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1.
Int J Nanomedicine ; 19: 8779-8796, 2024.
Article in English | MEDLINE | ID: mdl-39220192

ABSTRACT

Purpose: Atopic dermatitis (AD) is a chronic inflammatory skin condition that can affect individuals of all ages. Recent research has shown that oxidative stress plays a crucial role in the development of AD. Therefore, inhibiting oxidative stress may be an effective therapeutic approach for AD. Nano-molybdenum is a promising material for use as an antioxidant. We aimed to evaluate the therapeutic effects and preliminary mechanisms of molybdenum nanoparticles (Mo NPs) by using a murine model of chemically induced AD-like disease. Methods: HaCaT cells, a spontaneously immortalized human keratinocyte cell line, were stimulated by tumor necrosis factor-alpha /interferon-gamma after pre-treatment with Mo NPs. Reactive oxygen species levels, production of inflammatory factors, and activation of the nuclear factor kappa-B and the nuclear factor erythroid 2-related factor pathways were then evaluated. Mo NPs was topically applied to treat a murine model of AD-like disease induced by MC903, a vitamin D3 analog. Dermatitis scores, pruritus scores, transepidermal water loss and body weight were evaluated. AD-related inflammatory factors and chemokines were evaluated. Activation of the nuclear factor kappa-B and nuclear factor erythroid 2-related factor / heme oxygenase-1 pathways was assessed. Results: Our data showed that the topical application of Mo NPs dispersion could significantly alleviate AD skin lesions and itching and promote skin barrier repair. Further mechanistic experiments revealed that Mo NPs could inhibit the excessive activation of the nuclear factor kappa-B pathway, promote the expression of nuclear factor erythroid 2-related factor and heme oxygenase-1 proteins, and suppress oxidative stress reactions. Additionally, they inhibited the expression of thymic stromal lymphopoietin, inflammatory factors, and chemokines, thereby alleviating skin inflammation. Conclusion: Mo NPs present a promising alternative treatment option for patients with AD as they could address three pivotal mechanisms in the pathogenesis of AD concurrently.


Subject(s)
Dermatitis, Atopic , Heme Oxygenase-1 , Metal Nanoparticles , Molybdenum , NF-E2-Related Factor 2 , NF-kappa B , Reactive Oxygen Species , Signal Transduction , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Heme Oxygenase-1/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Molybdenum/pharmacology , Molybdenum/chemistry , Humans , Mice , Metal Nanoparticles/chemistry , Disease Models, Animal , Oxidative Stress/drug effects , HaCaT Cells , Antioxidants/pharmacology , Mice, Inbred BALB C , Nanoparticles/chemistry , Cell Line , Skin/drug effects , Skin/metabolism , Membrane Proteins
2.
Biomolecules ; 14(8)2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39199350

ABSTRACT

Graphene oxide (GO), a carbon-based material with oxygen-containing functional groups, can be applied in biomedicine for drug delivery, cancer therapy, and tissue regeneration. We have previously shown that nanoscale-sized graphene oxide (NGO), an oxidized graphene derivative, exhibits effective anti-inflammatory activity in a murine model of sepsis mediated by T helper (Th)1-promoting cytokines such as IFNγ and TNFα. However, whether NGO influences Th2-induced skin inflammation remains unclear. To address this issue, we employed an ovalbumin (OVA) plus aluminum hydroxide (Alum)-induced Th2-mediated skin inflammation model in conjunction with OVA-specific DO11.10 T cell receptor transgenic Balb/c mice. In vivo NGO injection upon OVA/Alum sensitization down-regulated OVA-elicited antigen-specific Th2 cells and GATA3-expressing Th2-type regulatory T cells. Next, we examined the effect of NGO injection on OVA/Alum-induced atopic dermatitis (AD)-like skin inflammation. NGO-injected mice exhibited significantly decreased Th2 disease phenotypes (e.g., a lower clinical score, decreased epidermal thickness and Th2 cell differentiation, and fewer infiltrated mast cells and basophils in skin lesions) compared with vehicle-injected control mice. Overall, our results suggest that NGOs are promising therapeutic materials for treating allergic diseases such as AD.


Subject(s)
Graphite , Mice, Inbred BALB C , Ovalbumin , Th2 Cells , Animals , Graphite/chemistry , Th2 Cells/immunology , Th2 Cells/drug effects , Mice , Alum Compounds/chemistry , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Dermatitis, Atopic/immunology , Female , Inflammation/drug therapy , Inflammation/pathology , Inflammation/chemically induced , Down-Regulation/drug effects , Skin/drug effects , Skin/pathology , Skin/immunology , Nanoparticles/chemistry
3.
Sci Rep ; 14(1): 17623, 2024 07 31.
Article in English | MEDLINE | ID: mdl-39085287

ABSTRACT

Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model.


