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Biomedicine & Pharmacotherapy =... Aug 2023Combined allergic rhinitis and asthma syndrome (CARAS) causes chronic respiratory inflammation in allergic individuals. Long-term exposure to particulate matter 2.5...
Bergapten ameliorates combined allergic rhinitis and asthma syndrome after PM2.5 exposure by balancing Treg/Th17 expression and suppressing STAT3 and MAPK activation in a mouse model.
Combined allergic rhinitis and asthma syndrome (CARAS) causes chronic respiratory inflammation in allergic individuals. Long-term exposure to particulate matter 2.5 (PM2.5; particles 2.5 µm or less in diameter) can aggravate respiratory damage. Bergapten (5-methoxysporalen) is a furocoumarin mostly found in bergamot essential oil and has significant antioxidant, anticancer, and anti-inflammatory activity. This study created a model in which CARAS was exacerbated by PM2.5 exposure, in BALB/c mice and explored the potential of bergapten as a therapeutic agent. The bergapten medication increased ovalbumin (OVA)-specific immunoglobulin (Ig) G2a level in serum and decreased OVA-specific IgE and IgG1 expression. Clinical nasal symptoms diminished significantly, with weakened inflammatory reaction in both the nasal mucosa and lungs. Furthermore, bergapten controlled the T helper (Th)1 to Th2 ratio by increasing cytokines associated with Th1-like interleukin (IL)-12 and interferon gamma and decreasing the Th2 cytokines IL-4, IL-5, and IL-13. Factors closely related to the balance between regulatory T cells and Th17 (such as IL-10, IL-17, Forkhead box protein P3, and retinoic-related orphan receptor gamma) were also regulated. Notably, pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-alpha were reduced by bergapten, which suppressed the activation of both the signal transducer and activator of transcription 3 signaling pathway and the mitogen-activated protein kinase signaling pathway. Therefore, bergapten might have potential as a therapeutic agent for CARAS.
Topics: Mice; Animals; 5-Methoxypsoralen; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Rhinitis, Allergic; Asthma; Inflammation; Cytokines; Particulate Matter; Ovalbumin; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 37267637
DOI: 10.1016/j.biopha.2023.114959 -
Redox Biology Dec 2023Interleukin-17A (IL-17A) levels are elevated in patients with asthma. Ferroptosis has been identified as the non-apoptotic cell death type associated with asthma. Data...
Interleukin-17A (IL-17A) levels are elevated in patients with asthma. Ferroptosis has been identified as the non-apoptotic cell death type associated with asthma. Data regarding the relation of ferroptosis with asthma and the effect of IL-17A on modulating ferroptosis in asthma remain largely unclear. The present work focused on investigating the role of IL-17A in allergic asthma-related ferroptosis and its associated molecular mechanisms using public datasets, clinical samples, human bronchial epithelial cells, and an allergic asthma mouse model. We found that IL-17A was significantly upregulated within serum in asthma cases. Adding IL-17A significantly increased ferroptosis within human bronchial epithelial cells (BEAS-2B). In ovalbumin (OVA)-induced allergic asthmatic mice, IL-17A regulated and activated lipid peroxidation induced ferroptosis, whereas IL-17A knockdown effectively inhibited ferroptosis in vivo by protection of airway epithelial cells via the xCT-GSH-GPX4 antioxidant system and reduced airway inflammation. Mouse mRNA sequencing results indicated that the tumor necrosis factor (TNF) pathway was the differential KEGG pathway in the OVA group compared to healthy controls and the OVA group compared to the IL-17A knockout OVA group. We further used N-acetylcysteine (TNF inhibitor) to inhibit the TNF signaling pathway, which was found to protect BEAS-2B cells from IL-17A induced lipid peroxidation and ferroptosis damage. Our findings reveal a novel mechanism for the suppression of ferroptosis in airway epithelial cells, which may represent a new strategy for the use of IL-17A inhibitors against allergic asthma.
