Effect of IL-9 neutralising antibody on pyroptosis via SGK1/NF-κB/NLRP3/GSDMD in allergic rhinitis mice.

Allergic rhinitis is a common non-infectious inflammatory disease that affects approximately 15 % of people worldwide and has a complex and unclear aetiology. In recent years, pyroptosis has been found to play a role in the development of allergic rhinitis. IL-9, pyroptosis, serum and glucocorticoid-induced protein kinase 1 (SGK1), NOD-like receptor 3 (NLRP3), and nuclear factor kappa B (NF-κB) have been shown to influence each other. Herein, we aimed to explore the role of IL-9 neutralising antibody in pyroptosis involving IL-9, SGK1, NF-κB, and NLRP3 in allergic rhinitis. We observed a decrease in cytokines involved in pyroptosis and gasdermin D (GSDMD) compared with those in mice with allergic rhinitis. Further, phosphorylation of NF-κB/p65 decreased compared with that in mice with allergic rhinitis; NLRP3 and ASC also decreased, although the levels were higher than those in controls. SGK1 levels decreased compared with that in mice with allergic rhinitis and increased after using IL-9 neutralising antibodies, thus demonstrating its negative regulatory effects. The IL-9 neutralising antibody reduced the inflammatory and pyroptosis responses via SGK1 and NF-κB/NLRP3/GSDMD pathway. Our research results indicate that IL-9 regulates allergic rhinitis via the influence of SGK1 and NF-κB/NLRP3/GSDMD signalling pathway, providing new insights for developing novel drugs to treat allergic rhinitis.

Exposure of nonylphenol promoted NLRP3 inflammasome and GSDMD-mediated pyroptosis in allergic rhinitis mice.

Studies have confirmed that the intake of nonylphenol (NP) can increase nasal symptoms, eosinophils, and Th2 responses in allergic rhinitis (AR) mice. However, the molecular mechanism of NP exacerbating AR inflammatory response remains unclear. Recent data suggest that NOD-like receptor 3 (NLRP3) inflammasome-mediated pyroptosis contributes to AR development. To investigate the effects of NP on NLRP3 inflammasomes and pyroptosis, an AR mouse model induced by ovalbumin (OVA) was established and treated with 0.5 mg/kg/d NP every other day. Nasal symptoms were evaluated after the final OVA instillation. Mast cells and Eosinophils in the nasal mucosa were observed using toluidine blue and Sirius red staining, respectively. The levels of NLRP3, Caspase-1, ASC, phospho-nuclear factor kappa B (NF-κB) p65, interleukin (IL)-6, TNF-α, IL-18, GSDMD and IL-1ß, were assessed by using immunohistochemical staining, ELISA, quantitative real-time PCR, or Western blot. Exposure to NP aggravates AR symptoms and promotes eosinophils, mast cells, and inflammatory factors release, along with significantly increased of NF-κB, NLRP3, Caspase-1, ASC, and GSDMD. It was concluded that NP exposure promotes NLRP3 inflammasome and GSDMD-mediated pyroptosis of the nasal mucosa. Targeted of NLRP3 and GSDMD-mediated pyroptosis may be a novel therapeutic strategy for AR exposed to NP.

Triptolide inhibits the proinflammatory potential of myeloid-derived suppressor cells via reducing Arginase-1 in rheumatoid arthritis.

Triptolide (TPT) is widely used in the treatment of rheumatoid arthritis (RA). However, its regulatory mechanisms are not fully understood. This study demonstrated that Myeloid-derived suppressor cells (MDSCs) were expanded in both RA patients and arthritic mice. The frequency of MDSCs was correlated with RA disease severity and T helper 17 (Th17) responses. MDSCs from RA patients promoted the polarization of Th17 cells in vitro, which could be substantially attenuated by blocking arginase-1 (Arg-1). TPT inhibited the differentiation of MDSCs, particularly the monocytic MDSCs (M-MDSCs) subsets, as well as the expression of Arg-1 in a dose dependent manner. Alongside, TPT treatment reduced the potential of MDSCs to promote the polarization of IL-17+ T cell in vitro. Consistently, TPT immunotherapy alleviated adjuvant-induced arthritis (AIA) in a mice model, and reduced the frequency of MDSCs, M-MDSCs and IL-17+ T cells simultaneously. The presented data suggest a pathogenic role of MDSCs in RA and may function as a novel and effective therapeutic target for TPT in RA.