Subject(s)
Administration, Topical , Dermatitis, Atopic , Dinitrochlorobenzene , Immunoglobulin E , Mice, Inbred BALB C , Skin , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Administration, Oral , Male , Mice , Immunoglobulin E/blood , Skin/drug effects , Skin/pathology , Skin/metabolism , Disease Models, Animal , Acetophenones/administration & dosage , Acetophenones/pharmacology , Acetophenones/therapeutic use , Eosinophils/drug effects , Interleukin-4/metabolism , Mast Cells/drug effects
4.
Int Immunopharmacol ; 139: 112706, 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-39032473

ABSTRACT

Emu oil is the oil extracted from the body fat of the Australian bird emu. Although previous studies have reported that emu oil has anti-inflammatory effects, the effect and mechanism of emu oil on the treatment of atopic dermatitis have not been reported. Here, 2, 4-dinitrofluorobenzene was used to induce atopic dermatitis-like appearance on the back skin of C57BL/6 mice. And then, the effect of emu oil in the atopic dermatitis treatment was evaluated. We found that emu oil reduced the transdermal water loss in the atopic dermatitis model. Additionally, the epidermal thickness treated with emu oil was significantly thinner. The number of mast cells and inflammatory cells were significantly decreased. The thymic stromal lymphopoietin (TSLP), which is secreted by keratinocyte, was decreased significantly after treatment. Moreover, the serum levels of cytokines TSLP, interleukin-4, interleukin-13, and immunoglobulin (Ig) E were decreased after emu oil treatment. Surprisingly, we found that the high level of Cdc42 expression in the atopic dermatitis, which was decreased after emu oil treatment. To detect the role of Cdc42 in atopic dermatitis, we constructed atopic dermatitis model in mice with sustained activation of Cdc42 signaling. Furthermore, we have confirmed that emu oil demonstrates anti-inflammatory effects in atopic dermatitis by inhibiting the expression of Cdc42 signaling in keratinocytes. In conclusion, we discovered a new role of Cdc42 in the development of atopic dermatitis, which mediated the therapeutic effect of emu oil on atopic dermatitis.


Subject(s)
Anti-Inflammatory Agents , Cytokines , Dermatitis, Atopic , Disease Models, Animal , Keratinocytes , Mice, Inbred C57BL , Signal Transduction , cdc42 GTP-Binding Protein , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/immunology , Keratinocytes/drug effects , Keratinocytes/metabolism , Cytokines/metabolism , Signal Transduction/drug effects , Mice , cdc42 GTP-Binding Protein/metabolism , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Thymic Stromal Lymphopoietin , Oils/pharmacology , Oils/therapeutic use , Immunoglobulin E/blood , Dinitrofluorobenzene , Skin/drug effects , Skin/pathology , Skin/metabolism , Humans , Mast Cells/drug effects , Mast Cells/immunology , Mast Cells/metabolism , Male
5.
J Ethnopharmacol ; 333: 118398, 2024 Oct 28.
Article in English | MEDLINE | ID: mdl-38823660

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Wikstroemia has been extensively utilized in traditional Chinese medicine (TCM) for the management of conditions such as coughs, edema, arthritis, and bronchitis. Studies have indicated that the crude extracts of Wikstroemia exhibit anti-inflammatory, anti-allergy, anti-aging, skin psoriasis, anti-cancer, and antiviral properties. In addition, these extracts are known to contain bioactive substances, including flavonoids, coumarins, and lignans. However, few studies have investigated the anti-inflammatory or anti-allergic activities of Wikstroemia trichotoma (Thunb.) Makino against atopic dermatitis (AD). AIM OF THE STUDY: The study aimed to explore the potential of a 95% ethanol extract of W. trichotoma (WTE) on the dysfunction of skin barrier and immune system, which are primary symptoms of AD, in 2,4-dinitrochlorobenzene (DNCB)-induced SKH-1 hairless mice and phorbol 12-myristate 13-acetate (PMA)/ionomycin or immunoglobulin E (IgE) + 2,4-dinitrophenylated bovine serum albumin (DNP-BSA) stimulated rat basophilic leukemia cell line (RBL-2H3). Furthermore, we sought to identify the chemical contents of WTE using high-performance liquid chromatography equipped with a photodiode array detector (HPLC-PDA). MATERIALS AND METHODS: An in vitro study was conducted using RBL-2H3 cells stimulated with PMA/ionomycin or IgE + DNP-BSA to assess the inhibitory effects of WTE on mast cell degranulation and interleukin-4 (IL-4) mRNA expression levels. For the in vivo study, AD was induced in SKH-1 hairless mice by applying 1% DNCB to the dorsal skin daily for 7 days. Subsequently, 0.1% DNCB solution was applied on alternate days, and mice were orally administered WTE (at 30 or 100 mg/kg/day) dissolved in 0.5% carboxymethyl cellulose (CMC) daily for 2 weeks. Transepidermal water loss (TEWL), skin hydration, skin pH, and total serum IgE levels were measured. RESULTS: In DNCB-stimulated SKH-1 hairless mice, WTE administration significantly improved AD symptoms and ameliorated dorsal skin inflammation. Oral administration of WTE led to a significant decrease in skin thickness, infiltration of mast cells, and level of total serum IgE, thus restoring skin barrier function in the DNCB-induced skin lesions. In addition, WTE inhibited ß-hexosaminidase release and reduced IL-4 mRNA levels in RBL-2H3 cells. Chemical profile analysis of WTE confirmed the presence of three phenolic compounds, viz. chlorogenic acid, miconioside B, and matteucinol-7-O-ß-apiofuranosyl (1 â†’ 6)-ß-glucopyranoside. CONCLUSIONS: WTE ameliorates AD symptoms by modulating in the skin barrier and immune system dysfunction. This suggests that W. trichotoma extract may offer therapeutic benefits for managing AD.


