ABSTRACT
Allergic diseases like asthma, allergic rhinitis and dermatitis pose a significant global health burden, driving the search for novel therapies. The NLRP3 inflammasome, a key component of the innate immune system, is implicated in various inflammatory diseases. Upon exposure to allergens, NLRP3 undergoes a two-step activation process (priming and assembly) to form active inflammasomes. These inflammasomes trigger caspase-1 activation, leading to the cleavage of pro-inflammatory cytokines (IL-1ß and IL-18) and GSDMD. This process induces pyroptosis and amplifies inflammation. Recent studies in humans and mice strongly suggest a link between the NLRP3 inflammasome, IL-1ß, and IL-18, and the development of allergic diseases. However, further research is needed to fully understand NLRP3's specific mechanisms in allergies. This review aims to summarize the latest advances in NLRP3 activation and regulation. We will discuss small molecule drugs and natural products targeting NLRP3 as potential therapeutic strategies for allergic diseases.
Subject(s)
Hypersensitivity , Inflammasomes , Inflammation , NLR Family, Pyrin Domain-Containing 3 Protein , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Humans , Inflammasomes/metabolism , Inflammasomes/immunology , Animals , Hypersensitivity/immunology , Hypersensitivity/drug therapy , Hypersensitivity/metabolism , Hypersensitivity/therapy , Inflammation/immunology , Inflammation/metabolismABSTRACT
BACKGROUND: The role of periodontal ligament stem cells (PDLSCs) in repairing periodontal destruction is crucial, but their functions can be impaired by excessive oxidative stress (OS). Nocardamine (NOCA), a cyclic siderophore, has been shown to possess anti-cancer and anti-bacterial properties. This study aimed to investigate the protective mechanisms of NOCA against OS-induced cellular dysfunction in PDLSCs. METHODS: The cytotoxicity of NOCA on PDLSCs was assessed using a CCK-8 assay. PDLSCs were then treated with hydrogen peroxide (H2O2) to induce OS. ROS levels, cell viability, and antioxidant factor expression were analyzed using relevant kits after treatment. Small molecule inhibitors U0126 and XAV-939 were employed to block ERK signaling and Wnt pathways respectively. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) activity staining and Alizarin Red S (ARS) staining of mineralized nodules. Expression levels of osteogenic gene markers and ERK pathway were determined via real-time quantitative polymerase chain reaction (RT-qPCR) or western blot (WB) analysis. ß-catenin nuclear localization was examined by western blotting and confocal microscopy. RESULTS: NOCA exhibited no significant cytotoxicity at concentrations below 20 µM and effectively inhibited H2O2-induced OS in PDLSCs. NOCA also restored ALP activity, mineralized nodule formation, and the expression of osteogenic markers in H2O2-stimulated PDLSCs. Mechanistically, NOCA increased p-ERK level and promoted ß-catenin translocation into the nucleus; however, blocking ERK pathway disrupted the osteogenic protection provided by NOCA and impaired its ability to induce ß-catenin nuclear translocation under OS conditions in PDLSCs. CONCLUSIONS: NOCA protected PDLSCs against H2O2-induced OS and effectively restored impaired osteogenic differentiation in PDLSCs by modulating the ERK/Wnt signaling pathway.
Subject(s)
Cell Differentiation , Hydrogen Peroxide , Osteogenesis , Oxidative Stress , Periodontal Ligament , Stem Cells , Periodontal Ligament/cytology , Periodontal Ligament/metabolism , Periodontal Ligament/drug effects , Humans , Oxidative Stress/drug effects , Stem Cells/metabolism , Stem Cells/drug effects , Hydrogen Peroxide/pharmacology , Hydrogen Peroxide/toxicity , Osteogenesis/drug effects , Cell Differentiation/drug effects , beta Catenin/metabolism , Cell Survival/drug effects , Wnt Signaling Pathway/drug effects , MAP Kinase Signaling System/drug effects , Cells, Cultured , Reactive Oxygen Species/metabolismABSTRACT
Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.
