Modulation of allergic contact dermatitis via gut microbiota modified by diet, vitamins, probiotics, prebiotics, and antibiotics.

Allergic contact dermatitis is one of the most common recorded occupational diseases. There are many different substances that the skin comes into contact with on a daily basis and that can cause ACD, e.g., preservatives, surfactants, and antimicrobial agents. The development of a mouse model of ACD has provided insight into the immune mechanisms involved. Drugs used in the treatment of skin diseases have many side effects. Therefore, alternative methods of suppressing the immune response to reduce the symptoms of skin diseases are being sought. In recent years, high hopes have been placed on dietary modulation and supplementation to affect the intestinal microbial composition and promote anti-inflammatory responses. In addition, other studies have shown the crucial role of intestinal microbiota in many immune-mediated diseases. Recognition and characterization of pro- and anti-inflammatory nutrients and supplements may be crucial to support the treatment of diseases such as atopic dermatitis, acne vulgaris, psoriasis, and allergic contact dermatitis.

Prinsepia utilis Royle leaf extract: Ameliorative effects on allergic inflammation and skin lesions in allergic contact dermatitis and polyphenolic profiling through UPLC-MS/MS coupled to chemometric analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Allergic contact dermatitis (ACD) is a common allergic inflammatory disease that is concomitant with skin swelling, redness, dry itching, and relapses. Prinsepia utilis Royle, a Chinese and Indian folk medicine, is rich in polyphenols with potential anti-inflammatory and skin-protective activities. However, the underlying mechanism of P. utilis leaf (PUL) in the treatment of ACD and its functional basis remains unclear. AIM OF THE STUDY: This study is aimed to explore and reveal the active substances and mechanism of PUL against ACD. MATERIALS AND METHODS: Hyaluronidase inhibitory assay and fluorescein isothiocyanate (FITC)-induced ACD mouse model were performed to assess the antiallergic effects of PUL in vitro and in vivo. Different solvents were applied to obtain multiple PUL extracts. The extracts were further tested for total phenolic content (TPC) and total flavonoid content (TFC) by using spectrophotometric assays. Polyphenolic profiles were analyzed by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), and a simultaneous quantification method was established using UPLC-QTrap-MS/MS through multiple reaction monitoring (MRM) and applied to analyze the pharmacokinetics of the multiple major polyphenols of PUL in mice. RESULTS: The water extract of PUL with the highest TPC/TFC exhibited the strongest antihyaluronidase effect (IC50 = 231.93 µg/mL). In vivo assays indicated that the oral administration of PUL water extract dose-dependently attenuated ACD-like symptoms by decreased interleukin (IL)-4, IL-5, IL-13, IL-33, thymic stromal lymphopoietin, and IgE production, suppressed eosinophil and basophil secretion, and increasing the expression of tight junction (TJ) proteins (claudin-1 [CLDN-1] and occludin). Concomitantly, UPLC-QTOF-MS/MS analysis enabled the identification of 60 polyphenols and the pharmacokinetic parameters of seven quantified constituents of PUL were characterized. Four compounds, trans-p-coumaric acid 4-O-ß-D-glucopyranoside (11), vicenin-2 (21), isoschaftoside (31), and kaempferol 3-O-(2″,6″-di-O-α-L-rhamnopyransoyl)-ß-D-glucopyranoside (38) which displayed satisfactory pharmacokinetic features, were considered as potential effective substances in PUL. CONCLUSIONS: PUL water extract ameliorated the allergic inflammation of ACD by repairing the epithelial barrier and alleviating Th2-type allergic inflammation. The anti-allergic effect of PUL is closely related to its phenolic substances, and compounds 11, 21, 31, and 38 were the active substances of PUL. It revealed that P. utilis could be developed as a new source of antiallergic agents for ACD therapy.

