cell infiltration into skin lesions. 0.5% ADM attenuated the levels of TNF-α, IFN-γ, IL-4, and VEGF in skin lesions and serum IgE. The production of Th1-/Th2-related cytokines in splenic tissues, including TNF-α, IFN-γ, IL-12, and IL-4, were also decreased by ADM treatment. ADM diminished corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosteroid (CORT) production in DNCB-induced mice. In vitro, ADM reduced the productions of TARC/CCL17, MDC/CCL22, IL-6, and ICAM-1 in TNF-α/IFN-γ- (TI-) stimulated HaCaT cells by suppressing the ERK and JNK signaling pathways. In addition, ADM inhibited corticotropin-releasing hormone/substance P- (CRH/SP-) induced VEGF production in HMC-1 cells. These results suggest that ADM may have therapeutic potential in AD by reducing inflammation and attenuating HPA axis activation.

Ornithonyssus sylviarum (Acari: Macronyssidae) parasitism among poultry farm workers in Minas Gerais state, Brazil

ABSTRACT: Ornithonyssus sylviarum is a hematophagous mite present in wild, domestic, and synanthropic birds. However, this mite can affect several vertebrate hosts, including humans, leading to dermatitis, pruritus, allergic reactions, and papular skin lesions. This study evaluated the epidemiological characteristics of O. sylviarum attacks on poultry workers, including data on laying hens, infrastructure and management of hen houses, and reports of attacks by hematophagous mites. In addition, a case of mite attack on a farm worker on a laying farm in the Midwest region in Minas Gerais is presented. It was found that 60.7% farm workers reported attacks by hematophagous mites. Correspondence analysis showed an association between reports of mite attacks in humans with (1) presence of O. sylviarum in the hen house, (2) manual removal of manure by employees, and (3) history of acaricide use. The specimens collected from the location were confirmatively identified as O. sylviarum. O. sylviarum attacks ave not been reported when manure was removed in a shorter time interval and did not use acaricide in the sheds when the removal was done by manure conveyor belt. Parasitism by O. sylviarum should be considered a relevant occupational hazard affecting employees working in direct contact with commercial egg-laying hens in Minas Gerais. We emphasized the need to monitor hen infestations by this mite to improve the development of mite control strategies.

Comparative genomics of the transportome of Ten Treponema species

Treponema is a diverse bacterial genus, the species of which can be pathogenic, symbiotic, or free living. These treponemes can cause various diseases in humans and other animals, such as periodontal disease, bovine digital dermatitis and animal skin lesions. However, the most important and well-studied disease of treponemes that affects humans is ‘syphilis’. This disease is caused by Treponema pallidum subspecie pallidum with 11–12 million new cases around the globe on an annual basis. In this study we analyze the transportome of ten Treponema species, with emphasis on the types of encoded transport proteins and their substrates. Of the ten species examined, two (T. primitia and T. azonutricium) reside as symbionts in the guts of termites; six (T. pallidum, T. paraluiscuniculi, T. pedis, T. denticola, T. putidum and T. brennaborense) are pathogens of either humans or animals, and T. caldarium and T. succinifaciens are avirulent species, the former being thermophilic. All ten species have a repertoire of transport proteins that assists them in residing in their respective ecological niches. For instance, oral pathogens use transport proteins that take up nutrients uniquely present in their ecosystem; they also encode multiple multidrug/macromolecule exporters that protect against antimicrobials and aid in biofilm formation. Proteins of termite gut symbionts convert cellulose into other sugars that can be metabolized by the host. As often observed for pathogens and symbionts, several of these treponemes have reduced genome sizes, and their small genomes correlate with their dependencies on the host. Overall, the transportomes of T. pallidum and other pathogens have a conglomerate of parasitic lifestyle-assisting proteins. For example, a T. pallidum repeat protein (TprK) mediates immune evasion; outer membrane proteins (OMPs) allow nutrient uptake and end product export, and several ABC transporters catalyze sugar uptake, considered pivotal to parasitic lifestyles. Taken together, the results of this study yield new information that may help open new avenues of treponeme research.

Tabetri™ (Tabebuia avellanedae Ethanol Extract) Ameliorates Atopic Dermatitis Symptoms in Mice.