Subject(s)
Dysidea , Porifera , Sesquiterpenes , Animals , Dysidea/chemistry , Porifera/chemistry , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Anti-Inflammatory Agents/pharmacology , NF-kappa B , Molecular StructureABSTRACT
An unusual secomeroterpenoid, dysambiol (1), was isolated from a Dysidea sp. marine sponge collected from the South China Sea. Dysambiol features an unprecedented secomeroterpene scaffold with a rare lactone bridge. The structure of 1 was determined by extensive spectroscopic analysis, Mosher's method, and electronic circular dichroism calculation. Dysambiol displayed potent anti-inflammatory activity in LPS-induced Raw 264.7 macrophages by regulating the NF-κB/MPAK signaling pathway.
Subject(s)
Dysidea , Porifera , Animals , Anti-Inflammatory Agents/pharmacology , China , Circular DichroismABSTRACT
Antibiotic exposure-induced dysbiosis of the intestinal flora increases the risk of developing allergic rhinitis. Hence, regulating the balance of intestinal flora may be useful for preventing and treating allergic rhinitis. However, the underlying mechanism is unclear. Dendrobium nobile (Shihu) exhibits anti-inflammatory and immune activities. Hence, in this study, we investigated the mechanism via which Shihu may improve allergic rhinitis. Mouse models of allergic rhinitis with intestinal flora dysbiosis (Model-D, antibiotics induce intestinal flora dysbiosis with ovalbumin-induced allergy) and normal intestinal flora with allergic rhinitis (Model-N, ovalbumin-induced allergy) were established. The effect of Shihu on intestinal flora and inflammation caused during allergic rhinitis were analyzed. Allergic symptoms, infiltration of hematoxylin and eosin in the lungs and nose, and the release of various factors [interleukin (IL)-2, IL-4, IFN-γ, IL-6, IL-10, and IL-17] in the lungs were evaluated. The results indicate that intestinal flora dysbiosis exacerbated lung and nose inflammation in allergic rhinitis. However, treatment with the Shihu extract effectively reversed these symptoms. Besides, the Shihu extract inhibited the PI3K/AKT/mTOR pathway and increased the level of Forkhead box protein in the lungs. Additionally, the Shihu extract reversed intestinal flora dysbiosis at the phylum and genus levels and improved regulator T cell differentiation. Furthermore, in the Model-D group, the Shihu extract inhibited the decrease in the diversity and abundance of the intestinal flora. Screening was performed to determine which intestinal flora was positively correlated with Treg differentiation using Spearman's correlation analysis. In conclusion, we showed that Shihu extract restored the balance in intestinal flora and ameliorated inflammation in the lungs of allergic rhinitis mice and predicted a therapeutic new approach using Traditional Chinese Medicine to improve allergic rhinitis.
Subject(s)
Dendrobium , Drugs, Chinese Herbal , Gastrointestinal Microbiome , Pneumonia , Rhinitis, Allergic , Animals , Cytokines/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Dysbiosis/chemically induced , Dysbiosis/drug therapy , Inflammation/drug therapy , Mice , Mice, Inbred BALB C , Ovalbumin , Phosphatidylinositol 3-Kinases , Rhinitis, Allergic/drug therapy , Rhinitis, Allergic/metabolismABSTRACT
IL-10-expressing regulatory B cells (B10 cells) are dysfunctional in patients with many immune disorders. The underlying mechanism remains to be further elucidated. Glutamine is an essential nutrient for cell metabolism. This study aims to elucidate the role of glutaminolysis in maintaining the immune regulatory capacity in B10 cells. Peripheral blood samples were collected from 50 patients with allergic rhinitis and 50 healthy control subjects. B cells were isolated from blood samples by cell sorting with flow cytometry. The role of glutaminolysis in regulating B10 cell activities was assessed by immunological and biochemical approaches. The results showed that B cells from patients with allergic rhinitis expressed low levels of the transporter of glutamine and neutral amino acid. Glutaminolysis was required in the IL-10 expression in B cells. The glutamine catabolism was required in B10 cell generation. The mTOR activation mediated the glutaminolysis-associated B10 cell induction, and the suppression of the B cell glycogen synthase kinase-3 (GSK3) activation. GSK3 activation suppressed IL-10 expression in B cells. Inhibition of GSK3 enhanced IL-10 expression in B cells and alleviated experimental allergic rhinitis by generating immune competent type 1 regulatory T cells.
