Safety of subcutaneous immunotherapy with Novo-Helisen-Depot in the children: a retrospective analysis from a single center in Northern China.

Background: Little is known about the safety of mite extract product Novo-Helisen Depot (NHD) as subcutaneous immunotherapy (SCIT) in the children with mite allergy especially immediate/late local reaction (LRs). Methods: We conducted a retrospective study analyzing the adverse events of the children undergoing subcutaneous immunotherapy with NHD. Adverse events included local and systemic adverse reactions (SRs) at the very early and late stage. The correlation of the basic characteristics, laboratory analysis results, LRs and SRs were analyzed. Results: Two hundred and eighty-seven patients received at least 15 months of subcutaneous immunotherapy with NHD were included in the analysis. Skin-prick testing (SPT) results of D. pteronyssinus was associated with an increased risk of immediate LRs in build-up phase (OR = 1.53, 95% CI: 1.02, 2.37) and delayed LRs in maintenance phase (OR = 1.58, 95% CI: 1.05, 2.46), while SPT results of D. farinae was associated with an increased risk of SRs (OR = 3.22, 95% CI: 1.17, 10.00) and severe SRs (OR = 7.68, 95% CI: 1.13, 109.50). Serum IgE level of D. pteronyssinus was associated with an increased risk of SRs (OR = 1.01, 95% CI: 1.00, 1.03). Patients with both asthma and allergic rhinitis was associated with an increased risk of SR, and severe SRs (P < 0.05). Conclusion: NHD as SCIT is safe. The children with higher SPT level with D. farinae or D. pteronyssinus, higher serum IgE level of D. pteronyssinus, children with both asthma and allergic rhinitis, and the children with treatment interruption had higher risk of adverse events.

Role of SYVN1 in the control of airway remodeling in asthma protection by promoting SIRT2 ubiquitination and degradation.

BACKGROUND: Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and degradation. However, the role of SYVN1 in the pathogenesis of asthma is unclear. RESULTS: In the present study, an ovalbumin (OVA)-induced murine model was used to evaluate the effect of SYVN1 on asthma. An increase in SYVN1 expression was observed in the lungs of mice after OVA induction. Overexpression of SYVN1 attenuated airway inflammation, goblet cell hyperplasia and collagen deposition induced by OVA. The increased ER stress-related proteins and altered epithelial-mesenchymal transition (EMT) markers were also inhibited by SYVN1 in vivo. Next, TGF-ß1-induced bronchial epithelial cells (BEAS-2B) were used to induce EMT process in vitro. Results showed that TGF-ß1 stimulation downregulated the expression of SYVN1, and SYVN1 overexpression prevented ER stress response and EMT process in TGF-ß1-induced cells. In addition, we identified that SYVN1 bound to SIRT2 and promoted its ubiquitination and degradation. SIRT2 overexpression abrogated the protection of SYVN1 on ER stress and EMT in vitro. CONCLUSIONS: These data suggest that SYVN1 suppresses ER stress through the ubiquitination and degradation of SIRT2 to block EMT process, thereby protecting against airway remodeling in asthma.

Human bone marrow-mesenchymal stem cell-derived exosomal microRNA-188 reduces bronchial smooth muscle cell proliferation in asthma through suppressing the JARID2/Wnt/ß-catenin axis.

The functions of exosomes in allergic diseases including asthma have aroused increasing concerns. This paper focuses on the effects of exosomes derived from human bone marrow-mesenchymal stem cells (hBM-MSCs) on the proliferation of bronchial smooth muscle cells in asthma and the mechanism involved. Exosomes were extracted from hBM-MSCs and identified. Human BSMCs were induced with transforming growth factor (TGF)-ß1 to mimic an asthma-like condition in vitro and then treated with exosomes. A mouse model with asthma was induced by ovalbumin (OVA) and treated with exosomes for in vivo study. The hBM-MSC-derived exosomes significantly reduced the abnormal proliferation and migration of TGF-ß1-treated BSMCs. microRNA (miR)-188 was the most enriched miRNA in exosomes according the microarray analysis, and JARID2 was identified as a mRNA target of miR-188. Either downregulation of miR-188 or upregulation of JARID2 blocked the protective effects of exosomes on BSMCs. JARID2 activated the Wnt/ß-catenin signaling pathway. In the asthmatic mice, hBM-MSC-derived exosomes reduced inflammatory cell infiltration, mucus production, and collagen deposition in mouse lung tissues. In conclusion, this study suggestes that hBM-MSC-derived exosomes suppress proliferation of BSMCs and lung injury in asthmatic mice through the miR-188/JARID2/Wnt/ß-catenin axis. This study may provide novel insights into asthma management.