Topics: Animals; Humans; Mice; Asthma; Disease Models, Animal; Epithelial Cells; Ferroptosis; Inflammation; Interleukin-17; Lung; Mice, Inbred BALB C; Ovalbumin
PubMed: 38035662
DOI: 10.1016/j.redox.2023.102970 -
Phytomedicine : International Journal... Oct 2023Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa that is mediated by immunoglobulin E (IgE). Xiao-qing-long-tang (XQLT) is a traditional...
BACKGROUND
Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa that is mediated by immunoglobulin E (IgE). Xiao-qing-long-tang (XQLT) is a traditional Chinese medicine compound that is widely used to treat respiratory diseases such as AR. However, the underlying mechanism of the effect of XQLT on AR remains unclear.
PURPOSE
To elucidate the effect of XQLT on ovalbumin (OVA)-induced AR and the mechanisms of action.
METHODS
The therapeutic efficacy of XQLT was evaluated in a well-established OVA-induced AR mouse model. Nasal symptoms were analyzed, type 2 cytokines and OVA-sIgE levels were measured, nasal mucosa tissues were collected for histological analysis, and the changes of Group 2 innate lymphoid cells (ILC2s) and the IL-33/ST2 and JAK/STAT signaling pathways in the nasal mucosa were observed.
RESULTS
XQLT significantly alleviated the nasal symptoms and histological damage to the nasal mucosa in AR mice, and reduced the levels of type 2 cytokines and OVA-sIgE. In addition, after XQLT treatment, the numbers of ILC2s in the nasal mucosa of AR mice were reduced, and the mRNA levels of the transcription factors GATA3 and ROR-α were decreased. Moreover, IL-33/ST2 signaling pathway was inhibited. The costimulatory cytokine associated JAK/STAT signaling pathway was also inhibited in ILC2s.
CONCLUSION
Our study demonstrated that XQLT regulated ILC2s through the IL-33/ST2 and JAK/STAT pathways to ameliorate type 2 inflammation in OVA-induced AR. These findings suggest that XQLT might be used to treat AR.
Topics: Animals; Mice; Ovalbumin; Immunity, Innate; Interleukin-1 Receptor-Like 1 Protein; Janus Kinases; Interleukin-33; Lymphocytes; Signal Transduction; STAT Transcription Factors; Rhinitis, Allergic; Cytokines; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 37586158
DOI: 10.1016/j.phymed.2023.155012 -
Phytomedicine : International Journal... Sep 2023Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airflow limitation, airway inflammation and remodeling. Icariside II (IS),...
TMT-based quantitative proteomics revealed protective efficacy of Icariside II against airway inflammation and remodeling via inhibiting LAMP2, CTSD and CTSS expression in OVA-induced chronic asthma mice.
BACKGROUND
Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airflow limitation, airway inflammation and remodeling. Icariside II (IS), derived from herbal medicine Herba Epimedii, exerts an anti-inflammatory property. However, underlying mechanisms with specifically targeted molecular expression by IS in asthma have not been fully understood, and whether IS could inhibit remodeling and EMT still remains unclear.
PURPOSE
The study aimed to clarify therapeutic efficacy of IS for attenuating airway inflammation and remodeling in asthma, and illustrate IS-regulated specific pathway and target proteins through TMT-based quantitative proteomics.
STUDY DESIGN AND METHODS
Murine model of chronic asthma was constructed with ovalbumin (OVA) sensitization and then challenge for 8 weeks. Pulmonary function, leukocyte count in bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory and fibrotic cytokines, and markers of epithelial-mesenchymal transition (EMT) were evaluated. TMT-based quantitative proteomics were performed on lung tissues to explore IS-regulated proteins.