Subject(s)
B-Lymphocytes, Regulatory , Glycogen Synthase Kinase 3 , B-Lymphocytes, Regulatory/metabolism , CD4-Positive T-Lymphocytes , Flow Cytometry , Glycogen Synthase Kinase 3/metabolism , Humans , Lymphocyte CountABSTRACT
House dust mites (HDMs) are a potent allergen source that are commonly found in human living environments. While HDMs are known to induce allergic diseases in humans, such as asthma, its other biological activities related to human health are less understood. Our laboratory recently purified the HDM protein PDI (protein disulfide isomerase). In this study, we assess the role of PDI in contributing to immune regulation. Using mass spectrometry, we analyzed the complexes of DEC205 and HDM extracts, and the role of PDI in the induction of tolerogenic dendritic cells (DCs) was assessed in human cell culture experiments and verified in a murine model. We found that more than 20 HDM-derived proteins, including PDI, bound to DCs by forming complexes with DEC205. Additionally, DEC205-mediated the endocytosis of PDI. HDM-derived PDI (HDM-PDI) promoted Foxp3 expression in DCs. HDM-PDI-primed DCs also showed tolerogenic properties that induced regulatory T cell development, indicating that the primed DCs were tolerogenic DCs. Our results suggested that the PDI/DEC205/TIEG1/Foxp3 signal pathway activation was involved in the HDM-PDI-induced Foxp3 expression in DCs. Finally, we found that HDM-PDI competitively counteracted the Th2 cytokines to restore DC's tolerogenicity, and administration of HDM-PDI could suppress experimental asthma. In conclusion, our data suggest that HDM-PDI contributes to immune regulation by inducing tolerogenic DC development. Administration of HDM-PDI can alleviate experimental asthma. These findings demonstrate that HDM-PDI has translational potential to be used in the treatment of immune disorders such as asthma.
Subject(s)
Dendritic Cells/immunology , Hypersensitivity/therapy , Protein Disulfide-Isomerases/metabolism , Pyroglyphidae/enzymology , Respiratory System/immunology , Animals , Cytokines/metabolism , Dendritic Cells/metabolism , Hypersensitivity/immunology , Hypersensitivity/metabolism , MiceABSTRACT
BACKGROUND: Marine natural products harbor a variety of pharmacological activities, and the sea species have been becoming a main source of new drug candidate. In pursuit of safer and more effective anti-inflammation drug, the anti-inflammatory activities, anti-oxygenation effects and underlying molecular mechanisms of compound dysiarenone from Dysidea arenaria were investigated via LPS-induced RAW 264.7 cell model. METHODS: Firstly, RAW 264.7 cells have been stimulated with LPS and treated with dysiarenone, and the cell viability of the LPS-treated RAW 264.7 cells was examined. One-step method, DCFH-DA fluorescence probe method was used to detect reactive oxygen species (ROS). The modulation of dysiarenone on anti-inflammation was detected by enzyme-linked immunosorbent assay by measuring the release of inflammatory cytokines (TNF-α and IL-6), and inflammatory mediators (LTB4). Further, the underlying anti-inflammatory mechanism of dysiarenone was explored by determining the expression of inducible 5-LOX, MAPKs, p-Akt, and p-NF-κB p65. Oxidative stress is tightly connected with inflammation, which was also evaluated through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (OH-1) signaling pathway. RESULTS: Our study unraveled that dysiarenone between 2 and 8 µM reduces the inflammation responses via suppressing the production of inflammatory cytokines (TNF-α and IL-6) and inflammatory mediators (LTB4). Dysiarenone down-regulated the protein levels of inducible 5-LOX via the inhibition of phosphorylation of MAPKs (including p38, ERK), Akt and NF-κB p65. Additionally, dysiarenone decreases ROS accumulation by upregulating HO-1 expression via nuclear translocation of Nrf2. CONCLUSION: In conclusion, we demonstrated that dysiarenone possesses anti-inflammation and anti-oxidation activity via inhibiting 5-LOX/NF-κB/MAPK and Nrf2/HO-1 signaling pathway. Dysiarenone might be a promising lead compound for inflammatory diseases.
