RESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by increased sensitivity to environmental allergens and irritants. Icariin, a natural compound extracted from the herb Epimedium, has been traditionally used for its potential anti-inflammatory and antioxidant properties. This study aimed to investigate the regulatory effects of icariin on AD-like symptoms and to elucidate its underlying mechanisms. The effects of icariin on TNF-α/IFN-γ-induced HaCaT cell injury were assessed using various assays, including cell counting kit-8 for cell viability, flow cytometry for reactive oxygen species (ROS) levels, and colorimetric assays for malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. In addition, the study performed enzyme-linked immunosorbent assays to assess cytokines (IL-1ß, IL-6, and IL-8) and chemokines (MDC, TARC, and RANTES) levels. Flow cytometry was used to quantify apoptotic rate, while a wound-healing assay was conducted to assess cell migration. The expression of WT1 associated protein (WTAP) and serpin family B member 4 (SERPINB4) at the mRNA and protein levels was determined using qRT-PCR and western blotting, respectively. The associations between WTAP and SERPINB4 were analyzed using RNA immunoprecipitation assay and m6A RNA immunoprecipitation assay. Icariin treatment significantly mitigated TNF-α/IFN-γ-induced oxidative stress, inflammatory response, and apoptosis in HaCaT cells, while also reversing the inhibitory effect on cell migration. Icariin reduced the expression of WTAP in TNF-α/IFN-γ-stimulated HaCaT cells. Overexpression of WTAP reversed the effects of icariin in TNF-α/IFN-γ-stimulated HaCaT cells. WTAP silencing inhibited the mRNA stability of SERPINB4 through the m6A modification. SERPINB4 overexpression attenuated the effects of WTAP silencing on oxidative stress, inflammatory response, apoptosis, and migration of TNF-α/IFN-γ-stimulated HaCaT cells. Icariin treatment downregulated SERPINB4 expression by regulating WTAP in TNF-α/IFN-γ-stimulated HaCaT cells. Icariin ameliorated TNF-α/IFN-γ-induced human immortalized epidermal cell injury through the WTAP/SERPINB4 axis, highlighting the potential for targeted interventions in AD pathogenesis.
Assuntos
Apoptose , Dermatite Atópica , Flavonoides , Células HaCaT , Interferon gama , Estresse Oxidativo , Fator de Necrose Tumoral alfa , Humanos , Flavonoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Interferon gama/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dermatite Atópica/metabolismo , Serpinas/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Movimento Celular/efeitos dos fármacos , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Citocinas/metabolismoRESUMO
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder, that emerges from intricate interplays among genetic predisposition, immune dysregulation, environmental factors, and compromised skin barrier. Understanding the inflammatory pathway in AD is important due to its fundamental role in the pathogenesis of AD. This study aimed to explore the diverse spectrum of proteins linked to the inflammation of AD and the relationship between systemic biomarkers and clinical severity in AD. METHODS: We examined the blood samples from 48 patients with AD and 48 healthy controls (HCs) using the Proximity Extension Assay (Olink). Differentially expressed proteins (DEPs) were identified and Pearson correlation analysis was conducted to determine systemic proteomic biomarkers associated with severity of AD. RESULTS: A total of 29 DEPs were significantly up-regulated and 2 DEPs were significantly down-regulated in AD compared with the HC. The MCP-4, IL-18, MCP-3, TNFRSF9, and IL-17C were the top 5 highest DEPs associated with the severity of AD. CONCLUSION: Our study sheds light on the intricate network of inflammatory proteins in AD and their potential implications for disease severity. Our results indicate that these systemic inflammatory proteins could be valuable for assessing AD severity and enhancing our understanding of the disease's complexity and its potential management strategies.