Understanding the role of NLRP3-mediated pyroptosis in allergic rhinitis: A review.

Allergic rhinitis (AR) is a chronic, inflammatory disease of the nasal mucosa, caused by the immunoglobulin E-mediated immune response. The annual incidence rate of AR is on the rise, exerting a significant impact on individuals' physical and mental wellbeing. The treatment effect in some patients is still not ideal, as the pathogenesis of AR is complex and diverse. Recent studies have shown that NLRP3 inflammasome-mediated pyroptosis is widely involved in the occurrence and development of AR through various pathways. This article reviews the mechanism of pyroptosis and its research progress in the field of AR, and puts forward possible therapeutic targets to offer innovative approaches for its management.

A population-based characterization study of anti-mitochondrial M2 antibodies and its consistency with anti-mitochondrial antibodies.

OBJECTIVE: This study aims to estimate the prevalence of anti-mitochondrial antibody subtype M2 (AMA-M2) and assess its consistency with AMA in a general population. METHODS: A total of 8954 volunteers were included to screen AMA-M2 using enzyme-linked immunosorbent assay. Sera with AMA-M2 >50 RU/mL were further tested for AMA using an indirect immunofluorescence assay. RESULTS: The population frequency of AMA-M2 positivity was 9.67%, of which 48.04% were males and 51.96% were females. The AMA-M2 positivity in males had a peak and valley value of 7.81% and 16.88% in those aged 40 to 49 and ≥70 years, respectively, whereas it showed a balanced age distribution in females. Transferrin and immunoglobulin M were the risk factors for AMA-M2 positivity and exercise was the only protective factor. Of 155 cases with AMA-M2 >50 RU/mL, 25 cases were AMA-positive, with a female-to-male ratio of 5.25:1. Only 2 people, with very high AMA-M2 of 760 and >800 RU/mL, met the diagnostic criteria of primary biliary cholangitis (PBC), making the prevalence of PBC 223.36 per million in southern China. CONCLUSION: We found that AMA-M2 has a low coincidence rate with AMA in the general population. A new decision-making point for AMA-M2 is needed to improve consistency with AMA and diagnostic accuracy.

IL-9 neutralizing antibody suppresses allergic inflammation in ovalbumin-induced allergic rhinitis mouse model.

Allergic rhinitis is mainly mediated by IgE after specific individuals are exposed to allergens. It is a common nasal mucosa disease of non-infectious chronic inflammatory disease and is often accompanied by asthma and conjunctivitis. In the study of allergic asthma, it was found that IL-9 participates in the pathogenic development of asthma. Because asthma and allergic rhinitis have the same airway and the same disease, it is inferred that IL-9 may also play an important role in allergic rhinitis. BALB/c mice received intranasal stimulation of ovalbumin (OVA) treatment at different times. The nasal mucosa of the mice were then sliced and stained with Sirius red and Toluidine blue, and eosinophils and mast cells in the mucosa were counted. ELISA was used to detect the expression of OVA-IgE in peripheral blood. The Th2 cell fraction in the mouse spleen was detected by flow cytometry. The expressions of IL-4, IL-5, IL-9, and IL-13 and their mRNA in mucosa were detected by real-time PCR and flow cytometry bead array analysis. Finally, the expression changes of Thymic stromal lymphopoietin related proteins and its mRNA, JAK1/2, and STAT5 proteins were detected by real-time PCR and Western blot. After the intervention with the IL-9 neutralizing antibody, the symptoms of allergic rhinitis in mice were significantly reduced. The expression of OVA-IgE in the peripheral blood of mice was inhibited, the fraction of Th2 cells in the spleen decreased, the related cytokines (IL-4, IL-5, and IL-13) were inhibited, and their functions decreased. The TSLP-OX40/OX40L signal pathway and JAK1/2-STAT5 signal are inhibited. IL-9 neutralizing antibody has a good therapeutic effect on the mouse model of allergic rhinitis, which may be related to the TSLP-OX40/OX40L pathway and JAK1/2-STAT5 signaling.