ABSTRACT
BACKGROUND: The causative factors and pathogenesis of food allergy (FA) is not fully understood yet. Cold stress (CS) occurs frequently in human life that influences physiological activities in the body. In this study, we aimed to investigate the chronic CS (CS) effects on promoting the expression of IL-33 in intestinal epithelial cells. METHODS: CS was carried out by placing mice at 4 °C for 1 h daily for 7 consecutive days. We developed a mouse model used to test the effects of CS on the FA development. RESULTS: We found that, similar to conventional FA mouse model, CS induced the core body temperature to drop markedly in mice, increased intestinal epithelial barrier permeability and facilitated FA development. CS promoted interleukin (IL)-33 expression in intestinal epithelial cells through the adrenocorticotropic hormone (ACTH)/cortisol axis and via inducing the Il33 promoter methylation. CS facilitated the FA development in mice, that could be blocked by depletion of IL-33 expression in intestinal epithelial cells. CONCLUSIONS: CS induces IL-33 expression in intestinal epithelial cells to promote Th2 polarization in the intestinal tissues and facilitates FA development.
Subject(s)
Cold-Shock Response/immunology , Epithelial Cells/immunology , Food Hypersensitivity/immunology , Gene Expression Regulation/immunology , Interleukin-33/immunology , Intestinal Mucosa/immunology , Animals , Disease Models, Animal , MiceABSTRACT
BACKGROUND: Yan Hou Qing (YHQ) is a Chinese medicinal formula designed to alleviate sore throat symptoms, but underlying mechanism of YHQ treatment for pharyngitis is poorly defined up to now. METHODS: In this study, the modulation of YHQ on pharyngitis is investigated in ammonia-induced acute pharyngitis rat models. After treatment with YHQ or dexamethasone respectively for five consecutive days, all rats were sacrificed for biomolecular and histopathologic study. Protein expressions of MAPKs, NF-κB, COX-2 and 5-LOX in pharyngitis tissue were evaluated by western blot analysis and the levels of TNF-α, IL-6, prostaglandin (PG) E2, leukotrienes (LT)-B4 and LT-D4 in pharyngeal tissue were measured via ELISA assay. Evans blue (EB) dye exudation test was performed parallelly to assess the integrity of pharyngeal tissue. RESULTS: Compared with normal control group, EB dye exudation, and inflammatory cytokines in the model group were significantly increased, and the pharynx tissue was obviously infiltrated by inflammatory cells. YHQ treatment improved the inflammatory infiltrate in pharyngeal tissue, and reduced EB dye exudation in AP rat models. The up-regulated TNF-α and IL-6 in pharyngeal tissue of AP were significantly reduced by YHQ through inhibition of phosphorylation of p38, Erk and NF-κB. YHQ treatment also reversed the increased level of PGE2 through down-regulation of COX-2. CONCLUSIONS: YHQ formula attenuated the pharyngitis related symptoms via suppression of COX-2 and phosphorylation of p38, Erk and NF-κB (p65).