Assuntos
Biomarcadores , Dermatite Atópica , Proteômica , Índice de Gravidade de Doença , Humanos , Dermatite Atópica/sangue , Dermatite Atópica/patologia , Dermatite Atópica/diagnóstico , Biomarcadores/sangue , Biomarcadores/metabolismo , Feminino , Masculino , Adulto , Estudos de Casos e Controles , Adulto Jovem , Inflamação/metabolismo , Adolescente , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Atopic dermatitis (AD) is characterized by compositional and structural changes to the skin at lesional sites. Alteration to the levels and organization of both protein and lipid components are associated with disease status and lead to impaired barrier and hydration. Corneodesmosin (CDSN) and the arrangement and length of the intercellular lipid lamellae (ICLL) are altered in disrupted skin states. The aim of this research was to profile the distribution of CDSN and the ICLL in the stratum corneum (SC) at lesional and non-lesional sites in AD-prone skin and to investigate the impact of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. METHODS: An IRB-approved study was conducted with participants with active AD. From a small subset of participants, tape strips were collected from lesional and non-lesional sites on the arm, prior to and after twice daily application, over 4 weeks of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. Fluorescent antibody staining was used to investigate the distribution of CDSN. Transmission electron microscopy (TEM) was used to characterize the ICLL. RESULTS: The distribution/coverage of CDSN was similar between lesional and non-lesional sites at baseline; application of the lotion resulted in a more defined honeycomb/peripheral distribution. Normalized ICLL (nICLL) was lower in baseline samples from lesional sites relative to non-lesional sites. Application of the lotion increased this parameter by the end of the study at all sites. CONCLUSION: The eczema calming lotion containing petroleum jelly, fatty acids and colloidal oatmeal provided changes in corneodesmosomal proteins distribution and ICLL, consistent with improvements in corneocyte maturation and improved barrier function in the skin of individuals with atopic dermatitis.
OBJECTIF: La dermatite atopique (DA) est caractérisée par des modifications de la composition et de la structure de la peau au niveau des sites lésionnels. L'altération des taux et de l'organisation des composants protéiques et lipidiques est associée au statut de la maladie, et entraîne une altération de la barrière et de l'hydratation. La cornéodesmosine (CDSN), et la disposition et la longueur des lamelles lipidiques intercellulaires (LLIC) sont altérées dans les états cutanés perturbés. L'objectif de cette étude était d'établir le profil de la distribution de la CDSN et des LLIC dans la couche cornée (CC) au niveau des sites lésionnels et non lésionnels dans la peau sujette à la DA, et d'étudier l'impact d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. MÉTHODES: Une étude approuvée par un CPP a été menée auprès de participants atteints de DA active. Dans un petit sousensemble de participants, des bandes adhésives ont été prélevées sur des sites lésionnels et non lésionnels du bras, avant et après l'application deux fois par jour pendant 4 semaines d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. Une coloration par anticorps fluorescents a été utilisée pour étudier la distribution de la CDSN. La microscopie électronique en transmission (MET) a été utilisée pour caractériser les LLIC. RÉSULTATS: La distribution/couverture de la CDSN était similaire entre les sites lésionnels et non lésionnels à l'entrée dans l'étude; l'application de la lotion a entraîné une distribution en nid d'abeille/périphérique plus définie. Le taux normalisé de LLIC (LLICn) était plus faible dans les échantillons prélevés à l'entrée dans l'étude au niveau des sites lésionnels par rapport aux sites non lésionnels. L'application de la lotion a augmenté ce paramètre à la fin de l'étude pour tous les sites. CONCLUSIONS: La lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale a entraîné des changements dans la distribution des protéines cornéodesmosomales et des LLIC, ce qui correspond à des améliorations de la maturation des cornéocytes et de la fonction de barrière de la peau des personnes atteintes de dermatite atopique.
Assuntos
Dermatite Atópica , Humanos , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Adulto , Masculino , Feminino , Glicoproteínas/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipídeos/química , Eczema/tratamento farmacológico , Eczema/patologia , Eczema/metabolismo , Creme para a Pele , Adulto Jovem , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease. Although murine studies have demonstrated that type 2 innate lymphoid cells (ILCs) mediate type 2 skin inflammation, their role in skin fibrosis in AD remains unclear. This study investigated whether type 2 ILCs are involved in skin fibrosis using an AD-like murine model. METHODS: C57BL/6 mice were treated epicutaneously with Aspergillus fumigatus (Af) for 5 consecutive days per week for 5 weeks to induce skin fibrosis. Mature lymphocyte deficient Rag1-/- mice were also used to investigate the role of type 2 ILCs in skin fibrosis. RESULTS: The clinical score and transepidermal water loss (TEWL) were significantly higher in the AD group than in the control group. The AD group also showed significantly increased epidermal and dermal thicknesses and significantly higher numbers of eosinophils, neutrophils, mast cells, and lymphocytes in the lesional skin than the control group. The lesional skin of the AD group showed increased stain of collagen and significantly higher levels of collagen than the control group (10.4 ± 2.2 µg/mg vs. 1.6 ± 0.1 µg/mg, P < 0.05). The AD group showed significantly higher populations of type 2 ILCs in the lesional skin compared to the control group (0.08 ± 0.01% vs. 0.03 ± 0.01%, P < 0.05). These findings were also similar with the AD group of Rag1-/- mice compared to their control group. Depletion of type 2 ILCs with anti-CD90.2 monoclonal antibodies significantly improved clinical symptom score, TEWL, and infiltration of inflammatory cells, and significantly decreased levels of collagen were observed in the AD group of Rag1-/- mice (1.6 ± 0.0 µg/mg vs. 4.5 ± 0.3 µg/mg, P < 0.001). CONCLUSION: In the Af-induced AD-like murine model, type 2 ILCs were elevated, with increased levels of collagen. Additionally, removal of type 2 ILCs resulted in decreased collagen levels and improved AD-like pathological findings. These findings suggest that type 2 ILCs play a role in the mechanism of skin fibrosis in AD.
