Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model.

Atopic dermatitis is a chronic relapsing skin disease characterized by recurrent, pruritic, localized eczema, while PDE4 inhibitors have been reported to be effective as antiatopic dermatitis agents. 3',4-O-dimethylcedrusin (DCN) is a natural dihydrobenzofuran neolignan isolated from Magnolia biondii with moderate potency against PDE4 (IC50 = 3.26 ± 0.28 µM) and a binding mode similar to that of apremilast, an approved PDE4 inhibitor for the treatment of psoriasis. The structure-based optimization of DCN led to the identification of 7b-1 that showed high inhibitory potency on PDE4 (IC50 = 0.17 ± 0.02 µM), good anti-TNF-α activity (EC50 = 0.19 ± 0.10 µM), remarkable selectivity profile, and good skin permeability. The topical treatment of 7b-1 resulted in the significant benefits of pharmacological intervention in a DNCB-induced atopic dermatitis-like mice model, demonstrating its potential for the development of novel antiatopic dermatitis agents.

Supercritical CO2 fluid extract from Stellariae Radix ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis by inhibit M1 macrophages polarization via AMPK activation.

Yin chai hu (Radix Stellariae) is a root medicine that is frequently used in Chinese traditional medicine to treat fever and malnutrition. In modern medicine, it has been discovered to have anti-inflammatory, anti-allergic, and anticancer properties. In a previous study, we were able to extract lipids from Stellariae Radix using supercritical CO2 extraction (SRE), and these sterol lipids accounted for up to 88.29% of the extract. However, the impact of SRE on the development of atopic dermatitis (AD) has not yet been investigated. This study investigates the inhibitory effects of SRE on AD development using a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. Treatment with SRE significantly reduced the dermatitis score and histopathological changes compared with the DNCB group. The study found that treatment with SRE resulted in a decrease of pro-inflammatory cytokines TNF-α, CXC-10, IL-12, and IL-1ß in skin lesions. Additionally, immunohistochemical analysis revealed that SRE effectively suppressed M1 macrophage infiltration into the AD lesion. Furthermore, the anti-inflammatory effect of SRE was evaluated in LPS + INF-γ induced bone marrow-derived macrophages (BMDMs) M1 polarization, SRE inhibited the production of TNF-α, CXC-10, IL-12, and IL-1ß and decreased the expression of NLRP3. Additionally, SRE was found to increase p-AMPKT172, but had no effect on total AMPK expression, after administration of the AMPK inhibitor Compound C, the inhibitory effect of SRE on M1 macrophages was partially reversed. The results indicate that SRE has an inhibitory effect on AD, making it a potential therapeutic agent for this atopic disorder.

Exosomes derived from human dermal fibroblasts (HDFn-Ex) alleviate DNCB-induced atopic dermatitis (AD) via PPARα.

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Skin barrier dysfunction is the initial step in the development of AD. Recently, exosomes have been considered as potential cell-free medicine for skin defects such as aging, psoriasis and wounds. The aim of this study was to investigate the effects of human dermal fibroblast-neonatal-derived exosome (HDFn-Ex) on AD. HDFn-Ex increased the expression of peroxisome proliferator activated receptor α (PPARα) and alleviated the 1-chloro-2,4-dinitrobenzene (DNCB)-mediated downregulation of filaggrin, involucrin, loricrin, hyaluronic acid synthase 1 (HAS1) and HAS2 in human keratinocyte HaCaT cells. However, these effects were inhibited by the PPARα antagonist GW6471. In the artificial skin model, HDFn-Ex significantly inhibited DNCB-induced epidermal hyperplasia and the decrease in filaggrin and HAS1 levels via a PPARα. In the DNCB-induced AD-like mouse model, HDFn-Ex administration reduced epidermis thickening and mast cell infiltration into the dermis compared to DNCB treatment. Moreover, the decreases in PPARα, filaggrin and HAS1 expression, as well as the increases in IgE and IL4 levels induced by DNCB treatment were reversed by HDFn-Ex. These effects were blocked by pre-treatment with GW6471. Furthermore, HDFn-Ex exhibited an anti-inflammatory effect by inhibiting the DNCB-induced increases in IκBα phosphorylation and TNF-α expression. Collectively, HDFn-Ex exhibited a protective effect on AD. Notably, these effects were regulated by PPARα. Based on our results, we suggest that HDFn-Ex is a potential candidate for treating AD by recovering skin barrier dysfunction and exhibiting anti-inflammatory activity.

Systemic Type 2 Inflammation-Associated Atopic Dermatitis Exacerbates Periodontitis.

