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International Immunopharmacology Jan 2020Xanthone is a phenolic compound found in a few higher plant families; it has a variety of biological activities, including antioxidant, anti-inflammatory, and anticancer...
Xanthone is a phenolic compound found in a few higher plant families; it has a variety of biological activities, including antioxidant, anti-inflammatory, and anticancer properties. However, the molecular and cellular mechanisms underlying the activity of xanthone in allergic contact dermatitis (ACD) remain to be explored. Therefore, this study aimed to investigate the regulatory effects of xanthone in ACD in human keratinocytes (HaCaT cell), and human mast cell line (HMC-1 cell) in vitro and in an experimental murine model. The results demonstrated that treatment with xanthone reduced the production of pro-inflammatory cytokines and chemokines including interleukin (IL)-1β, IL-6, IL-8, and expression of chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated HaCaT cells. Xanthone also suppressed the production of pro-inflammatory cytokines, chemokines, and allergic mediators in phorbol myristate acetate/A23187 calcium ionophore (PMACI)-stimulated HMC-1 cells. Xanthone significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) and activation of caspase-1 signaling pathway in vitro model. Additionally, xanthone administration alleviated 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis like-skin lesion by reducing the serum levels of immunoglobulin E (IgE), histamine, and pro-inflammatory cytokines and suppressing MAPKs phosphorylation. Xanthone administration also inhibited mortality due to compound 48/80-induced anaphylactic shock and suppressed the passive cutaneous anaphylaxis (PCA) reaction mediated by IgE. Collectively, these results suggest that xanthone has a potential for use in the treatment of allergic inflammatory diseases.
Topics: Administration, Oral; Anaphylaxis; Animals; Anti-Allergic Agents; Calcimycin; Cell Line; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Inflammation Mediators; Keratinocytes; Male; Mast Cells; Mice; Mitogen-Activated Protein Kinases; Phosphorylation; Skin; Tetradecanoylphorbol Acetate; Xanthones; p-Methoxy-N-methylphenethylamine
PubMed: 31821937
DOI: 10.1016/j.intimp.2019.106061 -
Scientific Reports Jan 2020Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important...
Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36Ra) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn mice. These data indicate that Il36rn mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response.
Topics: Animals; CD4-CD8 Ratio; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Interleukins; Loss of Function Mutation; Mice, Transgenic; Neutrophil Infiltration; Sulfonamides; Toll-Like Receptor 4
PubMed: 31959814
DOI: 10.1038/s41598-020-57550-5 -
Journal of Ethnopharmacology May 2021The flower buds of Sophora japonica L. are a major traditional medicine in China, Japan, and Korea and are used to stop bleeding and 'cool the blood'. Accordingly, they...
ETHNOPHARMACOLOGICAL RELEVANCE
The flower buds of Sophora japonica L. are a major traditional medicine in China, Japan, and Korea and are used to stop bleeding and 'cool the blood'. Accordingly, they are used to treat bleeding haemorrhoids, hypertension, and pyoderma. In addition, it was recently found that the flower buds of S. japonica (SJ) have cosmetic whitening properties.
MATERIALS AND METHODS
Compounds in SJ and their targets and related diseases were investigated using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform. Target gene information was obtained from the UniProt database. Network construction was carried out using Cytoscape 3.72. Contact dermatitis (CD)-related gene searching was performed using the Cytoscape string App. Docking analysis was conducted using AutoDock Vina. Six-week-old Balb/c male mice with DNFB (1-fluoro-2,4-dinitrofluorobenzene)-induced CD were treated with a methanol extract of the flower buds of S. japonica (MESJ), and its effects on skin colour, lesions, and immune cell infiltration, and on histopathological abnormalities such as epidermal hyperplasia were investigated.
RESULTS
Eleven compounds targeted 13 CD-related genes, that is, serum albumin (ALB), prostaglandin G/H synthase (COX) 2, C-X-C motif chemokine (CXCL) 2, CXCL10, ICAM1, IFN-γ, IL-10, IL-1α, IL-1β, IL-2, IL-6, E-selectin, and TNF. In the murine DNFB model, MESJ significantly suppressed scaling, erythema, and skin thickening as compared with DNFB controls and epithelial hyperplasia and immune cell infiltrations induced by repeated DNFB application.