Assuntos
Dermatite Atópica , Modelos Animais de Doenças , Fibrose , Proteínas de Homeodomínio , Imunidade Inata , Linfócitos , Camundongos Endogâmicos C57BL , Pele , Animais , Dermatite Atópica/patologia , Dermatite Atópica/imunologia , Linfócitos/imunologia , Camundongos , Pele/patologia , Pele/imunologia , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Aspergillus fumigatus/imunologia , Colágeno/metabolismo , Camundongos Knockout , Mastócitos/imunologia , Eosinófilos/patologia , Eosinófilos/imunologia , FemininoRESUMO
The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.
Assuntos
Dermatite Atópica , Interleucina-13 , Interleucinas , Prurigo , Prurido , Humanos , Dermatite Atópica/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/imunologia , Prurigo/metabolismo , Prurigo/patologia , Prurigo/genética , Feminino , Adulto , Masculino , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucinas/metabolismo , Interleucinas/genética , Prurido/metabolismo , Prurido/genética , Pessoa de Meia-Idade , Interleucina-4/metabolismo , Interleucina-4/genética , Doença Crônica , Pele/metabolismo , Pele/patologia , Adulto Jovem , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/genéticaRESUMO
Atopic dermatitis (AD) presents significant therapeutic challenges due to its poorly understood etiology. Eosinophilia, a hallmark of allergic inflammation, is implicated in AD pathogenesis. Interleukin-10 (IL-10)-producing regulatory B (Breg) cells exhibit potent anti-inflammatory effects. However, their role in controlling AD-related eosinophilia is not well understood. To investigate the impact of eosinophils on AD, we employed IL-5Rα-deficient (Il5ra-/-) mice, which lack functional eosinophils. Induction of AD in these mice resulted in attenuated disease symptoms, underscoring the critical role of eosinophils in AD development. Additionally, the adoptive transfer of purified Breg cells into mice with AD significantly alleviated disease severity. Mechanistic studies revealed that IL-10 produced by Breg cells directly inhibits eosinophil activation and infiltration into the skin. In vitro experiments further confirmed that Breg cells inhibited eosinophil peroxidase secretion in an IL-10-dependent manner. Our collective findings demonstrate that IL-10 from Breg cells alleviates AD by suppressing eosinophil activation and tissue infiltration. This study elucidates a novel regulatory mechanism of Breg cells, providing a foundation for future Breg-mediated therapeutic strategies for AD.