TRPA1 is involved in the inhibitory effect of Ke-teng-zi on allergic contact dermatitis via MAPK and JAK/STAT3 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Entada phaseoloides (Linn.) Merr. commonly named "Ke-teng-zi" is a traditional Chinese folk medicine and reported to treat dermatitis, spasm, and headache. However, the exact effect and the mechanism of Ke-teng-zi on the treatment of dermatitis is unclear. AIM OF THE STUDY: To elucidate the antipruritic effect and molecular mechanisms of Ke-teng-zi on the treatment of allergic contact dermatitis (ACD). MATERIALS AND METHODS: The main components of the n-butanol fraction of 70% ethanol extract from Ke-teng-zi (abbreviated as KB) were analyzed by HPLC. The chloroquine (CQ)-induced acute itch and squaraine dibutyl ester (SADBE)-induced ACD chronic itch in mice was established, and the TNF-α/IFN-γ stimulated Human keratinocytes (HaCaT) were used to evaluate the antipruritic and anti-inflammatory effects of KB. Behavioral tests, lesion scoring, and histology were also examined. The expression levels of molecules in MAPK and JAK/STAT3 pathways, the mRNA levels of chemokines and cytokines in both the skin of ACD mice and the HaCaT cells were detected by western blot and qPCR. Furthermore, whole-cell patch-clamp recordings in TRPA1-tranfected HEK293T cells were used to elucidate the effect of KB on TRPA1 channels. TRPA1 siRNA was used to evaluate the role of TRPA1 in the anti-inflammatory effect of KB in keratinocytes. RESULTS: The main compounds in KB could bind to the active sites of TRPA1 mainly through hydrogen bond and hydrophobic bond interactions. KB could inhibit the scratching behavior in CQ-induced acute itch, and the inhibitory effect of KB was blocked by TRPA1 inhibitor HC-030031. In addition, KB significantly decreased the scratching bouts of ACD mice, reduced the skin lesion scores, mast cells degranulation, and epidermal thickening, inhibited the production of inflammatory chemokines/cytokines and CGRP, and down-regulated the levels of p-ERK1/2, p-p38, and p-STAT3, compared to the ACD mice. Moreover, continuous application of KB induced the desensitization of TRPA1 channels. Also, KB inhibited the expression of p-ERK1/2, p-p38, and p-STAT3, and down-regulated the expression of inflammatory chemokines and cytokines in vitro, which were reversed by the TRPA1 siRNA. CONCLUSIONS: KB alleviated the pruritus and skin inflammation in ACD mice through TRPA1 channels desensitization and down-regulation of intracellular MAPK and JAK/STAT3 signaling pathways. Our results suggested that Ke-teng-zi is a potential drug for the treatment of inflammatory skin diseases such as ACD.