Subject(s)
Cyclooxygenase 2/drug effects , Drugs, Chinese Herbal/pharmacology , NF-kappa B/drug effects , Pharyngitis/drug therapy , Ammonia , Animals , China , Cyclooxygenase 2/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/chemistry , Female , Molecular Structure , NF-kappa B/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Immune dysregulation, such as defects in immune suppressor function, plays an important role in the pathogenesis of many immune disorders including allergic rhinitis (AR). Some Chinese traditional medical formulae have an immune regulatory function. This study aims to restore the immune suppressor function in regulatory B cells (Bregs) collected from AR patients with a Chinese medical formula, Yupingfeng San (YPFS). In this study, Bregs were isolated from blood samples collected from AR patients and healthy (HA) subjects. The capacity of Breg in suppressing effector T cell (Teff) proliferation was observed in an in vitro experiment to be used as an indicator of immune suppressor function of Breg. The effects of YPFS on promoting Bregs' immune suppressor functions were tested in a cell culture study. The results showed that the number of peripheral Breg in AR patients was not significantly different from that in HA subjects, while the immune suppressor function of AR Breg was compromised. Bcl2L12 expression was higher in AR Bregs than that in HA Bregs. A negative correlation was identified between expression of Bcl2L12 and IL-10 in AR Bregs. Exposure of AR Bregs to YPFS in the culture suppressed the expression of Bcl2L12 and improved their immune suppressor function. In conclusion, YPFS can restore the immune suppressor function of AR Bregs via inhibiting the expression of Bcl2L12. The data suggest that YPFS has the potential to be used in the improvement of immune dysfunction, such as AR.
ABSTRACT
The pathologic feature of food allergy (FA) is the aberrant Th2-biased immune response in the intestine. Regulatory T cells (Tregs) play an important role in the suppression of aberrant immune response. The activities of the TLRs regulate multiple cell functions. This study aims to investigate the role of TLR3 activation in the regulation of Th2-biased immune response in the intestine by the generation of inducible Tregs (iTregs). In this study, polyinosinic polycytidylic acid (polyI:C) was used as an activator of TLR3. An FA mouse model was developed to establish the Th2-biased inflammation in the intestine. The effects of TLR3 activation on the generation of iTreg were tested in the culture and in mice. We observed that exposure to polyI:C induced IFN-γ+ Foxp3+ iTregs in mouse intestine and in the culture. The IFN-γ+ Foxp3+ iTregs showed immune suppressive functions. Exposure to polyI:C increased T-bet levels in CD4+ T cells. The T-bet formed a complex with GATA3 to dissociate Foxp3 from GATA3/Foxp3 complex in CD4+ T cells. The Foxp3 thus gained the opportunity to move to TGF-ß promoter to generate iTregs. Administration with polyI:C prevented the development of FA and inhibited existing FA. In conclusion, activation of TLR3 induces IFN-γ+ Foxp3+ Tregs, which can prevent FA development and inhibit existing FA in mice.
Subject(s)
Food Hypersensitivity/etiology , Food Hypersensitivity/metabolism , Forkhead Transcription Factors/metabolism , Interferon-gamma/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Toll-Like Receptor 3/metabolism , Animals , Disease Models, Animal , Food Hypersensitivity/pathology , GATA3 Transcription Factor/metabolism , Immunomodulation , Immunophenotyping , Lymphocyte Activation/immunology , Lymphocyte Depletion , Mice , Poly I-C/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Toll-Like Receptor 3/agonistsABSTRACT
BACKGROUND: The biased T helper 2 (Th2) responses play a critical role in the pathogenesis of allergy. The underlying mechanism is not fully understood yet. Survivin can regulate multiple cellular activities. This study aims to elucidate the role of survivin in the development and maintenance of Th2 polarization. METHODS: CD4+ T cells were isolated from blood samples collected from patients with allergic asthma (AS) and HS control (HS) subjects. Mice carrying CD4+ T cells with survivin knockout (KO mice) were employed to test the role of survivin in the development of the biased Th2 responses. RESULTS: KO mice failed to induce airway allergy. Peripheral CD4+ T cells expressed survivin, which was higher in the AS group than that in the HS group. Naive CD4+ T cells with higher expression of survivin were prone to differentiating into Th2 cells. Survivin bound to the Il4 promoter in CD4+ T cells to enhance Il4 gene transcription. The expression of Fas was lower in CD4+ T cells of the AS group than that in the HS group. Overexpression of survivin suppressed the expression of Fas and impaired the activation-induced cell death (AICD) of CD4+ T cells. CONCLUSION: Survivin facilitates the development of biased Th2 polarization through promoting expression of interleukin 4 (IL-4) and impairing the AICD machinery of CD4+ T cells. To modulate the expression of survivin in CD4+ T cells has the translational potential in the treatment of allergic diseases.