Subject(s)
Dermatitis, Atopic , Dinitrochlorobenzene , Disease Models, Animal , Ethanol , Immunoglobulin E , Plant Extracts , Wikstroemia , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Wikstroemia/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Mice , Ethanol/chemistry , Immunoglobulin E/blood , Mice, Hairless , Anti-Inflammatory Agents/pharmacology , Mast Cells/drug effects , Mast Cells/metabolism , Female , Anti-Allergic Agents/pharmacology , Cell Line, Tumor , Skin/drug effects , Skin/pathology , Skin/metabolism , Male , Interleukin-4/metabolism
6.
J Ethnopharmacol ; 333: 118439, 2024 Oct 28.
Article in English | MEDLINE | ID: mdl-38862031

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Volatile oil is widely used in traditional Chinese medicine owing to its unique hydrophobic and lipophilic properties and rapid skin absorption. Artemisia annua L. (A.annua) essential oil (AAEO), a volatile oil extracted from A. annua, exhibits anti-inflammatory properties. However, few studies have investigated its effects on skin inflammation. AIM OF THE STUDY: To investigate and elucidate the mechanisms of action of AAEO in the treatment of atopic dermatitis (AD). MATERIALS AND METHODS: Network pharmacology was used to predict the targets and pathways of AAEO for the treatment of AD. The AD mouse model was established by topical application of 2,4-dintrochlorobenzene (DNCB), AAEO, and the positive control drug hydrocortisone butyrate cream (HBC). We evaluated the symptoms of AD, SCORAD scores, histological analysis, and serum IgE and TNF-α levels in mice. Immunofluorescence, western blotting, and qPCR were used to investigate the signaling pathways. RESULTS: Network pharmacology analysis indicated that AAEO may exert its effects via the MAPK/NF-κB signaling pathway. Animal experiments demonstrated that topical application of AAEO and HBC significantly ameliorated skin lesions, reduced dermatitis score, and decreased spleen weight compared to DNCB treatment. AAEO reduced skin epidermal thickness and mast cell infiltration. DNCB markedly reduced the protein levels of filaggrin (FLG) and loricrin (LOR), whereas AAEO reversed these changes. Notably, the 5% concentration of AAEO demonstrated substantial improvement in skin barrier function. Compared to the DNCB group, the levels of FLG and LOR remained almost unchanged following HBC treatment. DNCB markedly elevated IgE and TNF-α levels, which were reversed by AAEO and HBC treatment. Among the inflammatory cytokines, DNCB increased mRNA expression of TNF-α, IL-1ß, and IL-6, however, it reduced IL-10, with AAEO and HBC reversing these changes to various degrees. Additionally, DNCB-induced ERK, JNK, and P38 phosphorylation, associated with the upregulation of phosphorylation of NF-κB, whereas, AAEO and HBC exhibited potent inhibition of the MAPK/NF-κB signaling pathway. CONCLUSIONS: This study systematically demonstrated the possible therapeutic effects and mechanisms of AAEO in AD via network pharmacological analysis and experimental confirmation. These results revealed that topical application of AAEO can suppress skin inflammation and restore skin barrier function. These findings provide the potential application of AAEO in synthesizing external preparations for both pharmacological and cosmetic industries.


Subject(s)
Artemisia annua , Dermatitis, Atopic , Dinitrochlorobenzene , Filaggrin Proteins , Mice, Inbred BALB C , Oils, Volatile , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Oils, Volatile/pharmacology , Oils, Volatile/administration & dosage , Oils, Volatile/chemistry , Mice , Artemisia annua/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/administration & dosage , NF-kappa B/metabolism , Skin/drug effects , Skin/pathology , Skin/metabolism , Disease Models, Animal , Male , Administration, Cutaneous , Immunoglobulin E/blood , Administration, Topical , Signal Transduction/drug effects , Membrane Proteins/metabolism , Membrane Proteins/genetics
7.
Biomed Pharmacother ; 176: 116911, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38861857