Anti-inflammatory and anti-pruritic effects of Chi-Huang Solution in a murine model of allergic contact dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: In treating atopic dermatitis, multi-mode management is adopted, including trying to avoid the allergens, controlling and preventing secondary infections, and using drugs to control itching. At present, most of the commonly used anti-pruritic drugs in the clinic are single-target and lead to serious side effects. Many studies have shown that a variety of traditional Chinese medicines have significant anti-inflammatory and anti-pruritic effects, and have the characteristics of multiple components, multiple targets, and multiple effects. AIM OF THE STUDY: The study aimed to explore the anti-inflammatory and anti-pruritic effects of the Chi-Huang Solution in a murine model of Allergic contact dermatitis (ACD). This study considers the effectiveness of the Chi-Huang Solution for external use on skin to provide an experimental basis for the clinical development and application of Chinese medicine and related preparations for Canine atopic dermatitis (CAD). MATERIALS AND METHODS: Forty-two male SPF C57BL/6 mice were randomly divided into control group (n = 6), ACD model group (n = 6), HAC control group (n = 6), and 4 Chi-Huang Solution groups (n = 6 in each group). With SADBE induce the murine model of ACD chronic pruritus, and initially evaluate whether the model is successful by counting scratching behavior, measuring the skin fold thickness and skin lesion score within 1 h. After treating the ACD model mice with deionized water, HAC, 1CH, 2CH, 3CH, and 4CH for 7 days, behavioral changes were used to evaluate the anti-pruritic effect. The skin fold thickness, skin lesion score, and spleen index were used to evaluate the anti-inflammatory effect of the Chi-Huang Solution. H.E. staining was used for the epidermal thickness measurement and pathological evaluation. RT-qPCR was used to analyze the mRNA expression of related inflammatory factors such as IL-1ß, TNF-α, IL-33, IL-4, IL-17A, CXCL10, and its receptor CXCR3 in the skin of the lesion site, as well as to detect the mRNA expression of pruritus-related genes such as TRPV1, TRPA1, and GRP in DRG. RESULTS: After the treatment of low-dose (0.1 g/mL) and medium-dose (0.2 g/mL) Chi-Huang Solution, the scratching times both decreased significantly (P < 0.05), meanwhile the medium-dose Chi-Huang Solution had an obvious effect on reducing scratches/scab score (P < 0.05). Moreover, no matter what dose it takes, all Chi-Huang Solution can alleviate the epidermal thickening (P < 0.05) and the infiltration of mast cells in the ACD murine model of ACD. It is worth mentioning that the count of mast cells in the dermis was significantly down-regulated after the treatment of medium-dose Chi-Huang Solution (P < 0.005). Furthermore, Chi-Huang Solution can significantly down-regulate the mRNA expression of related inflammatory factors in the skin, and reduce the mRNA expression of pruritus-related genes, such as TRPA1, TRPV1, and GRP in the spinal cord. CONCLUSIONS: The results indicated that Chi-Huang Solution for external use exhibits significant anti-inflammatory and anti-pruritic effects on SADBE-induced ACD chronic pruritus murine models. Chi-Huang Solution might emerge as an effective drug for the treatment of CAD and high-dose Chi-Huang Solution (0.4 g/ml) has better comprehensive effects.

Dupilumab for Allergic Contact Dermatitis: An Overview of Its Use and Impact on Patch Testing.

Allergic contact dermatitis (ACD) has been estimated to affect up to 20% of the general population. Patch testing is the gold standard for identification of causative allergens. When allergen avoidance fails, current treatment options include topical and oral corticosteroids, systemic immunosuppressants, and phototherapy. Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved by the US Food and Drug Administration for the treatment of moderate to severe atopic dermatitis. It also has been used off label with some success in the treatment of ACD. This article discusses the evidence for using dupilumab to treat ACD as well as considerations for patch testing in patients who are taking this medication.

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity.

BACKGROUND: Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. METHODS: We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. RESULTS: We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4+CD25+Foxp3+, CD4+CD25+Foxp3-, and CD8+CD122+ cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. CONCLUSION: We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

Chromate-Induced Allergic Contact Dermatitis Treated With Dupilumab.

Chromate causes persistent, difficult to treat irritant and allergic contact dermatitis in cement-handling occupational workers. When therapeutics such as topical corticosteroids, topical calcineurin inhibitors, phototherapy and immune-modulating treatments like methotrexate fail, many patients are advised that avoidance may be the only remaining option – an option that may be particularly challenging if the patient’s occupation necessitates chromate exposure. We report a case of severe chromate-induced allergic contact dermatitis in a 55-year-old cement mason that presented to the outpatient dermatology clinic with multiple scaly, erythematous, >5 cm plaques scattered over the skin of his hands, head and neck. After a prior failed course of treatment with high potency topical corticosteroid, this patient was successfully treated with dupilumab. Given the success of dupilumab in our patient, we propose the consideration of dupilumab as an alternative treatment option for those suffering from chromate-induced allergic contact dermatitis that is refractory to ultra-high potency topical corticosteroids. J Drugs Dermatol. 2021;20(12):1340-1342. doi:10.36849/JDD.6246.