Tabebuia avellanedae has been traditionally used as an herbal remedy to alleviate various diseases. However, the plant's pharmacological activity in allergic and inflammatory diseases and its underlying mechanism are not fully understood. Therefore, we investigated the pharmacological activity of Tabetri (T. avellanedae ethanol extract (Ta-EE)) in the pathogenesis of AD. Its underlying mechanism was explored using an AD mouse model and splenocytes isolated from this model. Ta-EE ameliorated the AD symptoms without any toxicity and protected the skin of 2,4-dinitrochlorobenzene- (DNCB-) induced AD mice from damage and epidermal thickness. Ta-EE reduced the secreted levels of allergic and proinflammatory cytokines, including histamine, immunoglobulin E (IgE), interleukin- (IL-) 4, and interferon-gamma (IFN-γ) in the DNCB-induced AD mice. Ta-EE suppressed the mRNA expression of T helper 2-specific cytokines, IL-4 and IL-5, and the proinflammatory cytokine IFN-γ in the atopic dermatitis skin lesions of AD mice. Moreover, Ta-EE suppressed the mRNA expression of IL-4, IL-5, IFN-γ, and another proinflammatory cytokine, IL-12, in the Con A-stimulated splenocytes. It also suppressed IL-12 and IFN-γ in the LPS-stimulated splenocytes. Taken together, these results suggest that Ta-EE protects against the development of AD through the inhibition of mRNA expression of T helper 2-specific cytokines and other proinflammatory cytokines.

Current insights into the role of human β-defensins in atopic dermatitis.

Anti-microbial peptides or host defence peptides are small molecules that display both anti-microbial activities and complex immunomodulatory functions to protect against various diseases. Among these peptides, the human β-defensins (hBDs) are localized primarily in epithelial surfaces, including those of the skin, where they contribute to protective barriers. In atopic dermatitis skin lesions, altered skin barrier and immune dysregulation are believed to be responsible for reduced hBD synthesis. Impaired hBD expression in the skin is reportedly the leading cause of increased susceptibility to bacterial and viral infection in patients with atopic dermatitis. Although hBDs have considerable beneficial effects as anti-microbial agents and immunomodulators and may ameliorate atopic dermatitis clinically, recent evidence has also suggested the negative effects of hBDs in atopic dermatitis development. In the current review, we provide an overview of the regulation of hBDs and their role in the pathogenesis of atopic dermatitis. The efforts to utilize these molecules in clinical applications are also described.

House Dust Mite Increases pro-Th2 Cytokines IL-25 and IL-33 via the Activation of TLR1/6 Signaling

House dust mites have been implicated in the etiology and exacerbation of atopic dermatitis. Diverse factors contribute to house dust mite allergenicity through the activation of innate immunity. We investigated whether Dermatophagoides farinae extract (DFE) allergens mediate innate immune activation through specific toll-like receptors (TLRs) in epidermal keratinocytes, a DFE-induced murine atopic dermatitis model, and human atopic dermatitis lesions. DFE activated the expression of TLR1, TLR6, IL-25, and IL-33 in human primary keratinocytes and HaCaT cells. Knockdown of TLR6 inhibited DFE-induced upregulation of IL-25 or IL-33. In addition, the suppression of TLR1 inhibited the release of IL-33. DFE induced the expression of IL-25 and IL-33 by upregulation of IL-1 receptor-associated kinase 1, transforming growth factor-β activated kinase-1, IκB kinase, and NF-κB pathways. Tlr6-/- mice did not show DFE-induced upregulation of IL-25 and IL-33. Furthermore, DFE-induced upregulation of IL-25 was not induced in Tlr1-/- mice. We also identified upregulated mRNA and protein expression of TLR1, TLR6, IL-25, and IL-33 in human atopic dermatitis skin lesions with high house dust mite sensitization. We found that DFE-induced activation of TLR1 and TLR6 may cause polarization toward a T helper type 2 immune response via the release of IL-25 and IL-33.

Diospyros lotus leaf and grapefruit stem extract synergistically ameliorate atopic dermatitis-like skin lesion in mice by suppressing infiltration of mast cells in skin lesions.