ABSTRACT

Atopic dermatitis (AD) is a globally increasing chronic inflammatory skin disease with limited and potentially side-effect-prone treatment options. Monotropein is the predominant iridoid glycoside in Morinda officinalis How roots, which has previously shown promise in alleviating AD symptoms. This study aimed to systematically investigate the pharmacological effects of monotropein on AD using a 2, 4-dinitrochlorobenzene (DNCB)/Dermatophagoides farinae extract (DFE)-induced AD mice and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated keratinocytes. Oral administration of monotropein demonstrated a significant reduction in AD phenotypes, including scaling, erythema, and increased skin thickness in AD-induced mice. Histological analysis revealed a marked decrease in immune cell infiltration in skin lesions. Additionally, monotropein effectively downregulated inflammatory markers, encompassing pro-inflammatory cytokines, T helper (Th)1 and Th2 cytokines, and pro-inflammatory chemokines in skin tissues. Notably, monotropein also led to a considerable decrease in serum immunoglobulin (Ig)E and IgG2a levels. At a mechanistic level, monotropein exerted its anti-inflammatory effects by suppressing the phosphorylation of Janus kinase / signal transducer and activator of transcription proteins in both skin tissues of AD-induced mice and TNF-α/IFN-γ-stimulated keratinocytes. In conclusion, monotropein exhibited a pronounced alleviation of AD symptoms in the experimental models used. These findings underscore the potential application of monotropein as a therapeutic agent in the context of AD, providing a scientific basis for further exploration and development.


Subject(s)
Dermatitis, Atopic , Janus Kinases , Keratinocytes , Signal Transduction , Skin , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Dermatitis, Atopic/chemically induced , Signal Transduction/drug effects , Mice , Janus Kinases/metabolism , Skin/drug effects , Skin/pathology , Skin/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Cytokines/metabolism , Mice, Inbred BALB C , STAT Transcription Factors/metabolism , Humans , Dinitrochlorobenzene , Anti-Inflammatory Agents/pharmacology , Female , Disease Models, Animal , Inflammation/drug therapy , Inflammation/pathology , Immunoglobulin E/blood , Dermatophagoides farinae/immunology , Iridoids/pharmacology
8.
ACS Appl Mater Interfaces ; 16(26): 33121-33134, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38910289

ABSTRACT

Atopic dermatitis (AD) is a chronic and recurrent inflammatory disease caused by abnormalities in skin immunoregulation. House dust mite can directly damage the skin barrier and thus sensitize the skin, which is one of the main allergens inducing AD in humans and widely exists in daily life. Meanwhile, the accompanying bacterial infections and exposure to additional allergens exacerbate the condition by generating excessive reactive oxygen species (ROS). Herein, we have developed the CPDP hydrogel with injectable and self-healing ability to combat pathogenic microorganisms and inflammatory environments for AD therapy. In vitro experiments have affirmed the efficacy of the CPDP hydrogel in combating mites, killing bacteria, and scavenging ROS. In a mouse model closely mimicking HDM-induced AD, the CPDP hydrogel has shown superior therapeutic effects, including reducing epidermal thickness and mast cell count, increasing collagen deposition, as well as down-regulating pro-inflammatory factors.


Subject(s)
Dermatitis, Atopic , Hydrogels , Pyroglyphidae , Reactive Oxygen Species , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Dermatitis, Atopic/chemically induced , Animals , Reactive Oxygen Species/metabolism , Mice , Hydrogels/chemistry , Hydrogels/pharmacology , Pyroglyphidae/immunology , Inflammation/drug therapy , Humans , Mice, Inbred BALB C , Disease Models, Animal
9.
Sci Rep ; 14(1): 12874, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38834629

ABSTRACT

Atopic dermatitis is a chronic complex inflammatory skin disorder that requires sustainable treatment methods due to the limited efficacy of conventional therapies. Sargassum serratifolium, an algal species with diverse bioactive substances, is investigated in this study for its potential benefits as a therapeutic agent for atopic dermatitis. RNA sequencing of LPS-stimulated macrophages treated with ethanolic extract of Sargassum serratifolium (ESS) revealed its ability to inhibit a broad range of inflammation-related signaling, which was proven in RAW 264.7 and HaCaT cells. In DNCB-induced BALB/c or HR-1 mice, ESS treatment improved symptoms of atopic dermatitis within the skin, along with histological improvements such as reduced epidermal thickness and infiltration of mast cells. ESS showed a tendency to improve serum IgE levels and inflammation-related cytokine changes, while also improving the mRNA expression levels of Chi3l3, Ccr1, and Fcεr1a genes in the skin. Additionally, ESS compounds (sargachromanol (SCM), sargaquinoic acid (SQA), and sargahydroquinoic acid (SHQA)) mitigated inflammatory responses in LPS-treated RAW264.7 macrophages. In summary, ESS has an anti-inflammatory effect and improves atopic dermatitis, ESS may be applied as a therapeutics for atopic dermatitis.