CONCLUSIONS
Our animal study showed that the mode of action of MESJ was closely related to the prevention of epithelial hyperplasia and immune cell infiltration. The results obtained demonstrated that the flower buds of S. japonica offer a potential means of treating CD, and suggest that the therapeutic mechanism of CD is explained by relations between 11 major components of SJ, including kaempferol and quercetin, and 13 CD-related genes.
Topics: Animals; Cyclooxygenase 2; Cytokines; Databases, Factual; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Drugs, Chinese Herbal; Flowers; Gene Expression Regulation; Hyperplasia; Inflammation; Keratosis; Male; Metabolic Networks and Pathways; Mice, Inbred BALB C; Molecular Docking Simulation; Sophora; Mice
PubMed: 33493588
DOI: 10.1016/j.jep.2021.113843 -
International Journal of Molecular... Sep 2022Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, characterized by severe itching and recurrent skin lesions. We hypothesized that a novel...
Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, characterized by severe itching and recurrent skin lesions. We hypothesized that a novel treatment involving calcium-based antimicrobial peptide compounds (CAPCS), a combination of natural calcium extracted from marine shellfish, and a variety of antimicrobial peptides, may be beneficial for AD. We established a dinitrofluorobenzene (DNFB)-induced AD model in BALB/c mice to test our hypothesis. We observed mouse behavior and conducted histopathological and immunohistochemical analyses on skin lesions before and after CAPCS treatment. We also characterized the changes in the levels of cytokines, inflammatory mediators, and Toll-like receptors (TLRs) in plasma and skin lesions. The results showed that (i) topical application of CAPCS ameliorated AD-like skin lesions and reduced scratching behavior in BALB/c mice; (ii) CAPCS suppressed infiltration of inflammatory cells and inhibited the expression of inflammatory cytokines in AD-like skin lesions; (iii) CAPCS reduced plasma levels of inflammatory cytokines; and (iv) CAPCS inhibited TLR2 and TLR4 protein expression in skin lesions. Topical application of CAPCS exhibits a therapeutic effect on AD by inhibiting inflammatory immune responses via recruiting helper T cells and engaging the TLR2 and TLR4 signaling pathways. Therefore, CAPCS may be useful for the treatment of AD.
Topics: Animals; Antimicrobial Peptides; Calcium; Cytokines; Dermatitis, Atopic; Dinitrofluorobenzene; Inflammation Mediators; Mice; Mice, Inbred BALB C; Skin; T-Lymphocytes, Helper-Inducer; Toll-Like Receptor 2; Toll-Like Receptor 4
PubMed: 36232673
DOI: 10.3390/ijms231911371 -
International Immunopharmacology Sep 2018The aim of this study is to determine whether AST2017-01 which consists of Rumex crispus and Cordyceps militaris would improve atopic dermatitis (AD). We analyzed...
The aim of this study is to determine whether AST2017-01 which consists of Rumex crispus and Cordyceps militaris would improve atopic dermatitis (AD). We analyzed anti-AD effects of AST2017-01 and chrysophanol, a bioactive compound of AST2017-01, using a 2,4-dinitrofluorobenzene-induced AD murine model. AST2017-01 and chrysophanol relieved clinical severity in AD-like skin lesions and significantly decreased scratching behavior. The thickness of epidermis and infiltration of inflammatory cells in AD-like skin lesions were reduced by AST2017-01 or chrysophanol. AST2017-01 and chrysophanol significantly suppressed the levels of histamine, immunoglobulin E, thymic stromal lymphopoietin (TSLP), interleukin (IL)-4, IL-6, and tumor necrosis factor-α in serum of AD mice. The protein levels of TSLP, intercellular adhesion molecule-1, and macrophage inflammatory protein 2 were significantly inhibited in the skin lesions. The mRNA expressions of TSLP, thymus and activation-regulated chemokine/CCL17, and C-C chemokine receptor 3 were inhibited in the skin lesions by AST2017-01 or chrysophanol. In addition, AST2017-01 and chrysophanol significantly suppressed the expressions and activities of caspase-1 in the skin lesions. Taken together, these results suggest that AST2017-01 has beneficial effects on AD and may be used as a health functional food in AD.
