Mouse Model Of Atopic Dermatitis Research Articles

Novel anti-inflammatory Artemisia Naphta oil Extract Efficacious in in vivo Mouse Models of Atopic Dermatitis and Psoriasis

Novel anti-inflammatory Artemisia Naphta oil Extract Efficacious in in vivo Mouse Models of Atopic Dermatitis and Psoriasis

Effect of clothianidin exposure at the no-observed-adverse-effect level (NOAEL) in a mouse model of atopic dermatitis.

The effects of exposure to clothianidin (CLO), a neonicotinoid pesticide (NN), on the thymus and intestinal microbiota were recently revealed. Immune cells express nicotinic acetylcholine receptors (nAChRs), an NN target, suggesting CLO may disrupt the immune system. However, the relationship between CLO and atopic dermatitis (AD) is unknown. We administered a no-adverse-effect-level (NOAEL) dose of CLO to male NC/Nga mice with induced AD and measured, at three time points, key AD symptom indicators: epidermal thickening, mast cell number, total plasma IgE, and histamine levels. CLO increased total plasma IgE levels but reduced epidermal thickening, mast cell number, and plasma histamine levels in the early stages of AD. This demonstrates for the first time that CLO exposure inhibits AD's early symptoms.

Pediococcus pentosaceus KF159 alleviates house dust mite-induced atopic dermatitis by promoting IL10 production and regulatory T cell induction.

Atopic dermatitis (AD) is a chronic immune disease that requires long-term management owing to its relative ease of recurrence. However, steroid treatment is limited owing to the side effects. Therefore, research on therapeutics with proven safety is required. Here, we evaluated the anti-allergic activity of the probiotic strain Pediococcus pentosaceus KF159 (PPKF159) with an ex vivo mouse model sensitized with ovalbumin (OVA) and a mouse model of AD induced by house dust mites. Changes in pathological symptoms were confirmed based on the clinical status of the AD-induced lesion site and the levels of T helper type 2 (Th2)-derived cytokines and immunoglobulin E (IgE). In addition, cell-mediated responses and related mechanisms were elucidated using various kinds of primary cells including splenocytes, mesenteric lymph nodes, Peyer's patch, and bone marrow-derived dendritic cells (BMDCs) in vitro and ex vivo. Oral administration of PPKF159 alleviated AD-like clinical symptoms such as erythema, edema, hemorrhage, and increased tissue thickness, and suppressed the production of Th2-associated cytokines and serum IgE while increasing T helper type 1 (Th1)-mediated cytokine production. PPKF159 induced tolerogenic dendritic cells (tol-DCs) by increasing the expression of ICOS-L, PD-L1, and IDO which were closely related to Treg induction in PPKF159-treated BMDCs. In addition, BMDCs and naive T cells co-cultured in the presence of PPKF159 had elevated IL10 production and increased proportions of CD4+CD25+Foxp3+ Tregs compared to the absence of PPKF159. This study showed that PPKF159 relieved AD-like clinical symptoms, modulated the Th1/Th2 immune balance, and inhibited IgE production in a mouse AD model. PPKF159 induced the transformation of dendritic cells into tolerogenic versions. These induced tol-DCs directly enhanced the production of IL10 or improved the secretion of IL10 through the induction of CD4+CD25+Foxp3+ Treg cells, thereby improving AD. These results suggest that PPKF159 can be applied as a functional food material for the treatment and prevention of AD.

Expression of Epithelial-Mesenchymal Transition Markers in Epidermal Layer of Atopic Dermatitis.