Subject(s)
Dermatitis, Atopic , Dinitrochlorobenzene , Disease Models, Animal , Mice, Inbred BALB C , Sargassum , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Sargassum/chemistry , Mice , RAW 264.7 Cells , Humans , Ethanol/chemistry , Plant Extracts/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Skin/drug effects , Skin/pathology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Immunoglobulin E/blood , Cytokines/metabolism
10.
Immunopharmacol Immunotoxicol ; 46(4): 529-537, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38918174

ABSTRACT

OBJECTIVE: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. METHODS: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. RESULTS: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. CONCLUSION: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.


Subject(s)
Disease Models, Animal , Janus Kinase 1 , Janus Kinase 3 , Protein Serine-Threonine Kinases , Sulfonamides , Animals , Mice , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 3/antagonists & inhibitors , Sulfonamides/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Female , Autoimmune Diseases/drug therapy , Autoimmune Diseases/pathology , Purines/pharmacology , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/immunology , Azetidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Psoriasis/drug therapy , Psoriasis/immunology , Psoriasis/pathology , Psoriasis/chemically induced , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/pathology , Pyrazoles
11.
J Dermatolog Treat ; 35(1): 2333016, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38839072

ABSTRACT

Dupilumab is a novel treatment agent for moderate to severe atopic dermatitis (AD) with few adverse effects. Drug-induced psoriasiform lesions are rare.We report a 4-year-old boy with AD who developed pustular psoriasis during treatment with dupilumab.Pustular psoriasis appeared within 1 week of treatment and worsened in the second week. After stopping dupilumab administration, topical corticosteroids (desonide and mometasone furoate creams) and oral desloratadine without relief. Pustular psoriasis was confirmed by pathological examination, and thiamphenicol was administered. After 2 weeks of treatment, the lesions nearly resolved without recurrence in 1-year follow-up.Dupilumab-induced pustular psoriasis is rare in children.


Subject(s)
Antibodies, Monoclonal, Humanized , Dermatitis, Atopic , Psoriasis , Humans , Male , Psoriasis/chemically induced , Psoriasis/drug therapy , Psoriasis/pathology , Antibodies, Monoclonal, Humanized/adverse effects , Child, Preschool , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Mometasone Furoate , Dermatologic Agents/adverse effects
12.
J Dermatol Sci ; 115(1): 2-12, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38845244

ABSTRACT

BACKGROUND: Atopic dermatitis (AD), a chronic inflammatory skin disease with T cell activation as a key feature, in which Th2 cell-mediated responses play a pivotal role. Regulatory T cells (Treg) are central immune cells that restrict autoimmunity and inflammation in the body. Patients with immune dysregulation, polyendocrinopathy, or enteropathy X-linked syndrome, an immune disease characterized by a deficiency in Treg, develop skin inflammation and allergic disorders, indicating that Treg play a crucial role in the development of allergic skin inflammation. OBJECTIVE: we investigated the underlying mechanisms by which Treg control cutaneous allergic inflammation. METHODS: An allergic skin inflammation mouse model was constructed using MC903, and Treg-depleted mouse model was constructed using diphtheria toxin. Neutralization of IFN-γ was constructed using anti-mouse-IFN-γ mouse antibody. Neutrophil infiltration was analyzed by flow cytometry and immunohistochemistry. Neutrophil extracellular traps (NETs), a process called NETosis, were detected using immunofluorescence. In vitro neutrophil stimulation and immunocytochemistry was conducted to demonstrate the effect of IFN-γ on NETosis. RESULTS: The depletion of Foxp3+ Treg led to significantly exacerbated AD-like skin inflammation, including increased recruitment of neutrophils and expression of Th1 cytokine IFN-γ. Neutrophil infiltrating in skin of Treg-depleted mice released more NETs than wild type. Neutralization of IFN-γ abolished neutrophil infiltration and NETosis in Treg-depleted mice. Neutrophils stimulated with IFN-γ were more prone to release NETs in vitro. Finally, Foxp3+ Treg control cutaneous allergic inflammation by regulating IFN-γ-driven neutrophilic infiltration and NETosis. CONCLUSION: Our results highlight the previously underestimated Treg-IFN-γ-neutrophil inflammatory axis.


Subject(s)
Dermatitis, Atopic , Disease Models, Animal , Extracellular Traps , Forkhead Transcription Factors , Interferon-gamma , Neutrophil Infiltration , Neutrophils , Skin , T-Lymphocytes, Regulatory , Animals , T-Lymphocytes, Regulatory/immunology , Interferon-gamma/metabolism , Interferon-gamma/immunology , Forkhead Transcription Factors/metabolism , Mice , Extracellular Traps/immunology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Dermatitis, Atopic/chemically induced , Skin/immunology , Skin/pathology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Neutrophils/metabolism , Humans , Mice, Inbred C57BL , Female
13.
J Dermatol Sci ; 114(3): 104-114, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38806322