Assuntos
Linfócitos B Reguladores , Dermatite Atópica , Eosinófilos , Interleucina-10 , Animais , Dermatite Atópica/imunologia , Dermatite Atópica/terapia , Dermatite Atópica/patologia , Dermatite Atópica/metabolismo , Interleucina-10/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Camundongos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Pele/patologia , Pele/imunologia , Pele/metabolismo , Transferência AdotivaRESUMO
BACKGROUND: Inflammatory skin diseases, such as psoriasis, atopic eczema, and contact dermatitis pose diagnostic challenges due to their diverse clinical presentations and the need for rapid and precise diagnostic assessment. OBJECTIVE: While recent studies described non-invasive imaging devices such as Optical coherence tomography and Line-field confocal OCT (LC-OCT) as possible techniques to enable real-time visualization of pathological features, a standardized analysis and validation has not yet been performed. METHODS: One hundred forty lesions from patients diagnosed with atopic eczema (57), psoriasis (50), and contact dermatitis (33) were imaged using OCT and LC-OCT. Statistical analysis was employed to assess the significance of their characteristic morphologic features. Additionally, a decision tree algorithm based on Gini's coefficient calculations was developed to identify key attributes and criteria for accurately classifying the disease groups. RESULTS: Descriptive statistics revealed distinct morphologic features in eczema, psoriasis, and contact dermatitis lesions. Multivariate logistic regression demonstrated the significance of these features, providing a robust differentiation between the three inflammatory conditions. The decision tree algorithm further enhanced classification accuracy by identifying optimal attributes for disease discrimination, highlighting specific morphologic criteria as crucial for rapid diagnosis in the clinical setting. CONCLUSION: The combined approach of descriptive statistics, multivariate logistic regression, and a decision tree algorithm provides a thorough understanding of the unique aspects associated with each inflammatory skin disease. This research offers a practical framework for lesion classification, enhancing the interpretability of imaging results for clinicians.
Assuntos
Dermatite Atópica , Psoríase , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Psoríase/diagnóstico por imagem , Psoríase/patologia , Dermatite Atópica/diagnóstico por imagem , Dermatite Atópica/patologia , Algoritmos , Feminino , Masculino , Dermatite de Contato/diagnóstico por imagem , Dermatite de Contato/patologia , Adulto , Pele/diagnóstico por imagem , Pele/patologia , Pessoa de Meia-Idade , Diagnóstico Diferencial , Reprodutibilidade dos TestesRESUMO
Sinomenine hydrochloride is an excellent drug with anti-inflammatory, antioxidant, immune-regulatory, and other functions. Atopic dermatitis is an inherited allergic inflammation that causes itchiness, redness, and swelling in the affected area, which can have a significant impact on the life of the patient. There are many therapeutic methods for atopic dermatitis, and sinomenine with immunomodulatory activity might be effective in the treatment of atopic dermatitis. In this study, the atopic dermatitis model was established in experimental mice, and physical experiments were carried out on the mice. In the experiment, sinomenine hydrochloride liposomes-in-hydrogel as a new preparation was selected for delivery. In this case, liposomes were dispersed in the colloidal hydrogel on a mesoscopic scale and could provide specific transfer properties. The results showed that the sinomenine hydrochloride-loaded liposomes-in-hydrogel system could effectively inhibit atopic dermatitis.
Assuntos
Antioxidantes , Dermatite Atópica , Hidrogéis , Lipossomos , Morfinanos , Morfinanos/farmacologia , Morfinanos/química , Morfinanos/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Lipossomos/química , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/administração & dosagem , Hidrogéis/química , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos BALB CRESUMO
Gamma delta (γδ) T cells are a heterogeneous population of cells that play roles in inflammation, host tissue repair, clearance of viral and bacterial pathogens, regulation of immune processes, and tumor surveillance. Recent research suggests that these are the main skin cells that produce interleukin-17 (I-17). Furthermore, γδ T cells exhibit memory-cell-like characteristics that mediate repeated episodes of psoriatic inflammation. γδ T cells are found in epithelial tissues, where many cancers develop. There, they participate in antitumor immunity as cytotoxic cells or as immune coordinators. γδ T cells also participate in host defense, immune surveillance, and immune homeostasis. The aim of this review is to present the importance of γδ T cells in physiological and pathological diseases, such as psoriasis, atopic dermatitis, autoimmune diseases, cancer, and lymphoma.
Assuntos
Doenças Autoimunes , Dermatite Atópica , Linfócitos Intraepiteliais , Linfoma , Psoríase , Humanos , Psoríase/imunologia , Psoríase/patologia , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Animais , Linfoma/imunologia , Linfoma/patologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1ß, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.