The epithelial-mesenchymal transition (EMT) is a phenomenon, in which epithelial cells acquire a mesenchymal cell phenotype. It is important during wound healing; however, chronic inflammation leads to excessive EMT and causes tissue barrier dysfunction with hyperplasia. EMT is induced by several cytokines, such as interleukin (IL)-4 and IL-13. Additionally, IL-4 and IL-13 are known to increase in atopic dermatitis (AD) characterized by intense itching and eczema. Therefore, we assumed that there was commonality between the respective EMT and AD phenotypes. Herein, we evaluated EMT marker expression in AD skin and demonstrated that EMT-maker Snai1 and Twist expression were increased in AD mice model and patients with AD. Moreover, the epithelial-marker keratin 5 and mesenchymal marker Vimentin were co-expressed in the skin epidermis of mice with AD, suggesting the existence of hybrid epithelial-mesenchymal (E/M) cells possessing both epithelial and mesenchymal characteristics. In fact, we found that ΔNp63a, a stabilizing factor for hybrid E/M cells, was upregulated in the skin epidermis of the AD model mouse. Interestingly, increased expression of EMT markers was observed even at a nonlesion site in a patient with AD without initial inflammation or scratching. Therefore, EMT-like phenomena may occur independently of wound healing in skin of patients with AD.

Oral administration of Lactobacillus delbrueckii subsp. lactis LDL557 attenuates airway inflammation and changes the gut microbiota in a Der p-sensitized mouse model of allergic asthma.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 20% of children in developed countries. Although probiotics have shown promise as adjuvant treatments for AD, their mechanisms are not well understood. Building upon our previous studies, we investigated whether Lactobacillus gasseri and its moonlighting glyceraldehyde 3-phosphate dehydrogenase (GAPDH), namely LGp40, could be beneficial in AD management. In AD mouse models (SKH and C57BL/6J mice) with ovalbumin (OVA) and Dermatophagoides pteronyssinus (Der p) allergens, aligning with the "outside-in" and "inside-out" hypotheses, we administered L. gasseri orally and LGp40 intraperitoneally to investigate their protective effects. The evaluation involved measuring physiological, pathological, and immune function parameters. To delve deeper into the detailed mechanism of LGp40 protection in AD, additional assays were conducted using human skin keratinocytes (HaCaT) and monocytes (THP1) cell lines. L. gasseri and LGp40 enhanced skin barrier function and increased skin moisture retention. They also led to reduced infiltration of Langerhans cells in the dermis and mitigated skewed Th2 and Th17 immune responses. Moreover, LGp40 inhibited allergen-induced keratinocyte apoptosis through the blockade of the caspase-3 cascade and reduced the NLR family pyrin domain containing 3 (NLRP3) inflammasome in macrophages. These inhibitions were achieved through the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. The results of this study provide a novel insight into the mechanism of action of probiotics in the prevention and treatment for allergic disorders through the moonlighting GAPDH protein.

Skin delivery of synthetic benzoyl pterostilbenes suppresses atopic dermatitis-like inflammation through the inhibition of keratinocyte and macrophage activation

Atopic dermatitis (AD) is one of the most common skin autoimmune diseases needing continuous anti-inflammatory management. Pterostilbene is reported to exhibit anti-inflammatory activity with higher bioavailability and stability than its parent compound, resveratrol. In this study, a series of synthetic pterostilbene analogs were designed by the hybridization of pterostilbene with chalcones or benzoyl chloride. Seventeen analogs derived from pterostilbene were synthesized with differences in the positions of hydroxyl, methoxyl, or fluoro moieties. These compounds were screened by the inhibitory effect on the overexpressed Th2-associated cytokines/chemokines in the activated human keratinocytes (HaCaT). The anti-IL-5 and anti-CCL5 activity of these compounds led to the identification of three effective compounds: 3a ((E)− 4-(3,5-dimethoxystyryl)phenyl benzoate), 3d ((E)− 4-(3,5-dimethoxystyryl)phenyl 2-methoxybenzoate), and 3g ((E)− 4-(3,5-dimethoxystyryl)phenyl 2-fluorobenzoate). These benzoyl pterostilbenes also significantly decreased Th1/Th17-associated proinflammatory mediators in the activated macrophages (differentiated THP-1). The result showed that the conditioned medium of benzoyl pterostilbene-treated macrophages reduced the phosphorylated STAT3 in the keratinocytes, indicating the blockade of crosstalk between resident and immune cells. Compounds 3d and 3g generally showed greater skin absorption than 3a. The flux of 3g across barrier-defective skins mimicking the AD skin was 3-fold higher than that of across intact skin. The dinitrochlorobenzene (DNCB)-induced AD mouse model manifested that topical delivery with 3g improved the pathological signs through inhibiting cytokines/chemokines (IL-5, TNF-α, CCL17, and CCL22) and macrophage recruitment. The epidermal thickness was reduced from 76 to 55 µm after topical 3g delivery. The therapeutic activity of 3g was comparable to that of tacrolimus (TAC) used as a positive control. The benzoyl pterostilbenes attenuated the inflammation via the MAPK and c-Jun signaling. Furthermore, this study provided experimental evidence of benzoyl pterostilbene analogs for therapeutic potential on AD.