Subject(s)
Asthma/immunology , Survivin/metabolism , Th2 Cells/immunology , Adult , Animals , Asthma/pathology , Cell Death , Female , Gene Expression , Humans , Inflammation , Interleukin-4/genetics , Male , Mice , Mice, Knockout , Survivin/deficiency , Survivin/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathologyABSTRACT
BACKGROUND: Swertia chirayita, has been commonly used under the name "Zang-yin-chen" for the treatment of liver infections, inflammation, abdominal pain, and bacterial infection in traditional Tibetan medicine. However, the bioactive components with anti-inflammatory activities and underlying mechanisms remain poorly evaluated. STUDY DESIGN/METHODS: Repeated column chromatography yielded two main xanthones from petroleum ether (PE) and ethyl acetate fractions of whole plants of S. chirayita, and their structures were determined as bellidifolin (1) and swerchirin (2) on the basis of spectroscopic data and literature analysis. The anti-inflammatory activities and mechanisms of anti-inflammation of these two isolated xanthones were determined via enzyme-linked immunosorbent assay (ELISA) and western blot in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages in vitro. RESULTS: Anti-inflammation assay demonstrated that 1 and 2 inhibit the production of the pro-inflammatory cytokines interleukin-6 (IL-6) and TNF-α in LPS-stimulated RAW 264.7 macrophages. Xanthone 1 also potently inhibited the production of prostaglandin E2 (PGE2) by suppressing the protein expression of cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophages. Western blot showed that the phosphorylation of c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs were remarkably attenuated by 1 in a concentration-dependent manner. Particularly, Compound 1 suppressed the phosphorylation of the inhibitor κB kinase-ß (IKK-ß), Akt, and p65 subunit of nuclear factor-kappaB (NF-κB). CONCLUSION: The potent suppressive effects of 1 from S. chirayita on inflammatory mediators by blocking the expression of COX-2 and phosphorylation of Akt, IKK-ß, MAPK and NF-κB, activation in LPS-stimulated macrophages suggest that 1 can be a preventive therapeutic candidate for the management of inflammatory-mediated immune disorders.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cyclooxygenase 2/drug effects , Inflammation/drug therapy , Signal Transduction/drug effects , Swertia/chemistry , Xanthones/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , China , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Macrophages/drug effects , Mice , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plants, Medicinal/chemistry , RAW 264.7 Cells/drug effects , Xanthones/therapeutic useABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Yan-Hou-Qing (YHQ), a Chinese medicine formula containing fourteen kinds of materials, has been designed for pharyngitis and cough treatment in Oriental medicine. In the present study, the anti-allergic effects and underlying mechanisms of YHQ in inhibition of airway hyper responsiveness (AHR) was explored in an ovalbumin (OVA)-induced allergic asthma mouse model. MATERIALS AND METHODS: BALB/c mice were sensitized by OVA and cholera toxin (CT) and challenged with OVA intranasally to induce allergic asthma mouse model. YHQ (200â¯mg/kg) was orally administered for 3 weeks from week-2 after OVA sensitization. The AHR and histological changes of lung tissues were evaluated by whole-body barometric plethysmography analysis and hematoxylin and eosin (H&E) staining, respectively. The serum concentration of OVA-specific IgE and T helper 2 (Th2) cytokines (IL-4 and IL-13) were determined by enzyme-linked immune sorbent assay (ELISA). Flow cytometry was performed to evaluate the percentage of CD4+CD25+Foxp3+ regulatory T cells (Treg) in the spleen. RESULTS: The elevated AHR responses, heavier inflammatory