INTRODUCTION: Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin disease characterized by Th2 cell-mediated type 2 inflammation. Emerging evidence indicated that AD patients exhibit an increased incidence of oral disorders. In the present study, we sought mechanistic insights into how AD affects periodontitis. METHODS: Onset of AD was induced by 2,4-dinitrochlorobenzene (DNCB). Furthermore, we induced periodontitis (P) in AD mice. The effect of AD in promoting inflammation and bone resorption in gingiva was evaluated. Hematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, immunofluorescence assay, and flow cytometry were used to investigate histomorphology and cytology analysis, respectively. RNA sequencing of oral mucosa is used tissues to further understand the dynamic transcriptome changes. 16S rRNA microbial analysis is used to profile oral microbial composition. RESULTS: Compared to control group, mice in AD group showed inflammatory signatures and infiltration of a proallergic Th2 (Th2A)-like subset in oral mucosa but not periodontitis, as identified by not substantial changes in mucosa swelling, alveolar bone loss, and TRAP+ osteoclasts infiltration. Similarly, more Th2A-like cell infiltration and interleukin-4 levels were significantly elevated in the oral mucosa of DNCB-P mice compared to P mice. More importantly, AD exacerbates periodontitis when periodontitis has occurred and the severity of periodontitis increased with aggravation of dermatitis. Transcriptional analysis revealed that aggravated periodontitis was positively correlated with more macrophage infiltration and abundant CCL3 secreted. AD also altered oral microbiota, indicating the re-organization of extracellular matrix. CONCLUSIONS: These data provide solid evidence about exacerbation of periodontitis caused by type 2 dermatitis, advancing our understanding in cellular and microbial changes during AD-periodontitis progression.

Heat shock protein 90 (Hsp90) inhibitor STA-9090 (Ganetespib) ameliorates inflammation in a mouse model of atopic dermatitis.

Molecular chaperones belonging to the heat shock protein 90 (Hsp90) family are implicated in inflammatory processes and described as potential novel therapeutic targets in autoimmune/inflammatory skin diseases. While the pathological role of circulating Hsp90 has been recently proposed in patients with atopic dermatitis (AD), a chronic inflammatory skin disease characterized by intense itching and recurrent skin lesions, studies aimed at investigating the role of Hsp90 as a potential target of AD therapy have not yet been conducted. Here, the effects of the Hsp90 blocker STA-9090 (Ganetespib) applied systemically or topically were determined in an experimental mouse model of dinitrochlorobenzene (DNCB)-induced AD. Intraperitoneal administration of STA-9090 ameliorated clinical disease severity, histological epidermal thickness, and dermal leukocyte infiltration in AD mice which was associated with reducing the scratching behavior in DNCB-treated animals. Additionally, topically applied STA-9090 led to lowered disease activity in AD mice, reduced serum levels of IgE, and up-regulated filaggrin expression in lesional skin samples. Our observations suggest that Hsp90 may be a promising therapeutic target in atopic dermatitis and potentially other inflammatory or autoimmune dermatoses.

Morinda officinalis extract exhibits protective effects against atopic dermatitis by regulating the MALAT1/miR-590-5p/CCR7 axis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a genetic predisposition, and the traditional Chinese medicine Morinda officinalis and its roots are characterized with anti-inflammatory effects and have been used for the treatment of various disease. However, it is still largely unknown whether Morinda officinalis extract (MOE) can be used for the treatment of AD. OBJECTIVES: In our study we aimed to determine whether MOE could ameliorate 2,4-dinitrochlorobenzene (DNCB)-induced AD and elucidate molecular mechanisms. METHODS: We established an AD mouse model by using DNCB. Skin pathological analysis and ELISA assay were used to detect the effect of MOE on the inflammation of AD model mouse skin and the expression changes of inflammatory factors, and further functional verification was performed in TNF-α/IFN-γ-induced HaCaT cells. RESULTS: Our in vivo experiments confirmed that MOE remarkably reduced DNCB-induced AD lesions and symptoms, such as epidermal and dermal thickness and mast cell infiltration and inflammatory cytokines secretion in the mice models. In addition, the underlying mechanisms by which MOE ameliorated AD had been uncovered, and we verified that MOE inhibited MALAT1 expression in AD, resulting in attenuated expression of C-C chemokine receptor type 7 (CCR7) regulated by MALAT1-sponge miR-590-5p in a competing endogenous RNA (ceRNA) mechanisms-dependent manner, thereby inhibiting TNF-α/IFN-γ-induced cellular proliferation and inflammation.

Protective Effects of Topical Administration of Laminarin in Oxazolone-Induced Atopic Dermatitis-like Skin Lesions.