Characterization of Different Inflammatory Skin Conditions in a Mouse Model of DNCB-Induced Atopic Dermatitis

The mouse model of 2,4-dinitrochlorbenzene (DNCB)-induced human-like atopic dermatitis (hlAD) has been widely used to test novel treatment strategies and compounds. However, the study designs and methods are highly diverse, presenting different hlAD disease patterns that occur after sensitization and repeated challenge with DNCB on dorsal skin. In addition, there is a lack of information about the progression of the disease during the experiment and the achieved pheno- and endotypes, especially at the timepoint when therapeutic treatment is initiated. We here examine hlAD in a DNCB-induced BALB/cJRj model at different timepoints: (i) before starting treatment with dexamethasone, representing a standard drug control (day 12) and (ii) at the end of the experiment (day 22). Both timepoints display typical AD-associated characteristics: skin thickening, spongiosis, hyper- and parakeratosis, altered cytokine and gene expression, increased lipid mediator formation, barrier protein and antimicrobial peptide abnormalities, as well as lymphoid organ hypertrophy. Increased mast cell infiltration into the skin and elevated immunoglobulin E plasma concentrations indicate a type I allergy response. The DNCB-treated skin showed an extrinsic moderate sub-acute hlAD lesion at day 12 and an extrinsic mild sub-acute to chronic pheno- and endotype at day 22 with a dominating Th2 response. A dependency of the filaggrin formation and expression in correlation to the disease severity in the DNCB-treated skin was found. In conclusion, our study reveals a detailed classification of a hlAD at two timepoints with different inflammatory skin conditions and pheno- and endotypes, thereby providing a better understanding of the DNCB-induced hlAD model in BALB/cJRj mice.

Anti-Inflammatory Effects of the LK5 Herbal Complex on LPS- and IL-4/IL-13-Stimulated HaCaT Cells and a DNCB-Induced Animal Model of Atopic Dermatitis in BALB/c Mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease influenced by a complex interplay of genetic and environmental factors. The activation of the JAK-STAT pathway increases the expression of inflammatory cytokines such as IL-4 and IL-13, further deteriorating AD. Therefore, for the treatment of AD, the JAK-STAT pathway is emerging as a significant target, alongside inflammatory cytokines. This study investigates the potential therapeutic effects of a novel herbal complex, LK5, composed of Scutellaria baicalensis, Liriope platyphylla, Sophora flavescens, Dictammus dasycarpus, and Phellodendron schneider, known for their anti-inflammatory and immune-modulating properties. We examined the anti-inflammatory and anti-AD effects of the LK5 herbal complex in HaCaT cells stimulated by LPS and IL-4/IL-13, as well as in a mouse model of AD induced by DNCB. In HaCaT cells stimulated with LPS or IL-4/IL-13, the LK5 herbal complex demonstrated anti-inflammatory effects by inhibiting the expression of inflammatory cytokines including TNF-α, IL-6, and IL-1β, and downregulating the phosphorylation of STAT proteins. In a murine AD-like model induced by DNCB, administration of the LK5 herbal complex significantly ameliorated clinical symptoms, including dermatitis, ear thickness, and TEWL. Histological analysis revealed a reduction in epidermal thickness and mast cell infiltration. The LK5 herbal complex also inhibited pruritus induced by compound 48/80. Furthermore, the LK5 herbal complex treatment significantly decreased the levels of inflammatory cytokines such as TSLP, IL-6, and IgE in plasma and ear tissue of AD-induced mice. These findings suggest that the LK5 herbal complex may modulate the immune response and alleviate AD symptoms by inhibiting STAT pathways.