RESULTS
IS contributed to alleviative airway hyperresponsiveness (AHR) evidenced by declined R and increased Cdyn. After IS treatment, we observed a remarked down-regulation of leukocyte count, inflammatory cytokines in BALF, and peribronchial inflammation infiltration. Goblet cell hyperplasia, mucus secretion and peribronchial collagen deposition were attenuated, with the level of TGF-β and MMP-9 in BALF declined. Furthermore, IS induced a rise of Occludin and E-cadherin and a decline of N-cadherin and α-SMA in lung tissues. These results proved the protective property of IS against airway inflammation, remodeling and EMT. To further investigate underlying mechanisms of IS in asthma treatment, TMT-based quantitative proteomics were performed and 102 overlapped DEPs regulated by IS were identified. KEGG enrichment exhibited these DEPs were enriched in lysosome, phagosome and autophagy, in which LAMP2, CTSD and CTSS were common DEPs. WB, q-PCR and IHC results proofed expressional alteration of these proteins. Besides, IS could decrease Beclin-1 and LC3B expression with increasing p62 expression thus inhibiting autophagy.
CONCLUSIONS
The study demonstrated IS could ameliorate AHR, airway inflammation, remodeling and EMT in OVA-induced chronic asthma mice. Our research was the first to reveal that inhibition of LAMP2, CTSD and CTSS expression in autophagy contributed to the therapeutic efficacy of IS to asthma.
Topics: Mice; Animals; Ovalbumin; Proteomics; Asthma; Lung; Inflammation; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 37451150
DOI: 10.1016/j.phymed.2023.154941 -
Food Chemistry May 2024When subjected to dry-heating, egg white ovalbumin, a phosphoglycoprotein, undergoes fragmentation and forms soluble aggregates. We investigated the mechanisms of...
When subjected to dry-heating, egg white ovalbumin, a phosphoglycoprotein, undergoes fragmentation and forms soluble aggregates. We investigated the mechanisms of dry-heat-induced fragmentation of ovalbumin. SDS-PAGE analysis showed that ovalbumin fragmented into five polypeptides, and their amount increased over 6 h of dry-heat treatment at 120 °C. The fragments contained fewer or no phosphoserine, compared with that in crude ovalbumin. Liquid chromatography-tandem mass spectrometry analysis of tryptic digests revealed that the fragmentation sites were located on phosphoserine residues, S and S. During fragmentation, the phosphoserine residues underwent conversion into dehydroalanine residues, which were subsequently hydrolyzed. The nitrogen from the dehydroalanine became a newly formed terminal amide group on the N-terminal fragment, while the remaining molecule predominantly formed a new terminal pyruvoyl group. Furthermore, the fragments were incorporated into monomers or soluble aggregates of ovalbumin via covalent and non-covalent bonds. This study demonstrated a novel mechanism for dry-heat-induced fragmentation of phosphoproteins.
Topics: Ovalbumin; Phosphoserine; Hot Temperature; Peptides; Egg White
PubMed: 38159316
DOI: 10.1016/j.foodchem.2023.138263 -
Inflammation Jun 2024Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. Epithelial-mesenchymal transition (EMT) is an...
Scutellarin Alleviates Ovalbumin-Induced Airway Remodeling in Mice and TGF-β-Induced Pro-fibrotic Phenotype in Human Bronchial Epithelial Cells via MAPK and Smad2/3 Signaling Pathways.