Diagnosis and Management of Dermatitis, Including Atopic, Contact, and Hand Eczemas.

This is a comprehensive and current guide for the diagnosis, differential diagnosis, treatment, and management of eczematous dermatitis, with a focus on atopic dermatitis, irritant and allergic contact dermatitis, hand dermatitis including recurrent vesicular and hyperkeratotic types, asteatotic dermatitis, and nummular or discoid dermatitis. Diagnostic options highlighted are clinical history, physical examination, and patch testing. Therapeutic options highlighted are moisturizers, topical corticosteroids, topical calcineurin inhibitors, crisaborole, phototherapy, and systemic medications including biologics.

Effect of Cone of Pinus densiflora on DNCB-Induced Allergic Contact Dermatitis-Like Skin Lesion in Balb/c Mice.

Cone of Pinus densiflora (CP), or Korean red pinecone, is a cluster of Pinus densiflora fruit. CP has also been verified in several studies to have anti-oxidation, anti-fungal, anti-bacterial, and anti-melanogenic effects. However, anti-inflammatory effects have not yet been confirmed in the inflammatory responses of pinecones to allergic contact dermatitis. The purpose of this study is to prove the anti-inflammatory effect of CP on allergic contact dermatitis (ACD) in vitro and in vivo. CP inhibited the expression of TSLP, TARC, MCP-1, TNF-α, and IL-6 in TNF-α/IFN-γ-stimulated HaCaT cells and MCP-1, GM-CSF, TNF-α, IL-6, and IL-8 in PMACI (phorbol-12-myristate-13-acetate plus A23187)-stimulated HMC-1 cells. CP inhibited the phosphorylation of mitogen-activated protein kinase (MAPKs), as well as the translocation of NF-κB on TNF-α/IFN-γ stimulated in HaCaT cells. In vivo, CP decreased major symptoms of ACD, levels of IL-6 in skin lesion, thickening of the epidermis and dermis, infiltration of eosinophils and mast cells, and the infiltration of CD4+ T cells and CD8+ T cells. This result suggests that CP represents a potential alternative medicine to ACD for diseases such as chronic skin inflammation.

Red Grape Polyphenol Oral Administration Improves Immune Response in Women Affected by Nickel-Mediated Allergic Contact Dermatitis.

BACKGROUND: Our previous findings demonstrated that in vitro supplementation of polyphenols, extracted from seeds of red grape (Nero di Troia cultivar), to peripheral lymphomonocytes from patients affected by allergic contact dermatitis (ACD) to nickel (Ni) could reduce the release of proinflammatory cytokines and nitric oxide (NO), while increasing the levels of interleukin (IL)-10, an anti-inflammatory cytokine. OBJECTIVE: To assess whether an intervention with oral administration of polyphenols leads to a reduction of peripheral biomarkers in ACD patients. METHODS: At T0, 25 patients affected by ACD to Ni were orally administered with 300 mg polyphenols prodie extracted from seeds of red grape (Nero di Troia cultivar) (NATUR-OX®) for 3 months (T1). The other 25 patients affected by ACD to Ni received placebo only for the same period of time. Serum biomarkers were analyzed at T0 and T1. In both groups, seven dropouts were recorded. RESULTS: At T1 in comparison to T0, in treated patients, values of interferon-γ, IL-4, IL-17, pentraxin 3 and NO decreased, while IL-10 levels increased when compared with T0 values. Conversely, in placebo- treated patients, no modifications of biomarkers were evaluated at T1. CONCLUSION: Present laboratory data rely on the anti-oxidant, anti-inflammatory and anti-allergic properties of polyphenols.

Isatis tinctoria L.-derived Petroleum Ether Extract Mediates Anti-inflammatory Effects via Inhibition of Interleukin-6, Interleukin-33 and Mast Cell Degranulation.