Blockade of OSMRβ signaling ameliorates skin lesions in a mouse model of human atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. Although IL-31, a type 2 helper T (Th2)-derived cytokine, is important to the development of pruritus and skin lesions in AD, the blockade of IL-31 signaling does not improve the skin lesions in AD. Oncostatin M (OSM), a member of IL-6 family of cytokines, plays important roles in the regulation of various inflammatory responses through OSM receptor β subunit (OSMRβ), a common receptor subunit for OSM and IL-31. However, the effects of OSM on the pathogenesis of AD remain to be elucidated. When AD model mice were treated with OSM, skin lesions were exacerbated and IL-4 production was increased in the lymph nodes. Next, we investigated the effects of the monoclonal antibody (mAb) against OSMRβ on the pathogenesis of AD. Treatment with the anti-OSMRβ mAb (7D2) reduced skin severity score in AD model mice. In addition to skin lesions, scratching behavior was decreased by 7D2 mAb with the reduction in the number of OSMRβ-positive neurons in the dorsal root ganglia of AD model mice. 7D2 mAb also reduced the serum concentration of IL-4, IL-13, and IgE as well as the gene expressions of IL-4 and IL-13 in the lymph nodes of AD model mice. Blockade of both IL-31 and OSM signaling is suggested to suppress both pruritus and Th2 responses, resulting in the improvement of skin lesions in AD. The anti-OSMRβ mAb may be a new therapeutic candidate for the treatment of AD.

A Comparative Study to Examine the Effects of Topical Vinpocetine and Tacrolimus on Induced Atopic Dermatitis in Mice.

Background: Atopic dermatitis (AD) is a persistent and recurring inflammatory skin disorder distinguished by parched skin and severe itching. The pathogenesis of AD involves increased production of specific cytokines, such as Interlukin-4 (IL-4) and Interlukin-13 (IL-13), which are associated with the T helper 2 pathway. However, prolonged use of the current glucocorticoids and calcineurin inhibitors medications can lead to adverse effects. Aim of the study: To assess the efficiency of topical Vinpocetine and Tacrolimus in treating an induced atopic dermatitis mice model. Methods: Five sets of fifty male Albino mice, were randomly selected. One-chloro-2,4-dinitrobenzene (DNCB) was applied to the dorsal (back) skin of forty mice to cause atopic dermatitis. Ten control healthy mice were placed in Group I, ten mice with atopic dermatitis were placed in Group II; neither group received any treatment. Group III consists of 10 mice that received tacrolimus 0.1% ointment, group IV was administered a topical ointment comprising 5% Vinpocetine and lastly, group V underwent a vehicle ointment. Severity was assessed visually, IL-4 and IL-13 were measured by immunohistochemistry, in addition to general histopathological evaluation as well as examining WBCs. Results: The groups treated with Vinpocetine 5%, and Tacrolimus all had significantly lower levels of WBC counts, decreased IL-4 and IL-13 staining according to immunohistochemistry and lower histopathological scores. Vinpocetine 5% and tacrolimus treatment also showed a statistically significant reduction in hyperkeratosis and inflammation among the studied groups (P<0.001). Conclusions Topical Vinpocetine 5% ointment, and tacrolimus 0.1% were effective in the treatment of induced AD mouse model through the improvement of histopathological changes and their ability to decrease IL-4 and IL-13, Vinpocetine were effective in the treatment of induced AD. Keywords: Atopic dermatitis, Tacrolimus, Topical, Vinpocetine.