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. Epithelial-mesenchymal transition (EMT) is an essential player in these alterations. Scutellarin is isolated from Erigeron breviscapus. Its vascular relaxative, myocardial protective, and anti-inflammatory effects have been well established. This study was designed to detect the biological roles of scutellarin in asthma and its related mechanisms. The asthma-like conditions were induced by ovalbumin challenges. The airway resistance and dynamic compliance were recorded as the results of AHR. Bronchoalveolar lavage fluid (BALF) was collected and processed for differential cell counting. Hematoxylin and eosin staining, periodic acid-Schiff staining, and Masson staining were conducted to examine histopathological changes. The levels of asthma-related cytokines were measured by enzyme-linked immunosorbent assay. For in vitro analysis, the 16HBE cells were stimulated with 10 ng/mL transforming growth beta-1 (TGF-β1). Cell migration was estimated by Transwell assays and wound healing assays. E-cadherin, N-cadherin, and α-smooth muscle actin (α-SMA) were analyzed by western blotting, real-time quantitative polymerase chain reaction, immunofluorescence staining, and immunohistochemistry staining. The underlying mechanisms of the mitogen-activated protein kinase (MAPK) and Smad pathways were investigated by western blotting. In an ovalbumin-induced asthmatic mouse model, scutellarin suppressed inflammation and inflammatory cell infiltration into the lungs and attenuated AHR and airway remodeling. Additionally, scutellarin inhibited airway EMT (upregulated E-cadherin level and downregulated N-cadherin and α-SMA) in ovalbumin-challenged asthmatic mice. For in vitro analysis, scutellarin prevented the TGF-β1-induced migration and EMT in 16HBE cells. Mechanistically, scutellarin inhibits the phosphorylation of Smad2, Smad3, ERK, JNK, and p38 in vitro and in vivo. In conclusion, scutellarin can inactivate the Smad/MAPK pathways to suppress the TGF-β1-stimulated epithelial fibrosis and EMT and relieve airway inflammation and remodeling in asthma. This study provides a potential therapeutic strategy for asthma.
Topics: Apigenin; Airway Remodeling; Animals; Mice; Glucuronates; Ovalbumin; Humans; Asthma; Smad3 Protein; Smad2 Protein; Signal Transduction; Epithelial Cells; Transforming Growth Factor beta; Fibrosis; MAP Kinase Signaling System; Cell Line; Bronchi; Mice, Inbred BALB C; Epithelial-Mesenchymal Transition; Phenotype
PubMed: 38168709
DOI: 10.1007/s10753-023-01947-7 -
Journal of Ethnopharmacology Dec 2023Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be...
Pi-Pa-Run-Fei-Tang alleviates lung injury by modulating IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB signaling pathway and balancing Th17 and Treg in murine model of OVA-induced asthma.
ETHNOPHARMACOLOGICAL RELEVANCE
Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment.
AIM OF THE STUDY
The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism.
MATERIALS AND METHODS
A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1β, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO, NO, SOD, GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis.
RESULTS
PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation, and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1β, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine, and threonine metabolism.
CONCLUSION
This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.
Topics: Mice; Animals; NF-kappa B; Proto-Oncogene Proteins c-akt; Ovalbumin; Interleukin-6; Phosphatidylinositol 3-Kinases; Lung Injury; Tumor Necrosis Factor-alpha; Interleukin-17; T-Lymphocytes, Regulatory; Disease Models, Animal; Cytokines; Asthma; Signal Transduction; Lung; Immunoglobulin E; Superoxide Dismutase; Mice, Inbred BALB C
PubMed: 37268260
DOI: 10.1016/j.jep.2023.116719 -
The Journal of Allergy and Clinical... May 2024Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic...
BACKGROUND
Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis.
OBJECTIVE
We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation.
METHODS
Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR.
RESULTS
Basophils were important for epidermal hyperplasia, dermal infiltration by CD4 T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic T2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive T2 polarization of naive T cells.
CONCLUSION
Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.
Topics: Animals; Basophils; Mice; Interleukin-4; Dermatitis, Atopic; Ovalbumin; Th2 Cells; Skin; Mice, Inbred C57BL; Mice, Inbred BALB C; Disease Models, Animal; Dendritic Cells; Mice, Transgenic; Mast Cells
PubMed: 38336257
DOI: 10.1016/j.jaci.2024.01.022 -
Biomedicine & Pharmacotherapy =... Dec 2023Airway remodeling is associated with severity and treatment insensitivity in asthma. This study aimed to investigate the effects of G protein-coupled receptor 120...
BACKGROUND
Airway remodeling is associated with severity and treatment insensitivity in asthma. This study aimed to investigate the effects of G protein-coupled receptor 120 (GPR120) stimulation on alleviating allergic inflammation and remodeling of airway epithelium.