Assuntos
Citocinas , Proteínas do Citoesqueleto , Dermatite Atópica , Camundongos Endogâmicos BALB C , Dinâmica Mitocondrial , Triterpenos Pentacíclicos , Triterpenos , Animais , Dinâmica Mitocondrial/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dermatite Atópica/metabolismo , Humanos , Triterpenos/farmacologia , Camundongos , Citocinas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/genética , Linfopoietina do Estroma do Timo , Modelos Animais de Doenças , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células HaCaT , Fosforilação/efeitos dos fármacosRESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex causes involving immune factors. The presence of essential trace elements that support immune system function can influence the development of this condition. This study investigated how serum trace elements impact the pathogenesis of atopic dermatitis. Upon analyzing serum microelements in AD patients and control subjects, it was observed that patients with AD had notably lower zinc levels. Genomic analysis of AD skin revealed distinct gene expression patterns, specifically the increased expression of CXCL10 in the epidermis. The heightened levels of CXCL10 in AD skin lesions were found to correlate with reduced serum zinc levels. Treatment with zinc gluconate showed reduced chemotactic response and CXCL10 release, suggesting its potential to regulate CXCL10 expression of keratinocytes in AD. The mechanism behind this involved the downregulation of STAT phosphorylation through activating PPARα. In the AD-like dermatitis mouse model, zinc gluconate therapy decreased serum IgE levels, alleviated skin lesion severity, reduced skin thickness, and lowered CXCL10 expression, demonstrating its efficacy in managing AD-like skin conditions. These findings indicate that zinc gluconate can reduce inflammation in keratinocytes by activating PPARα, inhibiting STAT signaling, and decreasing CXCL10 release, thus highlighting its potential as a therapeutic target for AD.
Assuntos
Quimiocina CXCL10 , Dermatite Atópica , Gluconatos , Queratinócitos , PPAR alfa , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Quimiocina CXCL10/metabolismo , Animais , Humanos , Gluconatos/farmacologia , PPAR alfa/metabolismo , Masculino , Feminino , Camundongos , Adulto , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Administração Tópica , Dermatite Atópica , Dinitroclorobenzeno , Imunoglobulina E , Camundongos Endogâmicos BALB C , Pele , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Administração Oral , Masculino , Camundongos , Imunoglobulina E/sangue , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Modelos Animais de Doenças , Acetofenonas/administração & dosagem , Acetofenonas/farmacologia , Acetofenonas/uso terapêutico , Eosinófilos/efeitos dos fármacos , Interleucina-4/metabolismo , Mastócitos/efeitos dos fármacosRESUMO
Chronic exposure to harmful pollutants, chemicals, and pathogens from the environment can lead to pathological changes in the epithelial barrier, which increase the risk of developing an allergy. During allergic inflammation, epithelial cells send proinflammatory signals to group 2 innate lymphoid cell (ILC2s) and eosinophils, which require energy and resources to mediate their activation, cytokine/chemokine secretion, and mobilization of other cells. This review aims to provide an overview of the metabolic regulation in allergic asthma, atopic dermatitis (AD), and allergic rhinitis (AR), highlighting its underlying mechanisms and phenotypes, and the potential metabolic regulatory roles of eosinophils and ILC2s. Eosinophils and ILC2s regulate allergic inflammation through lipid mediators, particularly cysteinyl leukotrienes (CysLTs) and prostaglandins (PGs). Arachidonic acid (AA)-derived metabolites and Sphinosine-1-phosphate (S1P) are significant metabolic markers that indicate immune dysfunction and epithelial barrier dysfunction in allergy. Notably, eosinophils are promoters of allergic symptoms and exhibit greater metabolic plasticity compared to ILC2s, directly involved in promoting allergic symptoms. Our findings suggest that metabolomic analysis provides insights into the complex interactions between immune cells, epithelial cells, and environmental factors. Potential therapeutic targets have been highlighted to further understand the metabolic regulation of eosinophils and ILC2s in allergy. Future research in metabolomics can facilitate the development of novel diagnostics and therapeutics for future application.