Topics: Animals; Anthraquinones; Cordyceps; Cytokines; Dermatitis, Atopic; Dinitrofluorobenzene; Disease Models, Animal; Female; Histamine; Mice, Inbred BALB C; Rumex; Skin
PubMed: 30025384
DOI: 10.1016/j.intimp.2018.06.046 -
The Journal of Pharmacy and Pharmacology Feb 2023Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon.
OBJECTIVE
Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon.
METHODS
Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in albino male Sprague-Dawley rats. After 6, 12 and 18 days, macroscopic and microscopic damage, collagen and elastic fibre content were examined. At day 6, pro-fibrotic factors (collagen I and III, hydroxyproline, fibronectin, matrix metalloproteinase-2 and -9), transforming growth factor-beta (TGF-β) signalling [TGF-β, Ras homolog gene family member A (RhoA), phosphorylated small mother against decapentaplegic (pSMAD)-2 and -6] and peristalsis were assessed, and the effects of indomethacin, SC-560 or celecoxib were tested.
KEY FINDINGS
Six days after DNBS administration, significant histopathological signs of fibrotic remodelling were observed in rats. At day 6, pro-fibrotic factors were up-regulated and colonic peristalsis was altered. COX inhibitors reversed the histochemical, molecular and functional changes in the fibrotic colon. COX inhibition reduced TGF-β expression, SMAD2 phosphorylation and RhoA, and increased SMAD6 expression.
CONCLUSIONS
Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-β signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-β/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation.
Topics: Animals; Rats; Colitis; Collagen; Disease Models, Animal; Fibrosis; Matrix Metalloproteinase 2; Prostaglandin-Endoperoxide Synthases; Rats, Sprague-Dawley; Smad Proteins; Transforming Growth Factor beta; Male
PubMed: 36477570
DOI: 10.1093/jpp/rgac073 -
Biochemical and Biophysical Research... Oct 2023Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are common inflammatory diseases. We previously reported attenuated contact hypersensitivity (CHS) responses...
Tolerogenic phenotype of dendritic cells is induced after hapten sensitization followed by attenuated contact hypersensitivity response in atopic dermatitis model NC/Nga mice.
Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are common inflammatory diseases. We previously reported attenuated contact hypersensitivity (CHS) responses in AD model mice using 2,4-dinitrofluorobenzene, reflecting clinical experiments. However, previous studies have not addressed the commonality of findings across haptens and mechanisms focused on dendritic cells (DCs). Thus, this study evaluated CHS responses to fluorescein isothiocyanate (FITC) and DC migration and maturation in the sensitization phase of CHS in AD. CHS responses to FITC were compared between NC/Nga mice without and with AD induction (non-AD and AD mice, respectively). T-cell responses and DC migration and maturation after FITC-induced sensitization were examined in the draining lymph nodes of non-AD and AD mice. AD mice demonstrated reduced CHS responses to FITC under decreased T-cell proliferation following sensitization and interferon-γ production by hapten-specific T cells compared with non-AD mice. In addition, the number of FITCCD11cMHC class II migratory DCs 24 h after FITC sensitization was comparable between non-AD and AD mice. However, FITCCD11cMHC class II migratory DCs in AD mice exhibited lower expression levels of CD80 and CD86 and higher expression levels of PD-L1 and mRNA of transforming growth factor beta than non-AD mice. These findings suggest that attenuated CHS responses may be hapten-independent and the induction of the tolerogenic phenotype of hapten-bearing DCs can contribute to reduced T-cell proliferation after sensitization and CHS responses in AD.
Topics: Mice; Animals; Dermatitis, Atopic; Fluorescein-5-isothiocyanate; Phenotype; Fluorescein; Haptens; Dermatitis, Contact; Dendritic Cells
PubMed: 37611349
DOI: 10.1016/j.bbrc.2023.08.042 -
Pigment Cell & Melanoma Research Jan 2021Post-inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly...