Dysregulated Hippo Signaling Pathway and YAP Activation in Atopic Dermatitis: Insights from Clinical and Animal Studies.

The yes-associated protein (YAP) of the Hippo pathway regulates a variety of target genes involved in cell proliferation, survival, and inflammation. YAP and transcription activator with a PDZ-binding motif (TAZ) proteins act as mediators of the inflammatory response. Still, their role in atopic dermatitis (AD)-particularly, the association with the nuclear factor kappa-B and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways-is not fully understood. In this study, we found that YAP, is upregulated in AD patients and NC/Nga mouse model of AD. In addition, inhibition of YAP significantly reduced epidermal cell proliferation by 58% and mast cell numbers by 51% and attenuated the upregulation of both Th1- and Th2-associated cytokines. Among the JAK-STAT family proteins, the expressions of JAK1 and JAK2 and those of STAT1, STAT2, and STAT3 were also downregulated. These findings may explain the role of YAP in AD and suggest YAP inhibitors as promising therapeutic agents for AD.

Biofunctional Inorganic Layered Double Hydroxide Nanohybrid Enhances Immunotherapeutic Effect on Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a widespread, recurrent, and chronic inflammatory skin condition that imposes a major burden on patients. Conventional treatments, such as corticosteroids, are associated with various side effects, underscoring the need for innovative therapeutic approaches. In this study, the possibility of using indole-3-acetic acid-loaded layered double hydroxides (IAA-LDHs) is evaluated as a novel treatment for AD. IAA is an auxin-class plant hormone with antioxidant and anti-inflammatory effects. Following the synthesis of IAA-LDH nanohybrids, their ability to induce M2-like macrophage polarization in macrophages obtained from mouse bone marrow is assessed. The antioxidant activity of IAA-LDH is quantified by assessing the decrease in intracellular reactive oxygen species levels. The anti-inflammatory and anti-atopic characteristics of IAA-LDH are evaluated in a mouse model of AD by examining the cutaneous tissues, immunological organs, and cells. The findings suggest that IAA-LDH has great therapeutic potential as a candidate for AD treatment based on its in vitro and in vivo modulation of AD immunology, enhancement of macrophage polarization, and antioxidant activity. This inorganic drug delivery technology represents a promising new avenue for the development of safe and effective AD treatments.

Forsythia velutina Nakai extract: A promising therapeutic option for atopic dermatitis through multiple cell type modulation.

Atopic dermatitis (AD) is a complex condition characterized by impaired epithelial barriers and dysregulated immune cells. In this study, we demonstrated Forsythia velutina Nakai extract (FVE) simultaneously inhibits basophils, macrophages, keratinocytes, and T cells that are closely interrelated in AD development. We analyzed the effect of FVE on nitric oxide and reactive oxygen species (ROS) production in macrophages, basophil degranulation, T cell activation, and tight junctions in damaged keratinocytes. Expression of cell-type-specific inflammatory mediators was analyzed, and the underlying signaling pathways for anti-inflammatory effects of FVE were investigated. The anti-inflammatory effects of FVE were validated using a DNCB-induced mouse model of AD. Anti-inflammatory activity of compounds isolated from FVE was validated in each immune cell type. FVE downregulated the expression of inflammatory mediators and ROS production in macrophages through TLR4 and NRF2 pathways modulation. It significantly reduced basophil degranulation and expression of type 2 (T2) and pro-inflammatory cytokines by perturbing FcεRI signaling. Forsythia velutina Nakai extract also robustly inhibited the expression of T2 cytokines in activated T cells. Furthermore, FVE upregulated the expression of tight junction molecules in damaged keratinocytes and downregulated leukocyte attractants, as well as IL-33, an inducer of T2 inflammation. In the AD mouse model, FVE showed superior improvement in inflammatory cell infiltration and skin structure integrity compared to dexamethasone. Dimatairesinol, a lignan dimer, was identified as the most potent anti-inflammatory FVE compound. Forsythia velutina Nakai extract and its constituent compounds demonstrate promising efficacy as a therapeutic option for prolonged AD treatment by independently inhibiting various cell types associated with AD and disrupting the deleterious link between them.