ABSTRACT

BACKGROUND: Although several mouse models of exogenous-agent-induced atopic dermatitis (AD) are currently available, the lack of certainty regarding their similarity with human AD has limited their scientific value. Thus, comprehensive evaluation of the characteristics of mouse models and their similarity with human AD is essential. OBJECTIVE: To compare six different exogenous-agent-induced AD mouse models and find out the optimum models for study. METHODS: Female BALB/c mice underwent induction of AD-like dermatitis by MC903 alone or in combination with ovalbumin (OVA), dinitrofluorobenzene (DNFB) alone or in combination with OVA, OVA alone, or Staphylococcus aureus. Gross phenotype, total immunoglobulin E (IgE) level, histopathological manifestations, and skin lesion transcriptome were analyzed, and metagenomic sequencing of the gut microbiome was performed. RESULTS: The DNFB plus OVA model showed the highest disease severity, while the OVA model showed the lowest severity. The MC903 and MC903 plus OVA models showed high expression of T-helper (Th)2- and Th17-related genes; the DNFB and DNFB plus OVA models showed upregulation of Th1-, Th2-, and Th17-related genes; while the S. aureus inoculation model showed more enhanced Th1 and Th17 immune responses. In contrast to the other models, the OVA-induced model showed the lowest expression levels of inflammation-related genes, while the MC903 model shared the largest overlap with human AD profiles. The intestinal microbiota of all groups showed significant differences after modeling. CONCLUSION: Each AD mouse model exhibited different characteristics. The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent-induced AD models.


Subject(s)
Dermatitis, Atopic , Dinitrofluorobenzene , Disease Models, Animal , Mice, Inbred BALB C , Ovalbumin , Phenotype , Staphylococcus aureus , Transcriptome , Animals , Dermatitis, Atopic/immunology , Dermatitis, Atopic/microbiology , Dermatitis, Atopic/chemically induced , Female , Mice , Ovalbumin/immunology , Staphylococcus aureus/immunology , Humans , Skin/immunology , Skin/pathology , Skin/microbiology , Immunoglobulin E/blood , Immunoglobulin E/immunology , Gastrointestinal Microbiome/immunology , Severity of Illness Index , Gene Expression Profiling , Calcitriol/analogs & derivatives
14.
Biomed Pharmacother ; 176: 116765, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38788600

ABSTRACT

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and chronic inflammatory responses. Reynoutria japonica, known as Huzhang in traditional Chinese Medicine, can enhance blood circulation to eliminate wind pathogens and terminate coughing. Despite pharmacological evidence supporting the efficacy of R. japonica in suppressing edema-induced skin inflammation or connective tissue diseases, its pharmaceutical potential for treating AD-like skin inflammation remains unexplored. This study investigated the possible effects of R. japonica ethanol extract (RJE) on Dermatophagoides farinae extract (DfE)-induced AD-like skin inflammation in NC/Nga mice. To elucidate the underlying mechanisms by which RJE inhibits skin inflammation, we examined the effect of RJE on IFN-γ/TNF-α-induced signal transducer and activator of transcription (STAT) signaling in human epidermal keratinocytes (HEKs) and human dermal fibroblasts (HDFs). Our findings revealed that RJE mitigates DfE-induced AD-like symptoms and skin barrier disruptions in mouse skin lesions. Moreover, RJE attenuated DfE-induced mast cell infiltration and serum levels of inflammatory cytokines (IL-1α, IL-1ß, IL-6, IL-23, IFN-γ, TNF-α, and GM-CSF). RJE also inhibited IFN-γ/TNF-α-induced chemokine levels and STAT3 phosphorylation in HEKs and HDFs. Virtual binding analysis of the RJE components suggested that emodin-8-ß-D-glucoside binds to Janus kinase (JAK) 1/2, thereby suppressing STAT signaling, which was confirmed by Western blot analysis. In conclusion, our results suggest that RJE may alleviate DfE-induced skin barrier dysfunction by inhibiting JAK/STAT signaling and the proinflammatory immune response through the suppression of inflammatory mediators in AD-like skin disease. These findings suggest that RJE has potential as an effective therapy for AD management.


Subject(s)
Dermatitis, Atopic , Dermatophagoides farinae , Janus Kinases , STAT Transcription Factors , Signal Transduction , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Dermatitis, Atopic/chemically induced , Signal Transduction/drug effects , Mice , STAT Transcription Factors/metabolism , Janus Kinases/metabolism , Humans , Glucosides/pharmacology , Cytokines/metabolism , Male , Skin/drug effects , Skin/pathology , Skin/metabolism , Emodin/pharmacology , Emodin/analogs & derivatives , Keratinocytes/drug effects , Keratinocytes/metabolism , Plant Extracts/pharmacology , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology
15.
Chem Biodivers ; 21(8): e202400349, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38818651