Nonylphenol exacerbates ovalbumin-induced allergic rhinitis via the TSLP-TSLPR/IL-7R pathway and JAK1/2-STAT3 signaling in a mouse model.

Nonylphenol (NP) can be widely used as a plasticizer, surfactant, antioxidant, textile printing, dyeing additive, and pesticide emulsifier. Animal studies have shown that NP aggravates ovalbumin (OVA)-induced allergic rhinitis (AR); however, the exact mechanism underlying its action has not yet been detailed. This study aimed to explore the aggravation of the AR inflammatory response following NP exposure and its possible mechanism. The AR mouse model was constructed using OVA. Under NP exposure, allergic nasal symptoms were observed, eosinophil infiltration was assessed by Sirius red staining, and the levels of IL-4, IL-5, and IL-13 in nasal mucosa samples were detected using cytometric bead array. The mRNA levels of OX40/OX40L and GATA3 in nasal mucosa were detected by qPCR, and the expression levels of the TSLP and JAK1/2-STAT3 signaling pathway components were also identified. Our results suggest that NP exposure exacerbated allergic nasal symptoms and that eosinophils accumulated in nasal mucosa after OVA challenge. The levels of the typical T helper 2 cytokines, as well as the mRNA levels of OX40/OX40L and GATA3, were elevated in the nasal mucosa of OVA-challenged mice exposed to NP. In addition, NP exposure elevated the TSLP, TSLPR, IL-7R, p-JAK1, p-JAK2, and p-STAT3 levels in the nasal mucosa after OVA stimulation. Overall, the present study suggests NP can exacerbate OVA-induced AR inflammatory responses; furthermore, this aggravating effect of NP may be related to the TSLP-TSLPR/IL-7R and JAK1/2-STAT3 signaling pathways.

Endoscopic Resection of a Rare Chondromyxoid Fibroma From the Nasal Septum.

ABSTRACT: Chondromyxoid fibroma is a rare benign tumor mostly found in the metaphysis of long bones. In rare cases, it develops in unusual locations. We report a case of chondromyxoid fibroma from the nasal septum. Endoscopic surgery was performed with the patient under general anesthesia. A plasma knife was used to ablate the tumor. No recurrence was noted at the 4-year follow-up. The advantages of endoscopic surgery include direct observation, improved visibility and magnification, reduced intraoperative trauma, and fewer postoperative complications. The advantages of the plasma knife include its ability to separate and ablate the tumor simultaneously while effectively reducing bleeding and maintaining the visibility of the surgical field.

Bisphenol A attenuates the therapeutic effect of the selective G protein-coupled estrogen receptor agonist G-1 on allergic rhinitis inflammation in mice.