Post-inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for research has not been established. In order to analyze the pathomechanism of PIH, we successfully induced PIH in a hairless version of transgenic mice (hk14-SCF Tg/HRM) that have a human-type epidermis containing melanin by repeated hapten application of 2,4-dinitrofluorobenzene. Histopathologic observation showed epidermal hyperplasia, predominant infiltrations of inflammatory cells, and melanin-containing cells in the dermis just after elicitation of the atopic dermatitis-like condition. At week 2, the findings were similar to the characteristics of PIH, that is, an increase of melanin without spongiosis or liquid degeneration in the epidermis and an increase in dermal melanophages. Dynamic analysis of melanin showed that the melanin in the dermis remained for a longer duration than in the epidermis. Furthermore, immunohistochemical staining revealed that the majority of cells containing melanin were positive for the anti-CD68 antibody, but negative for the anti-F4/80 antibody. These data suggest that novel treatments of PIH should be targeted against macrophages and should eventually lead to the development of new treatment modalities.
Topics: Animals; Disease Models, Animal; Epidermis; Female; Humans; Hyperpigmentation; Inflammation; Male; Melanins; Mice; Mice, Transgenic
PubMed: 32623834
DOI: 10.1111/pcmr.12911 -
Nutrients Jun 2024Allergic dermatitis is a skin disease with growing prevalence worldwide that has been associated with diets high in fats and sugars. Regular consumption of...
Allergic dermatitis is a skin disease with growing prevalence worldwide that has been associated with diets high in fats and sugars. Regular consumption of sucrose-containing beverages may increase the risk for several health problems, including allergic diseases and particularly asthma, but the association between sucrose consumption and allergic dermatitis is understudied. We investigated the effects of sucrose solution intake on allergic contact dermatitis in rats and found early exacerbation of 2,4-dinitrofluorobenzene (DNFB)-induced disease symptoms and altered composition of the gut microbiota after 14 d of intake. The levels of short-chain fatty acids-produced by fermentation by the intestinal microbiota-were not affected in the cecal contents and feces but decreased in the blood; this effect was especially notable for acetate. To restore blood acetate concentrations, triacetin was mixed with a 10% sucrose solution and fed to the rat model. This strategy prevented the early exacerbation of DNFB-induced symptoms. The decreased absorption of short-chain fatty acids from the intestinal lumen was not linked to the decreased expression of short-chain fatty acid transporters in the small intestine; instead, the mechanism involves a reduction in the sodium concentration in the intestinal lumen due to increased expression of sodium-glucose transporter 1 (SGLT1).
Topics: Animals; Dinitrofluorobenzene; Rats; Male; Dermatitis, Allergic Contact; Gastrointestinal Microbiome; Fatty Acids, Volatile; Rats, Sprague-Dawley; Sucrose; Disease Models, Animal; Acetates; Dietary Sucrose
PubMed: 38931315
DOI: 10.3390/nu16121962 -
Frontiers in Immunology 2022Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating...
Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating development of new approaches for AD management. Here, we report that dietary grape powder (GP) mitigates AD-like symptoms in 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/NgaTndCrlj mice. Using prevention and intervention protocols, we tested the efficacy of 3% and 5% GP-fortified diet in a 13-weeks study. We found that GP feeding markedly inhibited development and progression of AD-like skin lesions, and caused reduction in i) epidermal thickness, mast cell infiltration, ulceration, excoriation and acanthosis in dorsal skin, ii) spleen weight, extramedullary hematopoiesis and lymph nodes sizes, and iii) ear weight and IgE levels. We also found significant modulations in 15 AD-associated serum cytokines/chemokines. Next, using quantitative global proteomics, we identified 714 proteins. Of these, 68 (normal control) and 21 (5% GP-prevention) were significantly modulated (≥2-fold) vs AD control (DNFB-treated) group, with many GP-modulated proteins reverting to normal levels. Ingenuity pathway analysis of GP-modulated proteins followed by validation using ProteinSimple identified changes in acute phase response signaling (FGA, FGB, FGG, HP, HPX, LRG1). Overall, GP supplementation inhibited DNFB-induced AD in NC/NgaTndCrlj mice in both prevention and intervention trials, and should be explored further.
Topics: Mice; Animals; Dermatitis, Atopic; Vitis; Dinitrofluorobenzene; Skin Diseases; Diet
PubMed: 36741360
DOI: 10.3389/fimmu.2022.1051472