High expression of S100A2 predicts poor prognosis in patients with endometrial carcinoma.

BACKGROUND: S100A2, a member of the S100 protein family, is abnormally expressed and plays a vital role in multiple cancers. However, little is known about the clinical significance of S100A2 in endometrial carcinoma. METHODS: Clinicopathological data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC). First, the expression and prognostic value of different S100 family members in endometrial carcinoma were evaluated. Subsequently, the Kaplan-Meier plotter and Cox regression analysis were used to assess the prognostic significance of S100A2, while the association between S100A2 expression and clinical characteristics in endometrial carcinoma was also analyzed using logistic regression. A receiver operating characteristic (ROC) curve and a nomogram were constructed. The putative underlying cellular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA). RESULTS: Our results revealed that S100A2 expression was significantly higher in endometrial carcinoma tissue than in non-cancerous tissue at both the mRNA and protein levels. Analysis of Kaplan-Meier plotter data revealed that patients with high S100A2 expression had shorter overall survival (OS) and disease specific survival (DSS) compared with those of patients with low S100A2 expression. Multivariate Cox analysis further confirmed that high S100A2 expression was an independent risk factor for OS in patients with endometrial carcinoma. Other clinicopathologic features found to be related to worse prognosis in endometrial carcinoma included age, clinical stage, histologic grade, and tumor invasion. Importantly, ROC analysis also confirmed that S100A2 has a high diagnostic value in endometrial carcinoma. KEGG enrichment analysis and GSEA revealed that the estrogen and IL-17 signaling pathways were significantly upregulated in the high S100A2 expression group, in which estrogen response, JAK-STAT3, K-Ras, and TNFα/NF-κB were differentially enriched. CONCLUSIONS: S100A2 plays an important role in endometrial carcinoma progression and may represent an independent diagnostic and prognostic biomarker for endometrial carcinoma.

p300 mediates the histone acetylation of ORMDL3 to affect airway inflammation and remodeling in asthma.

BACKGROUND: Bronchial asthma is affected by both environmental and genetic factors. The orosomucoid 1-like protein 3 (ORMDL3) gene is related to childhood asthma and is involved in airway inflammation and airway remodeling. The ORMDL3 promoter contains binding sites for the histone acetylase p300. Gene expression can be affected by epigenetic modifications. This study aimed to investigate whether the p300-mediated histone acetylation (HAT) of ORMDL3 gene affects airway inflammation and remodeling in asthma. METHODS: 16HBE14o- cells were transfected with various concentrations of a wild-type p300 plasmid or p300HAT-deletion plasmids. A dual luciferase reporter assay was used to examine the effect of p300-mediated HAT on the ORMDL3 promoter. Thirty BALB/c mice were randomly divided into a control group, an ovalbumin (OVA)-induced asthma group and an asthma + C646 (a selective inhibitor of p300) group. Noninvasive lung function tests were conducted to examine airway hyperreactivity (AHR) in the different groups. HE and Masson's trichrome staining was performed to examine airway remodeling and inflammation. Immunohistochemistry, western blotting and real-time PCR were used to analyze ORMDL3 expression in lung tissues. ELISA and western blotting were used to evaluate the HAT status in lung tissue. The ChIP assay was used to determine the relationship of the ORMDL3 promoter to p300 or acetylated histone H3 (aceH3). RESULTS: p300 activated transcription from the ORMDL3 promoter, resulting in an increase in endogenous ORMDL3 mRNA levels. ORMDL3 promoter activity was reduced when the HAT activity of p300 was lost. ORMDL3 expression was elevated, and HAT activity was high in the lung tissues of asthmatic mice. p300 and aceH3 bound to the promoter region of ORMDL3. In the asthma group, the amounts of p300 and aceH3 recruited to the ORMDL3 promoter were increased. C646 inhibited p300 expression and reduced HAT activity and aceH3 levels in asthmatic mice, thereby reducing ORMDL3 expression and relieving AHR and airway remodeling. CONCLUSION: p300-mediated HAT modulates the expression of the asthma susceptibility gene ORMDL3, thereby improving the process of airway inflammation and remodeling in asthma.