BACKGROUND: Bisphenol A (BPA) is found in many plastics widely used in everyday life and affects the immune system. Previous studies found that the selective G protein coupled estrogen receptor (GPER) agonist G-1 can reduce the inflammation associated with asthma and allergic rhinitis (AR). BPA also interferes with the protective effect of estradiol against myocardial ischemia-reperfusion injury. OBJECTIVE: We explored whether BPA attenuates the effect of G-1 on inflammation in a mouse AR model. METHODS: The AR model was established by sensitizing and stimulating female BALB/c mice with ovalbumin (OVA) and G-1/BPA. Eosinophils, neutrophils, and lymphocyte subsets (including T and B cells) in nasal mucosa and Th2 and Treg cells in the spleen were detected by flow cytometry. Cytokines and transcription factors characteristic of Th2 and Treg cells in nasal mucosa were detected using cytometric bead arrays and quantitative PCR, respectively. RESULTS: G-1 reduced OVA-induced nasal mucosal inflammation in mice. The proportions of eosinophils, neutrophils, Siglec-F+ neutrophils, lymphocytes, and T cell subsets were reduced by G-1, and this effect was attenuated by BPA. G-1 significantly decreased the Th2 population and levels of IL-4, IL-5, IL-13 and GATA-3; these effects were attenuated by BPA. The enhanced Treg response (as evidenced by an increased Treg population and higher IL-10 and Foxp3 levels) mediated by G-1 tended to be reduced by BPA. DISCUSSION: We found that G-1 reduced OVA-induced nasal mucosal inflammation and significantly decreased the Th2 response, while increasing the Treg response. These effects were attenuated by BPA.

A Method for Production of Human Adenosine Deaminase 1 (ADA1) in Pichia pastoris Provides Needed Quality Control Material for Clinical Laboratories.

OBJECTIVE: Adenosine deaminase (ADA) plays a major role in maintaining metabolic homeostasis via catalysis of hydrolytic deamination of adenosine to inosine. The ADA1 isoenzyme of ADA is an analyte tested in clinical laboratories; however, lack of quality control (QC) material in terms of enzyme homogeneity, stability, and coverage of the clinically relevant analytical measurement range (AMR), poses a challenge for adequate monitoring of this analyte. The aim of this study was to address the need for manufacture of QC material through recombinant expression of catalytically active ADA1 in eukaryotic cells (Pichia pastoris GS115). METHODS: The coding region of ADA1 gene was amplified by PCR and ligated into plasmid pPICZαA, followed by transfer into P. pastoris using electroporation. Recombinant ADA1 produced by P. pastoris was purified using a Ni-NTA resin column, yielding 5 mL of purified ADA1 with an activity of 4200.6 U/L. Purified ADA1 protein was added to human donor serum as the appropriate matrix for QC materials preparation. RESULTS: One hundred vials of lyophilized ADA1 were prepared at clinically significant concentrations at 41.6 U/L and 115.5 U/L (50 vials each). Both concentrations were homogenous and stable at room temperature (RT, 22-24°C) for at least 7 d, at 4°C for 3 months, and at -20°C for 12 months. Reconstituted aliquots of QC material were found to be stable at -20°C for up to 60 d and should be used within 8 h or 48 h when stored at RT or 4°C, respectively. CONCLUSION: Success of this ADA1 expression system presents a potential solution to increase production options available to clinical laboratories.

Analytical performance evaluation of different test systems on serum creatinine assay.

BACKGROUND: Serum creatinine (SCr) is a useful diagnostic marker for the assessment of renal function. Accurate quantitation of SCr is clinically important in calculation of glomerular filtration rate (GFR). METHOD: To confirm whether there are differences in SCr between enzymatic kits of different manufacturers, the analytical performance of the matched and open test system in the measurement of SCr was evaluated. The analytical performance evaluation was conducted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Precision, accuracy, linearity, dilution, lower limit of measurement and analytical interference were studied between the two test systems. RESULTS: The performance of SCr from the open test system was in compliance with the matched test system with good precision, accuracy, and linearity. In presence of most common interferents, both test systems could lead to accurate creatinine results except for the existence of specified drugs. For dobutamine, the open test system showed better anti-interference performance than the matched system. CONCLUSION: This study provides referable opinions for clinical laboratory selection on the test system and a framework for future analogous studies based on different test systems.

Endoscopic Resection of a Massive Ossifying Fibroma in the Sinonasal Cavity.