ABSTRACT

BACKGROUND: Atopic dermatitis (AD) has various detrimental effects on individuals with limited drug cure rates which necessitate the development of new treatment methods. PL-ReliefTMplus (PLR) is composed of SupraOlive, Crocus Sativus extracts and Citrus reticulata extracts. The effect of PLR on AD remains to be explored. METHODS: 2,4-dinitrofluorobenzene-induced AD model mice were involved and the histopathology of the skin lesions was observed along with the levels of inflammatory chemokines levels were measured. To further validate the molecular mechanism of PLR, RNA-seq was performed in HaCaT cells. Western blotting and immunofluorescence were performed to investigate NF-κB signaling pathways response in AD. RESULTS: Due to PLR treatment, the thickening of the epidermis and dermis was inhibited and the number of eosinophils, mast cells, and CD4+ T cells in the skin lesion was decreased. In addition, the levels of inflammatory cytokines were decreased in dorsal skin tissues and LPS-stimulated HaCat cells. Furthermore, KEGG pathway analysis suggested that most identified downstream biological functions were associated with inflammatory response. PLR inhibited NF-κB signaling in AD mice and HaCaT cells. CONCLUSIONS: These results indicate that PLR is a potent therapeutic agent for attenuating symptoms of AD.


Subject(s)
Dermatitis, Atopic , NF-kappa B , Signal Transduction , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Dermatitis, Atopic/metabolism , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Animals , Signal Transduction/drug effects , Mice , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , Dinitrofluorobenzene , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Inflammation/chemically induced , Disease Models, Animal , Citrus/chemistry , HaCaT Cells , Mice, Inbred BALB C , Cytokines/metabolism
16.
Arch Toxicol ; 98(7): 2173-2183, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38616237

ABSTRACT

This study investigated the immunotoxic effects of the mycotoxin nivalenol (NIV) using antigen-presenting cells and a mouse model of atopic dermatitis (AD). In vitro experiments were conducted using a mouse macrophage cell line (RAW 264.7) and mouse dendritic cell line (DC 2.4). After cells were exposed to NIV (0.19-5 µmol) for 24 h, the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNFα) was quantified. To further investigate the inflammatory cytokine production pathway, the possible involvement of mitogen-activated protein kinase (MAPK) pathways, such as ERK1/2, p-38, and JNK, in NIV exposure was analyzed using MAPK inhibitors and phosphorylation analyses. In addition, the pro-inflammatory effects of oral exposure to NIV at low concentrations (1 or 5 ppm) were evaluated in an NC/Nga mouse model of hapten-induced AD. In vitro experiments demonstrated that exposure to NIV significantly enhanced the production of TNFα. In addition, it also directly induced the phosphorylation of MAPK, indicated by the inhibition of TNFα production following pretreatment with MAPK inhibitors. Oral exposure to NIV significantly exacerbated the symptoms of AD, including a significant increase in helper T cells and IgE-produced B cells in auricular lymph nodes and secretion of pro-inflammatory cytokines, such as IL-4, IL-5, and IL-13, compared with the vehicle control group. Our findings indicate that exposure to NIV directly enhanced the phosphorylation of ERK1/2, p-38, and JNK, resulting in a significant increase in TNFα production in antigen-presenting cells, which is closely related to the development of atopic dermatitis.


Subject(s)
Cytokines , Dermatitis, Atopic , Trichothecenes , Animals , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/immunology , Trichothecenes/toxicity , Trichothecenes/administration & dosage , Mice , Administration, Oral , Cytokines/metabolism , RAW 264.7 Cells , Mitogen-Activated Protein Kinases/metabolism , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , MAP Kinase Signaling System/drug effects , Disease Models, Animal , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Dendritic Cells/immunology , Phosphorylation , Male , Tumor Necrosis Factor-alpha/metabolism , Female
17.
J Hazard Mater ; 470: 134226, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38593665

ABSTRACT

Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.


Subject(s)
Paraffin , Humans , Adolescent , Child , Male , Female , China/epidemiology , Paraffin/toxicity , Paraffin/analysis , Hypersensitivity/epidemiology , Environmental Exposure/adverse effects , Hydrocarbons, Chlorinated/toxicity , Hydrocarbons, Chlorinated/analysis , Air Pollutants/toxicity , Air Pollutants/analysis , Particulate Matter/toxicity , Particulate Matter/analysis , Dermatitis, Atopic/epidemiology , Dermatitis, Atopic/chemically induced , Rhinitis, Allergic/epidemiology , Rhinitis, Allergic/chemically induced
18.
J Dermatol ; 51(9): 1252-1255, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38507442