Isatis tinctoria L. (woad) has been used in medicine for centuries and has demonstrated anti-inflammatory effects. However, to date, no well-defined extracts with precise analysis of active substances have been developed. The aim of this study was to develop novel extracts of Isatis tinctoria L., and to characterize their active ingredients and anti-inflammatory properties. Various extracts of Isatis tinctoria L. were analysed for their active ingredients, and screened for anti-inflammatory effects using cyclooxygenase-2 activity assays. A petroleum ether extract was found to have the best effects, and was tested in a mouse model of acute allergic contact dermatitis. In the mouse model the petroleum ether extract resulted in significantly reduced ear swelling, oedema and inflammatory cell density. In mouse skin and human keratinocyte cultures, petroleum ether extract inhibited pro-inflammatory cytokine expression. Furthermore, human mast cell degranulation was significantly inhibited in LAD2 cell cultures. In conclusion, novel woad extracts were developed and shown to have anti-inflammatory properties in a contact hypersensitivity animal model and human keratinocytes. The production of such extracts and further characterization of their specific properties will enable determination of their potential dermatological effects in the treatment of inflamed and irritated skin.

Xanthone suppresses allergic contact dermatitis in vitro and in vivo.

Xanthone is a phenolic compound found in a few higher plant families; it has a variety of biological activities, including antioxidant, anti-inflammatory, and anticancer properties. However, the molecular and cellular mechanisms underlying the activity of xanthone in allergic contact dermatitis (ACD) remain to be explored. Therefore, this study aimed to investigate the regulatory effects of xanthone in ACD in human keratinocytes (HaCaT cell), and human mast cell line (HMC-1 cell) in vitro and in an experimental murine model. The results demonstrated that treatment with xanthone reduced the production of pro-inflammatory cytokines and chemokines including interleukin (IL)-1ß, IL-6, IL-8, and expression of chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated HaCaT cells. Xanthone also suppressed the production of pro-inflammatory cytokines, chemokines, and allergic mediators in phorbol myristate acetate/A23187 calcium ionophore (PMACI)-stimulated HMC-1 cells. Xanthone significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) and activation of caspase-1 signaling pathway in vitro model. Additionally, xanthone administration alleviated 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis like-skin lesion by reducing the serum levels of immunoglobulin E (IgE), histamine, and pro-inflammatory cytokines and suppressing MAPKs phosphorylation. Xanthone administration also inhibited mortality due to compound 48/80-induced anaphylactic shock and suppressed the passive cutaneous anaphylaxis (PCA) reaction mediated by IgE. Collectively, these results suggest that xanthone has a potential for use in the treatment of allergic inflammatory diseases.

[Therapeutic window analysis of Tripterygium wilfordii processed by liquorice: an instantiation using allergic contact dermatitis].

The present study was aimed to explore the dose-toxicity-effect relationship of Tripterygium wilfordii Hook f( TW) processed by liquorice,to establish the safe and effective therapeutic window,and further to provide scientific reference for the clinical use of TW. The toxicity and anti-inflammatory effect of six doses of raw TW and TW processed by liquorice( 0. 78,1. 56,3. 12,6. 24,12. 48,15. 60 g·kg-1) in 1-fluoro-2,4-dinitrobenzene( DNFB)-induced allergic contact dermatitis( ACD) model were mainly examined by histopathology and serum biochemistry. The liver biochemical parameters including ALT and AST,related inflammatory factors including TNF-α and IL-2,together with liver index,kidney index and the other pharmacodynamic indicators,were examined and compared. The results showed that compared with the control group,the serum levels of TNF-α and IL-2 of the model group were significantly increased( P<0. 01),which proved that the ACD model was successful. The comprehensive analysis of liver biochemical indexes,serum inflammatory factors and the other indexes showed that the safe and effective therapeutic window of TW processed by liquorice was 3. 12-12. 48 g·kg-1. The results showed the therapeutic window of TW processed by liquorice was much broader than that of raw TW. And it could provide scientific reference for the clinical rational use of TW.