Synthesis of 9-Cinnamyl-9H-purine Derivatives as Novel TLR4/MyD88/NF-κB Pathway Inhibitors for Anti-inflammatory Effects.

The novel 9-cinnamyl-9H-purine skeleton, inspired by resveratrol and curcumin, was developed to avoid a pan-assay interference compound (PAINS) related to invalid metabolic pancreas activity (IMPS). It replaced the phenol group with purine analogues, the building blocks of DNA and RNA. Alterations to the hydroxyl group in the cinnamyl group, such as H, Me, or F substitutions, were made to impede its oxidation to a PAINS-associated quinone. Among the compounds tested, 5e significantly inhibited nitric oxide production in LPS-induced macrophages (IC50: 6.4 vs 26.4 μM for resveratrol). 5e also reduced pro-inflammatory cytokine levels (IL-6, TNF-α, IL-1β) and lowered iNOS and COX-2 protein levels. Mechanistically, 5e disrupted the TLR4-MyD88 protein interaction, leading to the suppression of the NF-κB signaling pathway suppression. In an atopic dermatitis mouse model, 5e reduced ear edema and inflammation. These findings indicate that the novel 9-cinnamyl-9H-purine skeleton provides therapeutic insight into treating various human diseases by regulating inflammation.

Jiawei guomin decoction regulates the degranulation of mast cells in atopic dermatitis mice via the HIS/PAR-2 pathway

Ethnopharmacological relevanceGuomin decoction (GMD) is a traditional Chinese medicine commonly used in clinical practice. It has traditionally been used to treat all allergic diseases. Currently, Jiawei Guomin Decoction (JWGMD) is used to treat sensitive skin after initial therapy. Although it has a significant clinical therapeutic effect, the exact role of mast cell degranulation in treating atopic dermatitis (AD) is still unclear. Aim of the studyGMD and JWGMD can both treat allergic diseases, while JWGMD focuses on skin allergies. This study aims to explore the potential effect of JWGMD on the degranulation of mast cells in an AD mouse model induced by 2,4-dinitrofluorobenzene (DNFB) and investigate the effectiveness of JWGMD in alleviating disease progression to further provide specific therapeutic targets for treating AD. Materials and methodsThe scratching times and skin lesions of model mice induced by DNFB were observed, and skin tissues were collected for subsequent measurement. Histopathological changes in the back skin of mice were observed by haematoxylin eosin (H&E) staining, Toluidine blue staining was used to detect the degranulation of mouse skin mast cells, and the relationship between the expression of histamine (HIS), mast cell tryptase (MCT) and mast cell degranulation was analysed by enzyme-linked immunosorbent assay (ELISA). The expression of protease-activated receptor-2 (PAR-2), histamine 1 receptor (H1R), H2R, H4R and MCT proteins in AD mice was detected by Western blot (WB). Immunofluorescence assay (IFA) further confirmed the localization of PAR-2, H1R, H2R, H4R, and MCT proteins in the skin. Quantitative real-time PCR (qPCR) was used to determine PAR-2, H1R, H2R and H4R mRNA levels in skin lesions to further clarify the mechanism by which JWGMD amplifies mast cell degranulation in AD. In addition, a reliable ultrahigh-performance liquid chromatography-quadrupole electrostatic field orbitrap mass spectrometry (UPLC-QE-MS) nontargeted metabolomics analysis was performed to analyse the differences in metabolite abundance between GMD and JWGMD, and these results were used to identify the active components in JWGMD that may have antipruritic and anti-inflammatory properties and inhibit mast cell degranulation. ResultsAfter intermittent stimulation with DNFB, the skin lesions showed extensive desquamation, dryness, scabbing, skin thickening, and slight bleeding. Both treatments alleviated this phenomenon and reduced the number of scratches, with JWGMD being the most effective. JWGMD can significantly reduce inflammatory cell infiltration, oedema, and some capillary neogenesis in mice and reduce the degranulation of mast cells. The ELISA results showed that JWGMD can increase the levels of MCT and HIS proteins. The WB and IFA results demonstrated that JWGMD reduced the expression levels of PAR-2, H1R, H4R, and MCT proteins in skin lesions, with protein localization mainly in the epidermal layer, while H2R protein levels were increased and mainly localized in the dermis. In addition, JWGMD downregulates the mRNA expression of PAR-2, H1R, H2R, and H4R. Interestingly, through UPLC-QE-MS nontargeted metabolomic analysis, we detected the anti-inflammatory and antiallergy active substances in JWGMD, such as methyl eugenol, dictamnine and sinapine. ConclusionsJWGMD may alleviate itching through methyl syringol, dictamnine, sinapine and other substances, and its mechanism may be related to inhibiting the HIS/PAR-2 pathway in AD model mice and further regulating the self-amplification of mast cell degranulation. JWGMD is a potential drug for treating AD. Therefore, it deserves continuous attention and research.