Laminarin is a polysaccharide isolated from brown marine algae and has a wide range of bioactivities, including immunoregulatory and anti-inflammatory properties. However, the effects of laminarin on atopic dermatitis have not been demonstrated. This study investigated the potential effects of topical administration of laminarin using a Balb/c mouse model of oxazolone-induced atopic dermatitis-like skin lesions. Our results showed that topical administration of laminarin to the ear of the mice improved the severity of the dermatitis, including swelling. Histological analysis revealed that topical laminarin significantly decreased the thickening of the epidermis and dermis and the infiltration of mast cells in the skin lesion. Serum immunoglobulin E levels were also significantly decreased by topical laminarin. Additionally, topical laminarin significantly suppressed protein levels of oxazolone-induced proinflammatory cytokines, such as interleukin-1ß, tumor necrosis factor-α, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α in the skin lesion. These results indicate that topical administration of laminarin can alleviate oxazolone-induced atopic dermatitis by inhibiting hyperproduction of IgE, mast cell infiltration, and expressions of proinflammatory cytokines. Based on these findings, we propose that laminarin can be a useful candidate for the treatment of atopic dermatitis.

Vasicine alleviates 2,4-dinitrochlorobenzene-induced atopic dermatitis and passive cutaneous anaphylaxis in BALB/c mice.

Atopic dermatitis (AD), a type of skin inflammation, is associated with immune response mediated by T-helper 2 (Th2) cells, and mast cells. Vasicine is an alkaloid isolated from Adhatoda vasica, a popular Ayurvedic herbal medicine used for treating inflammatory conditions. In the present study, the anti-AD effects of vasicine were evaluated on 2,4-dinitrochlorobenzene-induced AD-like skin lesions in BALB/c mice. The potential anti-allergic effects of vasicine were also assessed using the passive cutaneous anaphylaxis (PCA) test. The results showed that the oral administration of vasicine improved the severity of AD-like lesional skin by decreasing histopathological changes and restoring epidermal thickness. Vasicine also inhibited the infiltration of mast cells in the skin and reduced the levels of pro-Th2 and Th2 cytokines as well as immunoglobulin E in the serum. Finally, vasicine inhibited the expression of pro-Th2 and Th2 cytokines in skin tissues, indicating the therapeutic potential of vasicine for AD.

Peucedanum japonicum Thunberg alleviates atopic dermatitis-like inflammation via STAT/MAPK signaling pathways in vivo and in vitro.

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disorder that exhibits clinical relapse. The disruption of the skin barrier increases the symptoms of AD, which is accompanied by a reduction in skin integrity. As an immune barrier, the skin plays a crucial role in regulating the inflammatory responses in AD. In this study, we used murine atopic dermatitis model using 2,4-dinitrochlorobenzen (DNCB), which is one of haptens to disrupt the skin barrier and generate the inflammation. As the small molecule, DNCB is easily penetrate the epidermis and binds to tissue proteins provoking immune responses. We evaluated the effects of an aqueous extract of Peucedanum japonicum Thunberg (PJT) in an experimental model of AD by measuring the mRNA and protein expression of cytokines and their related biomarkers. We examined the dorsal skin lesions, transepidermal water loss (TEWL), scratching behavior, expression of molecules related to skin barrier integrity, and histological changes in a murine model of DNCB- induced AD. We found out the down-regulatory effects of PJT on the AD-like symptoms or inflammatory dorsal lesions. For in vitro study, we used a mixture of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in human keratinocytes. The protein and mRNA expressions of skin barrier molecules and inflammatory markers were measured with western blotting and qRT-PCR assays, respectively. As a result, PJT alleviated the AD-like symptoms, and suppressed the inflammation caused by a TNF-α and IFN-γ in human keratinocytes. The regulatory effects of PJT appeared to be mediated via the mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription (STAT) signaling pathways both in vivo and in vitro. Altogether, the results indicated that PJT could serve as a promising therapeutic candidate for suppressing AD by inhibiting inflammation and improving the integrity of the skin barrier.

The anti-inflammatory properties of ethyl acetate fraction in ethanol extract from Sarcodia suiae sp. alleviates atopic dermatitis-like lesion in mice.

Atopic dermatitis (AD) is a chronic inflammatory and pruritic disease; it can be treated by inhibiting inflammation. Sarcodia suiae sp. is an edible, artificially cultivable red algae with multiple bioactivities. We assessed the anti-inflammatory activity of the ethyl acetate fraction of S. suiae sp. ethanol extract (PD1) on 1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced AD-like lesions. Results show that PD1 alleviated symptoms and significantly decreased clinical dermatitis score. PD1 inhibited serum immunoglobulin E expression and alleviated swelling in the spleen and subiliac lymph nodes. In skin tissues, PD1 alleviated aberrant hyperplasia, decreased epidermal thickness, and decreased the accumulation of mast cells. PD1 mediated the recovery of skin barrier-related proteins, such as claudin-1 and filaggrin. Our study demonstrated that PD1 has anti-inflammatory effects, alleviates AD symptoms, inhibits inflammatory responses in skin tissues, and restores barrier function in DNCB-induced AD mice. These findings reveal that S. suiae sp. extract provides an alternative protective option against AD.