Atopic dermatitis, a chronic relapsing and pruritic inflammation of the skin also thought to be involved in, or caused by immune system destruction is an upsetting health problem due to its continuously increasing incidence especially in developed countries. Mast cell infiltration in atopic dermatitis skin lesions and its IgE-mediated activation releases various cytokines and chemokines that have been implicated in the pathogenesis of atopic dermatitis. This study was aimed at investigating synergistic anti-inflammatory, anti-pruritic and anti-atopic dermatitis effects of Diospyros lotus leaf extract (DLE) and Muscat bailey A grapefruit stem extract (GFSE) in atopic dermatitis-like induced skin lesions in mice. Combinations of DLE and GFSE inhibited TNF-α and IL-6 production more than DLE or GFSE in PMA plus calcium ionophore A23187-activated HMC-1 cells. DLE and GFSE synergistically inhibited compound 48/80-induced dermal infiltration of mast cells and reduced scratching behavior than DLE or GFSE. Furthermore, DLE and GFSE synergistically showed a stronger ameliorative effect in skin lesions by reducing clinical scores; dermal infiltration of mast cells; ear and dorsal skin thickness; serum IgE and IL-4 production in atopic dermatitis-like mice. Collectively, these results suggest that DLE and GFSE synergistically exhibit anti-atopic dermatitis effects in atopic dermatitis-like skin lesions in mice.

The Natural Course of Atopic Dermatitis and the Association with Asthma.

In this paper, we aimed to explore the potential mechanism underlying atopic dermatitis (AD) and its association with asthma. The BALB/c mice were randomly assigned to three groups, including the vehicle control (VD) group, the AD group, and the treatment (TR) group. The AD mice model was successfully constructed in the AD and TR group. The dermatitis severity scores and skin lesions were significantly increased in AD mice after DNCB application. Airway responsiveness in the AD group was significantly higher than in the TR group. The number of inflammatory cells was increased in skin lesions and bronchoalveolar lavage fluid (BALF) of AD mice. The levels of IL-4, IL-5, IFN-γ, and OVA-IgE in BALF supernatants of mice in the AD group were higher than those in the VC group. All the changes in AD mice were decreased by tacrolimus. These results indicate that AD may be a significant risk factor for atopic asthma development.

Early Activation of Th2/Th22 Inflammatory and Pruritogenic Pathways in Acute Canine Atopic Dermatitis Skin Lesions

Determining inflammation and itch pathway activation in patients with atopic dermatitis (AD) is fraught with the inability to precisely assess the age of skin lesions, thus affecting the analysis of time-dependent mediators. To characterize inflammatory events occurring during early experimental acute AD lesions, biopsy samples were collected 6, 24, and 48 hours after epicutaneous application of Dermatophagoides farinae house dust mites to sensitized atopic dogs. The skin transcriptome was assessed using a dog-specific microarray and quantitative PCR. Acute canine AD skin lesions had a significant up-regulation of genes encoding T helper (Th) 2 (e.g., IL4, IL5, IL13, IL31, and IL33), Th9 (IL9), and Th22 (IL22) cytokines as well as Th2-promoting chemokines such as CCL5 and CCL17. Proinflammatory (e.g., IL6, LTB, and IL18) cytokines were also up-regulated. Other known pruritogenic pathways were also activated: there was significant up-regulation of genes encoding proteases cathepsin S (CTSS), mast cell chymase (CMA1), tryptase (TPS1) and mastin, neuromedin-B (NMB), nerve growth factor (NGF), and leukotriene-synthesis enzymes (ALOX5, ALOX5AP, and LTA4H). Experimental acute canine house dust mite-induced AD lesions exhibit an activation of innate and adaptive immune responses and pruritogenic pathways similar to those seen in humans with acute AD, thereby validating this model to test innovative therapeutics modalities for this disease.

Inhibitory Effect of Valencene on the Development of Atopic Dermatitis-Like Skin Lesions in NC/Nga Mice.

Valencene (VAL) isolated from Cyperus rotundus possesses various biological effects such as antiallergic and antimelanogenesis activity. We investigated the effect of VAL on atopic dermatitis (AD) skin lesions and their molecular mechanisms. We topically applied VAL to 1-chloro-2,4-dinitrobenzene (DNCB) sensitized NC/Nga mice. Modified scoring atopic dermatitis index, scratching behavior, and histological/immunohistochemical staining were used to monitor disease severity. RT-PCR, western blotting, and enzyme-linked immunosorbent assay were used to determine the level of IgE, proinflammatory cytokines/chemokines production, and skin barrier proteins expression. Topical application of VAL significantly reduced AD-like symptoms and recovered decreased expression of filaggrin in DNCB-sensitized NC/Nga mice. The levels of serum IgE, IL-1β, IL-6, and IL-13 in skin/splenic tissue were reduced. In vitro studies using TNF-α and IFN-γ treated HaCaT cells revealed that VAL inhibited the exaggerated expression of Th2 chemokines including TARC/CCL17, MDC/CCL22, and proinflammatory chemokines such as CXCL8, GM-CSF, and I-CAM through blockade of the NF-κB pathway. In addition, expression of the skin barrier protein, involucrin, was also increased by VAL treatment. VAL inhibited the production and expression of proinflammatory cytokines IL-1β and IL-6 in LPS-stimulated RAW 264.7 cells. These results suggest that VAL may serve as a potential therapeutic option for AD.