ABSTRACT: An ossifying fibroma (OF) is a type of benign fibro-osteoma that rarely involves the sinonasal cavity. Recent developments in endoscopic sinus surgery allow the removal of large benign tumors from the nasal cavity and sinuses. Here, the athors report the case of a 48-year-old female who underwent endoscopic sinus surgery under general anesthesia to completely remove a large OF involving the sphenoid sinus and nasal cavity. No recurrence was noted during the recent 3-year follow-up. Endoscopic resection of OFs is an excellent choice for very experienced surgeons, affording the advantages of direct observation as well as visual enhancement and magnification, thus reducing intra- and post-operative morbidity.

Difference between CD25+Tregs and Helios+Tregs in a murine model of allergic rhinitis.

INTRODUCTION: Regulatory T or Treg cells, balance the peripheral immune response to allergens in allergic rhinitis. Traditionally, Treg (CD25+ Treg) is identified by the coexpression of Foxp3 and CD25, but this strategy does not represent the true inhibitory function of Treg cells. Helios has been thought of as novel marker of activated Tregs, with an important inhibitory function. Consequently, Helios was proposed as a marker of Treg. Recent articles have shown that Foxp3 and Helios co-expression (Helios+Tregs) is an important functional stage of Treg. OBJECTIVE: To compare the prevalence of CD25+Tregs and Helios+Tregs using a mouse model of allergic rhinitis. METHODS: Twenty mice were randomized into two groups. The test group comprised 10 allergic rhinitis model mice exposed to ovalbumin; the control group was exposed to saline. The fractions of CD25+Tregs, Helios+Tregs, Helios+CD25+, and Helios+Foxp3+CD25+Tregs present in the two groups were determined using flow cytometry. RESULTS: CD25+Tregs and Helios+Tregs were less abundant in the spleen and nasal mucosa cells of the allergic rhinitis model compared with the control. We also observed fewer Helios+Tregs than CD25+Tregs in nasal mucosa and splenic cells of both control and test groups. Moreover, we observed fewer Helios+Foxp3+, Helios+CD25+, and Helios+Foxp3+CD25+ Tregs in the nasal mucosa in the allergic rhinitis model. Helios was expressed the most in CD4+ CD25+Foxp3+ T-cells, followed by CD4+ CD25-Foxp3- T-cells. Approximately 75% of CD25+Tregs were Helios+ in spleens of allergic rhinitis and control mice. CONCLUSION: This is the first report of the proportions of Helios+Tregs in nasal mucosa and spleens of allergic rhinitis mice. Gating true inhibitory Tregs with the coexpression of Foxp3 and Helios might be more useful than relying on the expression of CD25. This study provides a new insight for Treg studies of allergic rhinitis, and the potential utility of the marker as a therapeutic target.

Combination of Serum Amyloid A and C-Reactive Protein Exhibit Synergistic Effect in Angiogenesis by Inducing Inflammation and Vascular Network.

The role of angiogenesis in tumor progression has been recognized as one of the hallmarks of cancer, but the mechanism of its action remains unclear. Inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) are proposed to play causal roles in the development of various disorders, including malignancies. Previously, we identified the complex of CRP and SAA (CRP-SAA) with diagnostic and prognostic value better than either one of them in the serum of lung cancer patients. In this study, we further explored the stimulation function of CRP-SAA on angiogenesis and inflammation. To explore possible mechanisms, microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and multi-bioinformatics analysis revealed that THP-1 and human umbilical vein endothelial cells (HUVECs) responded to SAA stimulation with upregulation of two pro-angiogenic cytokines in common, i.e., C-X-C motif ligand 6 (CXCL6) and CXCL8, which were validated by subsequent experiments in vitro. CRP had weak effects as a single stimulus, but it can efficiently potentiate the SAA induction of cytokines, which was stronger than the sum of the both (P < 0.001). The synergistical effect of the combination of CRP and SAA enhanced HUVECs transwell and constricted morphology by upregulating the pro-angiogenic genes. These results indicated that the binding of CRP and SAA acted synergistically in pro-angiogenesis by increasing inflammation and inducing vascular network.

Bisphenol A Exacerbates Allergic Inflammation in an Ovalbumin-Induced Mouse Model of Allergic Rhinitis.