Treatment of warts with contact allergens.

Contact immunotherapy is an increasingly used, effective means of treating cutaneous viral warts. Dinitrochlorobenzene, diphencyprone, and squaric acid dibutylester are the most frequently used modalities, showing slight variances in adverse effect profiles and efficacy. All of these agents serve as safe treatment modalities when administered according to the guidelines recommended herein. We review the value of contact immunotherapy in the treatment of cutaneous viral warts.

Alopecia areata: an evidence-based treatment update.

BACKGROUND: There is no cure for alopecia areata, nor is there any universally proven therapy that induces and sustains remission. Treatment choices are frequently based on disease duration, extent, and activity as well as the age of the patient. OBJECTIVE: Our objective was to review all randomized controlled studies on the treatment of alopecia areata. METHODS: We performed a search in the biomedical literature database PubMed, and used the terms 'alopecia areata treatment' and article type 'randomized controlled trials'. RESULTS: Following this algorithm, we reviewed, analyzed, and reported on 29 trials that examined the efficacy of anthralin, antidepressants, biologics, calcineurin inhibitors, corticosteroids (topical and systemic), minoxidil, prostaglandin analogs, sensitizers, and a miscellaneous group of topical and oral drugs with less scientific evidence (aromatherapy, photodynamic therapy, azelaic acid, garlic gel, bexarotene, triiodothyronine, inosiplex, and total glucosides of paeony). CONCLUSION: Using the American College of Physicians Guideline grading system, our assessment is that the majority of published randomized controlled studies of alopecia areata are only of moderate quality. A number of treatments were found to be effective, for example, topical and oral corticosteroids and the sensitizing agents diphenylcyclopropenone and dinitrochlorobenzene; however, most studies had major limitations that hinder the interpretation of these results.

Immunomodulation of malignant melanoma by contact sensitizing agents.

The importance of host defense against malignant melanoma is underlined by the use of immunomodulating agents as effective therapies. Diphencyprone and 2,4-dinitrochlorobenzene (DNCB) have been used successfully as contact sensitizing agents in this regard. Through haptenation of cell surface and cytoplasmic proteins, these agents trigger a CD8(+) T-lymphocyte predominant allergic contact hypersensitivity response. Th17 cells may also play a critical role. The effectiveness of these agents at stimulating tumor defense may be limited to melanoma of the skin. Response to immunotherapy using diphencyprone and DNCB is governed by the immune status of the host, which is affected by tumor burden, UV light and age. Additionally, diphencyprone and DNCB elicit synergy with other methods of treatment and thus may be used as adjuncts. Two current prospective trials may aid in elucidating the impact that this treatment modality has on the prognosis and quality of life of patients with melanoma.

DNCB use in treating extensive alopecia areata.

The author has been treating extensive cases of alopecia areata with 1-chloro-2, 4-dinitrobenzene (DNCB) for 35 years with considerable success. This presentation outlines the protocol that has been used.

Liquen nitidus: respuesta favorable a fototerapia UVB de banda estrecha. Presentación de dos casos / No disponible

No disponible

Immunotherapy for childhood warts.

Treatment-resistant warts are a common and frustrating problem for patients, parents, and providers alike. No wart treatment is uniformly effective. Indeed, well-designed randomized controlled trials are sorely needed to establish the true efficacy of all wart therapies. Treatment should be tailored to each individual patient. Although none of the immunologically-based treatments listed above (see Table, page 377) is FDA-approved for warts, they provide the treating physician with options for patients with warts that are resistant to standard treatments.

Microtubule inhibitors as a potential treatment for malaria.

The spread of parasitic resistance has necessitated the development of new drugs and drug targets for the treatment of malaria. Microtubules, which have gained outstanding importance as target molecules for the development of anticancer drugs, are likely to be potent antimalarial targets. The clinical implementation of microtubule inhibitors has given rise to a detailed mechanistic understanding of their interaction with tubulin on the molecular level and their effects on the cellular level. By comparison, our knowledge on Plasmodium falciparum, the causative agent of the most severe form of malaria, is rather poor. This article gives an overview on the microtubule inhibitors that have been explored in the parasite, reviews their effects on parasite growth and assesses their potential as novel antimalarials.