Assuntos
Hipersensibilidade , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/imunologia , Animais , Eosinófilos/metabolismo , Eosinófilos/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Imunidade Inata , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Linfócitos/metabolismo , Linfócitos/imunologia , Rinite Alérgica/metabolismo , Rinite Alérgica/imunologiaRESUMO
Atopic dermatitis (AD), a prevalent chronic inflammatory disease with multifactorial etiology, features epidermal barrier defects and immune overactivation. Synthetic glucocorticoids (GCs) are widely prescribed for treating AD due to their anti-inflammatory actions; however, mechanisms are incompletely understood. Defective local GC signaling due to decreased production of endogenous ligand and/or GC receptor (GR) levels was reported in prevalent inflammatory skin disorders; whether this is a consequence or contributing factor to AD pathology is unclear. To identify the chromatin-bound cell-type-specific GR protein interactome in keratinocytes, we used rapid immunoprecipitation of endogenous proteins and mass spectrometry identifying 145 interactors that increased upon dexamethasone treatment. GR-interacting proteins were enriched in p53/p63 signaling, including epidermal transcription factors with critical roles in AD pathology. Previous analyses indicating mirrored AD-like phenotypes between P63 overexpression and GR loss in epidermis, and our data show an intricate relationship between these transcription factors in human keratinocytes, identifying TP63 as a direct GR target. Dexamethasone treatment counteracted transcriptional up-regulation of inflammatory markers by IL4/IL13, known to mimic AD, causing opposite shifts in GR and P63 genomic binding. Indeed, IL4/IL13 decreased GR and increased P63 levels in cultured keratinocytes and human epidermal equivalents (HEE), consistent with GR down-regulation and increased P63 expression in AD lesions vs normal skin. Moreover, GR knockdown (GRKD) resulted in constitutive increases in P63, phospho-P38 and S100A9, IL6, and IL33. Also, GRKD culture supernatants showed increased autocrine production of TH2-/TH1-/TH17-TH22-associated factors including IL4, CXCL10, CXCL11, and CXCL8. GRKD HEEs showed AD-like features including hyperplasia and abnormal differentiation, resembling phenotypes observed with GR antagonist or IL4/IL13 treatment. The simultaneous GR/P63 knockdown partially reversed constitutive up-regulation of inflammatory genes in GRKD. In summary, our data support a causative role for GR loss in AD pathogenesis via functional interactions with P63 and autocrine signaling in epidermal keratinocytes.
Assuntos
Comunicação Autócrina , Dermatite Atópica , Dexametasona , Queratinócitos , Receptores de Glucocorticoides , Queratinócitos/metabolismo , Queratinócitos/patologia , Humanos , Dermatite Atópica/patologia , Dermatite Atópica/metabolismo , Dermatite Atópica/genética , Receptores de Glucocorticoides/metabolismo , Dexametasona/farmacologia , Epiderme/metabolismo , Epiderme/patologia , Inflamação/patologia , Inflamação/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
Atopic skin is dry and itchy and lacks integrity. Impaired skin barrier results from altered lipid composition of the skin. A crucial skin lipid, cholesterol, provides flexibility and homeostasis of the cell membranes' lipid bilayer. Cholesterol-based creams and natural oils, especially blackcurrant seed oil, are beneficial for skin care as they hydrate the skin and improve its integrity. The major atopic symptom, skin dryness, can be overcome by the application of porous patches enhanced with cholesterol and natural oil. The base of the patches is constructed of polyimide (PI) nanofibers with cholesterol coatings and externally added blackcurrant seed oil. The presence of cholesterol in PI mats hinders the passage of oil through the patches to the skin, resulting in sustained and prolonged skin hydration. The theoretical and numerical investigations of oil dynamics in porous mats confirmed the experimental results, showing a prolonged skin hydration effect up to 6 h. Additionally, as demonstrated by in vivo tests on atopic mice, cholesterol patches lower serum immunoglobulin E levels and expression of proinflammatory cytokines in the skin, thereby accelerating skin healing. Our results hold great promise for the long-term application of the patches in atopic dermatitis treatment.
Assuntos
Colesterol , Dermatite Atópica , Nanofibras , Pele , Colesterol/química , Nanofibras/química , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Camundongos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Inflamação/tratamento farmacológico , Óleos de Plantas/química , Óleos de Plantas/farmacologia , HumanosRESUMO
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.
Assuntos
Dermatite Atópica , Dinitroclorobenzeno , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Sargassum , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Sargassum/química , Camundongos , Células RAW 264.7 , Humanos , Etanol/química , Extratos Vegetais/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Imunoglobulina E/sangue , Citocinas/metabolismoRESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex etiology that lacks effective treatment. The therapeutic goals include alleviating symptoms, such as moisturizing and applying antibacterial and anti-inflammatory medications. Hence, there is an urgent need to develop a patch that effectively alleviates most of the AD symptoms. In this study, we employed a "green" cross-linking approach of poly(vinyl alcohol) (PVA) using glycerol, and we combined it with polyacrylonitrile (PAN) to fabricate core-shell (CS) nanofibers through electrospinning. Our designed structure offers multiple benefits as the core ensures controlled drug release and increases the strength of the patch, while the shell provides skin moisturization and exudate absorption. The efficient PVA cross-linking method facilitates the inclusion of sensitive molecules such as fermented oils. In vitro studies demonstrate the patches' exceptional biocompatibility and efficacy in minimizing cell ingrowth into the CS structure containing argan oil, a property highly desirable for easy removal of the patch. Histological examinations conducted on an ex vivo model showed the nonirritant properties of developed patches. Furthermore, the eradication of Staphylococcus aureus bacteria confirms the potential use of CS nanofibers loaded with argan oil or norfloxacin, separately, as an antibacterial patch for infected AD wounds. In vivo patch application studies on patients, including one with AD, demonstrated ideal patches' moisturizing effect. This innovative approach shows significant promise in enhancing life quality for AD sufferers by improving skin hydration and avoiding infections.