PURPOSE: Bisphenol A (BPA) is found in many plastic products and is thus a common environmental endocrine disruptor. Plastic-related health problems, including allergic diseases, are attracting increasing attention. However, few experimental studies have explored the effect of BPA on allergic rhinitis (AR). We explore whether BPA was directly related to the allergic inflammation induced by ovalbumin (OVA) in AR mice. METHODS: We first constructed OVA-induced mouse model, and after BPA administration, we evaluated nasal symptoms and measured the serum OVA-specific IgE levels by ELISA. Th2 and Treg-related cytokines of nasal mucosa were measured by cytometric bead array. Th2 and Treg-specific transcription factor levels were assayed by PCR. The proportions of CD3+CD4+IL-4+Th2 and CD4+Helios+Foxp3+ T cells (Tregs) in spleen tissue were determined by flow cytometry. RESULTS: Compared to OVA-only-induced mice, BPA addition increased nasal symptoms and serum OVA-specific IgE levels. OVA and BPA coexposure significantly increased IL-4 and IL-13 protein levels compared to those after OVA exposure alone. BPA plus OVA tended to decrease the IL-10 protein levels compared to those after OVA alone. Coexposure to OVA and BPA significantly increased the GATA-3-encoding mRNA level, and decreased the levels of mRNAs encoding Foxp3 and Helios, compared to those after OVA exposure alone. BPA increased the Th2 cell proportion, and decreased that of Tregs, compared to the levels with OVA alone. CONCLUSION: BPA exerted negative effects by exacerbating AR allergic symptoms, increasing serum OVA-specific IgE levels, and compromising Th2 and Treg responses.

Detection of Mitochondrial Mutations Through Isothermal Nucleic Acid Amplification Coupled With Clustered Regularly Interspaced Short Palindromic Repeat-Associated Endonuclease Cas13a.

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated endonuclease Cas13a can specifically bind and cleave RNA. After nucleic acid pre-amplification, bacterial Cas13a has been used to detect genetic mutations. In our study, using a transcription-mediated amplification together with Cas13a, we can isothermally amplify and detect mitochondrial point mutations under non-denaturing conditions from human genomic DNA. Unlike previous reports, we prepared CRISPR DNA with T7 promoter sequences and generated CRISPR RNA via transcription-mediated amplification instead of synthesizing and adding CRISPR RNA in a separate step. As a proof-of-concept, we showed that both m.1494C > T and m.1555A > G mutations were detected within 90 min. In addition, we explored various designs of CRISPR DNA to improve assay specificity, including the location and number of nucleotide mismatches, length of protospacer sequence, and different buffering conditions. We also confirmed the possibility of a "one-step single-tube" reaction for mutation detection. This assay can robustly distinguish circular DNA templates that differ by a single nucleotide. It has the potential to be adapted for automated applications, such as the screening of mitochondrial diseases.

The environmental hormone nonylphenol interferes with the therapeutic effects of G protein-coupled estrogen receptor specific agonist G-1 on murine allergic rhinitis.