ABSTRACT

Bullous pemphigoid (BP), an autoimmune bullous dermatosis, occurs predominantly in older individuals. Nemolizumab, a humanized monoclonal antibody against the interleukin (IL)-31 receptor A, is used to treat severe atopic dermatitis (AD) in Japan. However, it can cause several adverse events, such as exacerbation of AD, erythema, and eosinophilia. Herein, we describe a case of prurigo-type AD developing BP after nemolizumab administration. A 62-year-old man with prurigo-type AD and asthma presented with serious, refractory itching. After nemolizumab injection, his pruritus was relieved for 2 days. However, on day 3, erythema with blisters and erosions suddenly appeared throughout his body. Pathological examination showed typical BP and the patient's serum anti-BP180-NC16a antibody level was 882.5 U/mL. Oral prednisolone (PSL) was initiated and nemolizumab was never used again. Despite high-dose PSL, new blisters continued to develop, with a rapid elevation of anti-BP180-NC16a antibodies to 6930 U/mL. Adding high-dose cyclosporine and intravenous gamma globulin reduced new blister formation after 9 weeks, and PSL and cyclosporine were gradually tapered. Dupilumab, an anti-IL-4 receptor antibody, was initiated after 16 weeks, resulting in continued remission without PSL and cyclosporine. The sudden occurrence of BP in this case suggested that the patient had occult BP before the nemolizumab initiation and that nemolizumab exacerbated BP and made it overt. Blocking the IL-31 pathway may exacerbate inflammation in AD or BP, resulting in the acceleration of blister formation. This may be countered by blocking the IL-4/13 pathway with dupilumab. To our knowledge, this is the first case of nemolizumab-exacerbated BP.


Subject(s)
Antibodies, Monoclonal, Humanized , Pemphigoid, Bullous , Receptors, Interleukin , Humans , Pemphigoid, Bullous/chemically induced , Pemphigoid, Bullous/immunology , Pemphigoid, Bullous/diagnosis , Pemphigoid, Bullous/drug therapy , Male , Antibodies, Monoclonal, Humanized/adverse effects , Middle Aged , Receptors, Interleukin/antagonists & inhibitors , Receptors, Interleukin/immunology , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Dermatitis, Atopic/chemically induced , Non-Fibrillar Collagens/immunology , Collagen Type XVII , Prurigo/immunology , Prurigo/chemically induced , Prurigo/drug therapy , Prurigo/diagnosis , Prurigo/pathology , Autoantigens/immunology , Prednisolone/therapeutic use , Autoantibodies/blood , Autoantibodies/immunology , Skin/pathology , Skin/drug effects , Cyclosporine/adverse effects , Cyclosporine/therapeutic use
19.
Life Sci ; 344: 122560, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38490296

ABSTRACT

AIMS: Ursodeoxycholic acid (UDCA) is a hydrophilic dihydroxy bile acid used for cholestatic liver disease and exhibits antioxidant, antitumor, and anti-inflammatory effects. However, its potential effects on atopic dermatitis (AD) have not been elucidated. This study aimed to evaluate the efficacy of UDCA in inhibiting the inflammatory response and alleviating lesions in AD-like mice. MAIN METHODS: To investigate the efficacy of UDCA in AD-like inflammatory responses, tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-stimulated HaCaT cells and anti-dinitrophenyl immunoglobulin E (DNP-IgE)- and human serum albumin (HSA)-stimulated RBL-2H3 cells were used to investigate the levels of inflammatory factors and their mechanisms. AD-like lesions were induced by applying DNCB/DFE to mice. The effect of UDCA administration in AD-like mice was analyzed by assessing organ weight, serum IgE and inflammatory cytokine levels, and histopathological changes using immunohistochemical and immunofluorescent staining. KEY FINDINGS: In HaCaT cells, UDCA significantly diminished TARC, MDC, MCP-1, and IL-6 expression by inhibiting the phosphorylation of nuclear NF-κB and cytoplasmic IκB, and also increased the levels of skin barrier protein. In RBL-2H3 cells, UDCA reduced ß-hexosaminidase and IL-4 levels. In AD-like mice, UDCA suppressed organ hypertrophy, ear edema, SCORAD index, DFE-specific IgE levels, inflammatory cytokine levels, skin hypertrophy, mast cell invasion, skin barrier loss, and thymic stromal lymphopoietin-positive areas. SIGNIFICANCE: UDCA suppressed the expression of pro-inflammatory cytokines by keratinocytes and mast cells. It also alleviated atopy by suppressing symptoms without organ toxicity in AD-like mice. UDCA may be an effective and safe treatment for AD.


Subject(s)
Dermatitis, Atopic , Humans , Animals , Mice , Rats , Dermatitis, Atopic/chemically induced , Skin , Dinitrochlorobenzene , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/metabolism , Cytokines/metabolism , NF-kappa B/metabolism , Immunoglobulin E , Hypertrophy/metabolism , Mice, Inbred BALB C
20.
J Med Chem ; 67(6): 4855-4869, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38489246

ABSTRACT

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.


Subject(s)
Dermatitis, Atopic , Lignans , Phosphodiesterase 4 Inhibitors , Mice , Animals , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic use , Dinitrochlorobenzene/pharmacology , Dinitrochlorobenzene/therapeutic use , Lignans/pharmacology , Lignans/therapeutic use , Tumor Necrosis Factor Inhibitors/pharmacology , Tumor Necrosis Factor Inhibitors/therapeutic use , Cytokines/pharmacology , Skin
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