Environmental exposure to per- and polyfluoroalkyl substances mixture and asthma in adolescents.

BACKGROUND: Previous epidemiological studies about the relationship between per- and polyfluoroalkyl substances (PFAS) concentrations and adolescent asthma have typically examined single PFAS, without considering the mixtures effects of PFAS. METHODS: Using data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), 886 adolescents aged 12-19 years were included in this study. We explored the association between PFAS mixture concentrations and adolescent asthma using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models, respectively. RESULTS: After adjusting for confounders, the results of the WQS regression and BKMR models were consistent, with mixed exposure to the five PFAS not significantly associated with asthma in all adolescents. The association remained nonsignificant in the subgroup analysis by sex. CONCLUSIONS: Our study demonstrated no significant association between mixed exposure to PFAS and adolescent asthma, and more large cohort studies are needed to confirm this in the future.

Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats.

Environmental estrogen exposure has increased dramatically over the past 50 years. In particular, prenatal exposure to estrogen causes many congenital diseases, among which reproductive system development disorders are extremely serious. In this study, the molecular mechanism of hypospadias and the therapeutic effect of genistein (GEN) were investigated through in vivo models prepared by Di-(2-ethylhexyl) phthalate (DEHP) exposure between 12 and 19 days of gestation. With increased DEHP concentrations, the incidence of hypospadias increased gradually. DEHP inhibited the key enzymes involved in steroid synthesis, resulting in decreasing testosterone synthesis. At the same time, DEHP increased reactive oxygen species (ROS) and produced inflammatory factors via NADPH oxidase-1 (NOX1) and NADPH oxidase-4 (NOX4) pathways. It also inhibited Steroid 5 α Reductase 2 (Srd5α2) and decreased dihydrotestosterone (DHT) synthesis. Additionally, DEHP inhibited the androgen receptor (AR), resulting in reduced DHT binding to the AR that ultimately retarded the development of the external reproductive system. GEN, a phytoestrogen, competes with DEHP for binding to estrogen receptor ß (ERß). This competition, along with GEN's antiestrogen and antioxidant properties, could potentially reverse impairments. The findings of this study provide valuable insights into the role of phytoestrogens in alleviating environmental estrogen-induced congenital diseases.

Identification and Validation of CXCL2 as a Key Gene for Childhood Obesity.

This study aims to identify the key genes and their regulatory networks by bioinformatics, increasing understanding of childhood obesity. The data comes from the GEO and Immport database. The immune microenvironment was explored in GSE104815. Key genes were identified by intersection of DEGs with the immune gene set. Enrichment analysis revealed gene-related functions and correlation analysis explored the relationship. Regulatory networks were constructed based on miRcode, TarBase and TargetScan databases. GSE29718 was used to validate our findings. Intercellular communication and cell differentiation trends were further explored using single-cell data from GSE153643. Based on our research, the immune microenvironment in the obese group showed higher immune infiltration. We found 962 DEGs and CXCL2 was identified as the key gene. The co-regulatory network of lncRNA-miRNA-mRNA suggested that obtaining TM4SF19-AS1, GUSBP11, AC105020.1, LINC00189, COL4A2-AS2, VIPR1-AS1 and LINC00242 may regulate CXCL2 (r > 0.9 and P < 0.01). Differential expression of CXCL2 was validated in GSE29718 (P < 0.05) and CXCL2 was identified as a biomarker for childhood obesity (AUC = 0.885). GSVA enrichment analysis revealed many pathways of high group obtaining the TNF-α signaling via NF-κB pathway and interferon γ response pathway. In GSE153643, 11 cell types were identified and CXCL2 was highly expressed in monocyte, macrophage, endothelial cell and pericyte. In CXCL2 high expressing macrophages, there was a tendency for cells to polarize toward M1 macrophages (P < 0.05). In summary, we identified CXCL2 as a potential biomarker of childhood obesity. The development of childhood obesity may be associated with the activation of immune infiltration of macrophage M1 polarization by CXCL2 expression.