The G protein-coupled estrogen receptor (GPER) specific agonist G-1 has therapeutic effects in patients with allergic diseases, but any role for G-1 as a therapy for inflammation associated with allergic rhinitis (AR) remains unclear. The structure of the environmental hormone nonylphenol (NP) is very similar to that of estrogen; it binds to the estrogen receptor to produce estrogen-like effects and thus may also bind to the membrane GPER. We explored whether NP administration would reduce the effects of G-1 on AR, the interactions between the two materials, and their mechanisms of action using a murine model of AR. Mice were randomly assigned into control, AR, G-1, and G-1 + NP groups (n = 10/group). AR nasal symptoms were scored. Eosinophils in nasal mucosa were counted after staining with hematoxylin and eosin. Serum ovalbumin (OVA)-specific IgE was determined by ELISA. The proportions of splenic Th1, Th2, and Treg cells were determined by flow cytometry. The expression of transcription factors unique to Th1, Th2, Treg cells and cytokine levels in nasal mucosa were evaluated by real-time PCR and cytometric bead arrays. AR nasal symptoms, including sneezing, nasal scratching, eosinophil infiltration of nasal mucosa, and serum IgE, were reduced in G-1 group. After injection, Th2 cells proportions, Th2-immune response-related cytokines (IL-4, IL-5, and IL-13), and a Th2 cell-specific transcription factor (GATA-3) were significantly decreased in G-1 group. Treg immune response was enhanced (as reflected by Treg cell, IL-10, and Foxp3 levels). The levels of all of these were significantly increased after adding NP, and the Treg immune response was significantly decreased. These results indicate that G-1 attenuated the nasal symptoms, serum OVA-specific IgE, and Th2 cell immune response, whereas it enhanced Treg immune response, in mice with AR. Adding NP weakened these therapeutic effects.

Expression patterns of intermediate filament proteins desmin and lamin A in the developing conduction system of early human embryonic hearts.

Since embryonic heart development is a complex process and acquisition of human embryonic specimens is challenging, the mechanism by which the embryonic conduction system develops remains unclear. Herein, we attempt to gain insights into this developmental process through immunohistochemical staining and 3D reconstructions. Expression analysis of T-box transcription factor 3, cytoskeleton desmin, and nucleoskeleton lamin A protein in human embryos in Carnegie stages 11-20 showed that desmin is preferentially expressed in the myocardium of the central conduction system compared with the peripheral conduction system, and is co-expressed with T-box transcription factor 3 in the central conduction system. Further, lamin A was first expressed in the embryonic ventricular trabeculations, where the terminal ramifications of the peripheral conduction system develop, and extended progressively to all parts of the central conduction system. The uncoupled spatiotemporal distribution pattern of lamin A and desmin indicated that the association of cytoskeleton desmin and nucleoskeleton lamin A may be a late event in human embryonic heart development. Compared with model animals, our data provide a direct morphological basis for understanding the arrhythmogenesis caused by mutations in human DES and LMNA genes.

Nonylphenol can aggravate allergic rhinitis in a murine model by regulating important Th cell subtypes and their associated cytokines.

Nonylphenol (NP) is a widely distributed, toxic endocrine-disrupting chemical exhibiting estrogenic activity. However, its effect on allergic rhinitis (AR) remains unclear. In this study, the effects of NP on a murine model of AR were investigated. Mice were divided into ovalbumin (OVA), NP, and control groups. OVA was used for sensitization and challenge. Mice in the NP group were administered NP during the sensitization period. Allergic nasal symptoms and eosinophil counts in nasal mucosa were measured. Serum levels of OVA-specific IgE were determined by enzyme-linked immunosorbent assay. The mRNA levels of transcription factors of Th cells were determined with real-time polymerase chain reaction. Th cell subtypes and Treg numbers were counted with the aid of multi-color flow cytometry. Cytokine concentrations in nasal mucosa were determined using the cytometric bead array method. Subcutaneous injection of NP into mice exhibiting AR enhanced not only the nasal allergic symptoms, but also eosinophil infiltration and OVA-specific IgE. Moreover, NP upregulated IL-4, IL-5, IL-13, IL-9, IL-6 and IL-17, and downregulated IL-10, in the AR mouse model; IFN-γ and IL-23 were not affected. Transcription factors and Th cell percentages were evaluated to determine whether NP regulates Th cell subtypes in an AR mouse model. GATA3, PU.1, and RORγt levels were significantly increased, but FoxP3 and Helios were decreased. In addition, Th2, Th9, and Th17 subtype percentages significantly increased, and Treg cell percentages decreased, in NP administration groups; the percentage of Th1 subtypes was not affected. NP enhanced allergic inflammation in the AR mouse model through upregulation of Th2, Th9, and Th17 responses and negative regulation of Treg responses. These results suggest that NP may be trigger AR.