Ishige okamurae Extract: Diphlorethohydroxycarmalol with Effect of Atopic Dermatitis-Like Skin Inflammation

Ishigeokamurae Yendo 1907, Fucaceae, a brown alga, has garnered attention for its antipyretic, anti-inflammatory, and anti-edema properties. While numerous studies have explored the effects of a 95% ethanol extract of I. okamurae, limited research has been conducted on its 70% ethanol extract. This study focuses on diphlorethohydroxycarmalol, a bioactive compound identified in the 70% ethanol extract of I. okamurae. Diphlorethohydroxycarmalol has garnered significant interest due to its potential health benefits, including antioxidant, anti-inflammatory, antiviral, and anticancer properties. We investigate the impact of the 70% ethanol extract of I. okamurae and diphlorethohydroxycarmalol on atopic dermatitis using human keratinocyte cell lines (HaCaT) and atopic dermatitis mouse models induced by dinitrochlorobenzene and house dust mite. Treatment with extract of I. okamurae effectively reduced dinitrochlorobenzene/house dust mite -induced ear edema, ear thickness, mast cell infiltration, as well as levels of immunoglobulin (Ig) E, IgG1, IgG2a, cytokines, and chemokines in atopic dermatitis mice. In HaCaT cells, extract of I. okamurae also suppressed TNF-α/IFN-γ-induced cytokine and chemokine production. To further understand the anti-atopic and anti-inflammatory properties of extract of I. okamurae, we evaluated the effects of diphlorethohydroxycarmalol on atopic dermatitis mice and HaCaT cells. In atopic dermatitis mice, diphlorethohydroxycarmalol demonstrated the ability to reduce the inflammatory response induced by TNF-α/IFN-γ. These findings highlight the potential of extract of I. okamurae as an anti-inflammatory agent for inflammatory skin disorders and suggest that diphlorethohydroxycarmalol may represent a promising therapeutic approach for the treatment of inflammatory skin diseases.Graphical

Helicobacter pylori infection attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in C57/BL6 mice