The potential effects and mechanism of echinacoside powder in the treatment of Hirschsprung's Disease.

Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. Genes related to the disease were obtained through analysis of the GSE96854 dataset and four databases: OMIM, DisGeNET, Genecard and NCBI. The targets of echinacoside were obtained from three databases: PharmMapper, Drugbank and TargetNet. The intersection of disease genes and drug targets was validated by molecular docking. The valid docked targets were further explored for their expression by using immunohistochemistry. In this study, enrichment analysis was used to explore the mechanistic pathways involved in the genes. Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. RIMS2 possesses a high mutation phenomenon in pan-cancer, while a validated ceRNA network of eight genes was constructed. The core genes are involved in several signaling pathways, including the one-carbon metabolic process, carbonate dehydratase activity and others. This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.

Identification of the molecular subtypes and construction of risk models in neuroblastoma.

The heterogeneity of neuroblastoma directly affects the prognosis of patients. Individualization of patient treatment to improve prognosis is a clinical challenge at this stage and the aim of this study is to characterize different patient populations. To achieve this, immune-related cell cycle genes, identified in the GSE45547 dataset using WGCNA, were used to classify cases from multiple datasets (GSE45547, GSE49710, GSE73517, GES120559, E-MTAB-8248, and TARGET) into subgroups by consensus clustering. ESTIMATES, CIBERSORT and ssGSEA were used to assess the immune status of the patients. And a 7-gene risk model was constructed based on differentially expressed genes between subtypes using randomForestSRC and LASSO. Enrichment analysis was used to demonstrate the biological characteristics between different groups. Key genes were screened using randomForest to construct neural network and validated. Finally, drug sensitivity was assessed in the GSCA and CellMiner databases. We classified the 1811 patients into two subtypes based on immune-related cell cycle genes. The two subtypes (Cluster1 and Cluster2) exhibited distinct clinical features, immune levels, chromosomal instability and prognosis. The same significant differences were demonstrated between the high-risk and low-risk groups. Through our analysis, we identified neuroblastoma subtypes with unique characteristics and established risk models which will improve our understanding of neuroblastoma heterogeneity.

Posttranslational modification of Aurora A-NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma.

BACKGROUND: t(4;14)(p16;q32) cytogenetic abnormality renders high level of histone methyltransferase NSD2 in multiple myeloma (MM) patients, and predicts poor clinical prognosis, but mechanisms of NSD2 in promoting chemoresistance have not been well elucidated. METHODS: An epigenetics compound library containing 181 compounds was used to screen inhibitors possessing a prior synergistic effect with bortezomib (BTZ) in vitro. Molecular biology techniques were applied to uncover underlying mechanisms. Transcriptome profile assay was performed by RNA-seq. NSG mouse-based xenograft model and intra-bone model were applied to qualify the synergistic effect in vivo. RESULTS: We identified an Aurora kinase A inhibitor (MLN8237) possessed a significant synergistic effect with BTZ on t(4;14) positive MM cells. Aurora A protein level positively correlated with NSD2 level, and gain- and loss-of-functions of Aurora A correspondingly altered NSD2 protein and H3K36me2 levels. Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. Transcriptome profile assay of MM cells with AURKA depletion identified IL6R, STC2 and TCEA2 as the downstream target genes responsible for BTZ-resistance (BR). Clinically, higher expressions of these genes correlated with poorer outcomes of MM patients. Combined administration of MLN8237 and BTZ significantly suppressed tumour growth in LP-1 cells derived xenografts, and remarkably alleviated bone lesion in femurs of NSG mice. CONCLUSIONS: Aurora A phosphorylates NSD2 at S56 residue to enhance NSD2 methyltransferase activity and form a positive regulating loop in promoting MM chemoresistance, thus pharmacologically targeting Aurora A sensitizes t(4;14) positive MM to the proteasome inhibitors treatment. Our study uncovers a previously unknown reason of MM patients with t(4;14) engendering chemoresistance, and provides a theoretical basis for developing new treatment strategy for MM patients with different genomic backgrounds.