RESEARCH DESIGN AND METHODS
Ovalbumin (OVA)-challenged BALB/c mice and type-2-cytokine (IL-4 and IL-13)-exposed 16HBE human bronchial epithelial cells were treated with GSK137647A, a selective GPR120 agonist. Markers of allergic inflammation and airway remodeling were determined.
RESULTS
GSK137647A attenuated inflammation and mucus secretion in airway epithelium of OVA-challenged mice. Stimulation of GPR120 in 16HBE suppressed expression of asthma-associated cytokines and cytokine-induced expression of pathogenic mucin-MUC5AC. These effects were abolished by co-treatment with AH7614, a GPR120 antagonist. Moreover, GPR120 stimulation in 16HBE cells reduced expression of fibrotic markers including fibronectin protein and ACTA2 mRNA and inhibited epithelial barrier leakage induced by type-2 inflammation via rescuing expression of zonula occludens-1 protein. Furthermore, GPR120 stimulation prevented the cytokine-induced airway epithelial remodeling via suppression of STAT6 and Akt phosphorylation.
CONCLUSIONS
Our findings suggest that GPR120 activation alleviates allergic inflammation and remodeling of airway epithelium partly through inhibition of STAT6 and Akt. GPR120 may represent a novel therapeutic target for diseases associated with remodeling of airway epithelium, including asthma.
Topics: Humans; Animals; Mice; Interleukin-13; Proto-Oncogene Proteins c-akt; Interleukin-4; Airway Remodeling; Signal Transduction; Disease Models, Animal; Asthma; Cytokines; Receptors, G-Protein-Coupled; Inflammation; Ovalbumin; Mice, Inbred BALB C; Lung; STAT6 Transcription Factor
PubMed: 37924784
DOI: 10.1016/j.biopha.2023.115774 -
Cellular Immunology 2023Asthma is a common chronic respiratory disease characterized by airways inflammation, hyperresponsiveness and remodeling. IL-37, an anti-inflammatory cytokine, consists...
BACKGROUND
Asthma is a common chronic respiratory disease characterized by airways inflammation, hyperresponsiveness and remodeling. IL-37, an anti-inflammatory cytokine, consists of five splice isoforms, that is, a-e. Although it has been previously shown that recombinant human IL-37b is able to inhibit airway inflammation and hyperresponsiveness in animal models of asthma, the effects and difference of other IL-37 isoforms, such as IL-37a on features of asthma are unknown.
METHODS
Animal models of chronic asthma were established using IL-37a and IL-37b transgenic mice with C57BL/6J background and wild-type (WT) mice sensitized and nasally challenged with ovalbumin (OVA). Airway hyperresponsiveness was measured using FlexiVent apparatus, while histological and immunohistological stainings were employed to measure airways inflammation and remodeling indexes, including goblet cell metaplasia, mucus production, deposition of collagen, hypertrophy of airway smooth muscles and pulmonary angiogenesis.
RESULTS
Compared to WT mice, both IL-37a and IL-37b transgenic mice had significant reduced airway hyperresponsiveness and the declined total numbers of inflammatory cells, predominant eosinophils into airways and lung tissues. Furthermore, all features of airways remodeling, including degrees of mucus expression, collagen deposition, hypertrophy of smooth muscles, thickness of airways and neovascularization markedly decreased in IL-37 transgenic mice compared with OVA-treated WT mice.
CONCLUSION
Our data suggest that both IL-37a and IL-37b isoforms are able to not only ameliorate airways inflammation and airways hyperresponsiveness, but also greatly reduce airways structural changes of animal models of chronic asthma.
Topics: Mice; Humans; Animals; Ovalbumin; Mice, Transgenic; Mice, Inbred C57BL; Asthma; Lung; Inflammation; Respiratory Hypersensitivity; Collagen; Hypertrophy; Protein Isoforms; Disease Models, Animal; Mice, Inbred BALB C; Bronchoalveolar Lavage Fluid
PubMed: 37689011
DOI: 10.1016/j.cellimm.2023.104759