BackgroundAlthough numerous studies have suggested a negative correlation between Helicobacter pylori (H. pylori) infection and allergies, there has been limited research on the relationship between H. pylori infections and atopic dermatitis (AD). The present study aimed to investigate the effects of H. pylori infection in an AD mouse model and identify potential mechanisms related to type 2 immunity, skin barrier defects, and pruritus.MethodsA model of AD-like symptoms was established with 2,4-dinitrochlorobenzene (DNCB) after infection of the gastric cavity with H. pylori. Analysis of the expression of key inflammatory cytokines and serum levels of immunoglobulin E (IgE) was based on enzyme-linked immunosorbent assay (ELISA). The expression of filaggrin (FLG) and loricrin (LOR) were analyzed by immunohistochemistry staining. The evaluation of STAT1, STAT3, phosphorylated STAT1 (phospho-STAT1), and phosphorylated STAT3 (phospho-STAT1) expression levels in skin lesions was performed using western blot.ResultsThe present study showed that the H. pylori-positive AD group (HP+AD+) exhibited milder skin lesions, including erythema, erosion, swelling, and scaling, than the H. pylori-negative AD group (HP−AD+). Additionally, HP+AD+ displayed lower levels of IgE in serum, and downregulated expression of interleukins 4 and 31 (IL-4 and IL-31) in serum. Furthermore, HP+AD+ demonstrated higher expression of filaggrin and loricrin than HP−AD+. Notably, H. pylori significantly reduced the amount of phosphorylated STAT1 and STAT3.ConclusionHelicobacter pylori infection negatively regulates the inflammatory response by affecting inflammatory factors in the immune response, and repairs the defective epidermal barrier function. In addition, H. pylori infection may reduce IL-31, thereby alleviating pruritus. These effects may be associated with the inhibition of JAK–STAT signaling activation.

RETRACTED ARTICLE: Topical bismuth oxide-manganese composite nanospheres alleviate atopic dermatitis-like inflammation

Atopic dermatitis (AD) is a common skin disease involving important immune mechanisms. There is an unmet need for a treatment for this condition. Herein, we focused on elucidating the role of Bi2-xMnxO3 nanospheres (BM) in alleviating skin inflammation in AD-like C57BL/6 mice. The BM was fabricated via sacrificial templates and its biosafety was systematically evaluated. The BM was applied topically to skin lesions of AD-like C57BL/6 mice. The phenotypic and histological changes in the skin were examined carefully. The responses of barrier proteins, inflammatory cytokines and cells to BM were evaluated in HaCaT cells and AD mouse models. The data demonstrated that BM treatment alleviated the AD phenotypes and decreased the level of inflammatory factors, while increasing the expression of the barrier proteins filaggrin/involucrin in the skin. BM effectively reduced the expression of phosphorylated STAT6, which in turn reduced the expression of GATA3, and further decreased the differentiation ratio of Th2 cells, thereby reducing the expression of IL-4. In conclusion, topical drug therapy with BM provides a safe and effective treatment modality for AD by reducing IL-4 and increasing barrier proteins.Graphical

Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses. Methods: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms. Results: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca2+ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment. Conclusions: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

Macrophage autophagy deficiency-induced CEBPB accumulation alleviates atopic dermatitis via impairing M2 polarization

Macroautophagy/autophagy plays a pivotal role in immune regulation. Its significance is evident in modulation of immune cell differentiation and maturation, physiologically and pathologically. Here, we investigate the role of macrophage autophagy on the development of atopic dermatitis (AD). By employing an MC903-induced AD mice model, we observe reduced cutaneous inflammation in macrophage Atg5 cKO mice compared with WT mice. Notably, there is a decreased infiltration of M2 macrophages in lesional skin from Atg5 cKO mice. Furthermore, impaired STAT6 phosphorylation and diminished expression of M2 markers are detected in autophagy-deficient macrophages. Our mechanistic exploration reveals that CEBPB drives the transcription of SOCS1/3 and SQSTM1/p62-mediated autophagy degrades CEBPB normally. Autophagy deficiency leads to CEBPB accumulation, and further promotes the expression of SOCS1/3. This process inhibits JAK1-STAT6 pathway activation and M2 marker expression. Together, our study indicates that autophagy is required for M2 activation and macrophage autophagy may be a promising target for AD intervention.