Assuntos
Antibacterianos , Dermatite Atópica , Staphylococcus aureus , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Antibacterianos/química , Antibacterianos/farmacologia , Humanos , Staphylococcus aureus/efeitos dos fármacos , Nanofibras/química , Adesivo Transdérmico , Adesivos/química , Adesivos/farmacologia , Nanoestruturas/química , Animais , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Atopic dermatitis (AD), a chronic skin condition characterized by itching, redness, and inflammation, is closely associated with heightened levels of endogenous reactive oxygen species (ROS) in the skin. ROS can contribute to the onset and progression of AD through oxidative stress, which leads to the release of proinflammatory cytokines, T-cell differentiation, and the exacerbation of skin symptoms. In this study, we aim to develop a therapeutic antioxidant hydrogel patch for the potential treatment of AD using lignin, a biomass waste material. Lignin contains polyphenol groups that enable it to scavenge ROS and exhibit antioxidant properties. The lignin hydrogel patches, possessing optimized mechanical properties through the control of the lignin and cross-linker ratio, demonstrated high ROS-scavenging capabilities. Furthermore, the lignin hydrogel demonstrated excellent biocompatibility with the skin, exhibiting beneficial properties in protecting human keratinocytes under high oxidative conditions. When applied to an AD mouse model, the hydrogel patch effectively reduced epidermal thickness in inflamed regions, decreased mast cell infiltration, and regulated inflammatory cytokine levels. These findings collectively suggest that lignin serves as a therapeutic hydrogel patch for managing AD by modulating oxidative stress through its ROS-scavenging ability.
Assuntos
Antioxidantes , Dermatite Atópica , Hidrogéis , Lignina , Estresse Oxidativo , Pele , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Lignina/química , Lignina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Camundongos , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Citocinas/metabolismoRESUMO
Atopic dermatitis (AD) is a chronic cutaneous disease with a complex underlying mechanism, and it cannot be completely cured. Thus, most treatment strategies for AD aim at relieving the symptoms. Although corticosteroids are topically applied to alleviate AD, adverse side effects frequently lead to the withdrawal of AD therapy. Tacrolimus (TAC), a calcineurin inhibitor, has been used to treat AD, but its high molecular weight and insolubility in water hinder its skin permeability. Herein, we developed and optimized TAC-loaded chitosan-based nanoparticles (TAC@CNPs) to improve the skin permeability of TAC by breaking the tight junctions in the skin. The prepared nanoparticles were highly loadable and efficient and exhibited appropriate characteristics for percutaneous drug delivery. TAC@CNP was stable for 4 weeks under physiological conditions. CNP released TAC in a controlled manner, with enhanced skin penetration observed. In vitro experiments showed that CNP was non-toxic to keratinocyte (HaCaT) cells, and TAC@CNP dispersed in an aqueous solution was as anti-proliferative as TAC solubilized in a good organic solvent. Importantly, an in vivo AD mouse model revealed that topical TAC@CNP containing ~1/10 of the dose of TAC found in commercially used Protopic® Ointment exhibited similar anti-inflammatory activity to that of the commercial product. TAC@CNP represents a potential therapeutic strategy for the management of AD.
Assuntos
Quitosana , Dermatite Atópica , Nanopartículas , Tacrolimo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Tacrolimo/química , Tacrolimo/farmacologia , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , Quitosana/química , Animais , Nanopartículas/química , Camundongos , Humanos , Portadores de Fármacos/química , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Administração Tópica , Absorção Cutânea/efeitos dos fármacos , Liberação Controlada de Fármacos , Modelos Animais de Doenças , Células HaCaTRESUMO
Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.