Differential expression of inflammation-related genes in IL-4 transgenic mice before and after the onset of atopic dermatitis skin lesions

IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD), a common chronic inflammatory skin disease. We have generated IL-4 transgenic (Tg) mice by over-expressing IL-4 in the epidermis. These mice spontaneously develop chronic pruritic inflammatory skin lesions, which meet the clinical and histological diagnostic criteria for human AD. Systemic survey of immune-related genes in this mouse model, however, has not been performed. In this study, we utilize PCR array technique to examine hundreds of inflammation-related genes in the IL-4 Tg mice before and after the onset of skin lesions as well as in their wild type (WT) littermates. Only those genes with at least 2-fold up-regulation or down-regulation and with a P-value of less than 0.05 in comparison to WT controls were identified and analyzed. In the skin lesions, many chemokines, pro-inflammatory cytokines, and other AD-related factors are dysregulated compared to the wild type mice. Particularly, CXCL5, IL-1β, IL-24, IL-6, oncostatin M, PTGS2, FPR1 and REG3γ are up-regulated several hundred-fold. In the pre-lesional group that shows no obvious skin abnormality on clinical observation, 30 dysregulated genes are nevertheless identified though the fold changes are much less than that of the lesional group, including CCL6, CCL8, CCL11, CCL17, CXCL13, CXCL14, CXCR3 and IL-12Rβ2. Finally using ELISA, we demonstrate that 4 most dramatically up-regulated factors in the skin are also elevated in the peripheral blood of the IL-4 Tg mice. Taken together, our data have identified hundreds of dysregulated factors in the IL-4 Tg mice before and after the onset of skin lesions. Future detailed examination of these factors will shed light on our understanding of the development and progression of AD and help to discover important biomarkers for clinical AD diagnosis and treatment.

Antioxidant Therapies for Ulcerative Dermatitis: A Potential Model for Skin Picking Disorder.

Skin Picking Disorder affects 4% of the general population, with serious quality of life impacts, and potentially life threatening complications. Standard psychoactive medications do not help most patients. Similarly, Mouse Ulcerative Dermatitis (skin lesions caused by excessive abnormal grooming behavior) is very common in widely used inbred strains of mice, and represents a serious animal welfare issue and cause of mortality. Treatment options for Ulcerative Dermatitis are largely palliative and ineffective. We have proposed mouse Ulcerative Dermatitis as a model for human Skin Picking Disorder based on similar epidemiology, behavior, and its comorbidity and mechanistic overlap with hair pulling (trichotillomania). We predicted that mouse Ulcerative Dermatitis would be treated by N-Acetylcysteine, as this compound is highly effective in treating both Skin Picking Disorder and Trichotillomania. Furthermore, we hypothesized that N-Acetylcysteine’s mode of action is as a precursor to the production of the endogenous antioxidant glutathione in the brain, and therefore intranasal glutathione would also treat Ulcerative Dermatitis. Accordingly, we show in a heterogenous prospective trial, the significant reduction in Ulcerative Dermatitis lesion severity in mice receiving either N-acetylcysteine (oral administration) or glutathione (intranasal). The majority of mice treated with N-acetylcysteine improved slowly throughout the course of the study. Roughly half of the mice treated with glutathione showed complete resolution of lesion within 2-4 weeks, while the remainder did not respond. These findings are the first to show that the use of N-acetylcysteine and Glutathione can be curative for mouse Ulcerative Dermatitis. These findings lend additional support for mouse Ulcerative Dermatitis as a model of Skin Picking Disorder and also support oxidative stress and glutathione synthesis as the mechanism of action for these compounds. As N-Acetylcysteine is poorly tolerated by many patients, intranasal glutathione warrants further study as potential therapy in Skin Picking, trichotillomania and other body-focused repetitive behavior disorders.