cell infiltration and Th2 cytokines in allergic asthma group indicated Ovalbumin-induced asthmatic mouse models were built successfully. Compared to allergic asthma group, OVA-induced AHR responses and eosinophil infiltration in lung were improved significantly, and the productions of OVA-specific IgE and Th2 cytokines, IL-4 and IL-13, in the serum were also reduced dramatically after the treatment of YHQ. Moreover, YHQ treatment significantly increased the percentage of CD4+CD25+Foxp3+ Treg in OVA-induced allergic asthma mouse model. CONCLUSIONS: YHQ improves the allergic asthma related symptoms via promotion of CD4+CD25+Foxp3+ Treg and suppression of Th2 responses in mouse model, suggesting YHQ can be used as a potent agent to alleviate allergic asthma related symptoms.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Drugs, Chinese Herbal/therapeutic use , T-Lymphocytes, Regulatory/drug effects , Th2 Cells/drug effects , Allergens , Animals , Anti-Asthmatic Agents/pharmacology , Asthma/blood , Asthma/immunology , Cholera Toxin , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Female , Immunoglobulin E/blood , Interleukin-13/blood , Interleukin-4/blood , Mice, Inbred BALB C , Ovalbumin , T-Lymphocytes, Regulatory/immunology , Th2 Cells/immunologyABSTRACT
The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4+ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4+ T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4+ T cells from UC patients. Naive CD4+ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4+ T cells. CD4+ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.
Subject(s)
Inflammation/immunology , Inflammatory Bowel Diseases/immunology , Intestinal Mucosa/immunology , Muscle Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Th2 Cells/immunology , Adult , Animals , Cells, Cultured , Cytokines/metabolism , Female , Humans , Lymphocyte Activation , Male , Mice , Mice, Inbred BALB C , RNA, Small Interfering/genetics , Young AdultABSTRACT
Dysiarenone (1), a dimeric C21 meroterpenoid featuring an unprecedented 2-oxaspiro[bicyclo[3.3.1]nonane-9,1'-cyclopentane] carbon skeleton, was isolated from the marine sponge Dysidea arenaria. The structure of 1 was determined by HRMS and NMR spectroscopic analyses coupled with ECD calculations. Dysiarenone showed inhibitory activities against COX-2 expression and the production of prostaglandin E2 with an IC50 value of 6.4 µM in LPS-stimulated RAW264.7 macrophages.
Subject(s)
Dysidea/chemistry , Animals , Cyclooxygenase 2 , Magnetic Resonance Spectroscopy , Molecular Structure , TerpenesABSTRACT
Objective:To analyze the impact of sublingual immunotherapy(SLIT)on the quality of life in children with allergic rhinitis.Method:Fifty children with allergic rhinitis who have received sublingual immunotherapy were enrolled in this study.Quality of life was evaluated via measurement of VAS score and rhinoconjunctivitis quality of life questionnaire(RQLQ)before and after treatment.Result:Twenty patients after treatment had complete remission,13 cases were partly alleviated and 17 cases had no response.The total effective rate was 66%.The Multi-VAS scores and Uni-VAS scores in each observation time point(at half a year,one year,two years after treatment)had statistically significant difference compared with that of pre-treatment with SLIT(P<0.05).According to RQLQ scores,the quality of life,nasal symptoms,conjunctiva symptoms,non-nasal(ocular)symp-toms,behaviors and emotional responses were greatly improved in each time point compared with that of pretreatment(P<0.05).Symptomatic treatment scores in each time point after treatment were significantly different and had a positive correlation with the scores of RQLQ(P<0.05).Conclusion:SLIT can improve the nasal allergic symptoms,children's life quality and reduce the use of symptomatic treatment medicines.