Maternal exposure to di-n-butyl phthalate (DBP) induces renal fibrosis in adult rat offspring Maternal exposure to di-n-butyl phthalate (DBP) induces renal fibrosis in adult rat offspring

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet β cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in β cell viability.

Introduction: We aimed to develop a copper-related gene (CRG) signature that can be used to evaluate prognosis and guide therapeutic management in bladder cancer patients.Methods: The raw transcriptome profiles and clinical data of 405 bladder samples were downloaded from The Cancer Genome Atlas (TCGA) database, and differentially expressed copper-related genes were identifified using the Molecular Signatures Database (MSigDB) database and univariate and multivariate Cox regression analysis. A multigene prognostic signature based on 14 CRGs was developed by least absolute shrinkage and selection operation (LASSO) analysis in the TCGA cohort and validated in the Gene Expression Omnibus (GEO) cohort. Multiple analyses were then conducted in which the nomograms, clinicopathological features, immune-related cell infifiltration characteristics, and therapy responses of the high- and low-risk score groups were compared.Results: A 14 CRGs signature was constructed and used to classify patients into high-risk and low-risk groups. Compared to patients classifified as high-risk, low-risk patients in both the TCGA cohort and the GEO cohort had better overall survival. Patients in high-risk groups had more aggressive clinical features, immunologically “cold” infifiltrating characteristics, and experienced lower therapeutic effificacy. We identifified a CRG signature of bladder cancer and validated it using unsupervised clustering analysis. Monooxygenase DBH-like 1 (MOXD1) was further identifified, and its potential for evaluating the tumor immune microenvironment and predicting the immunotherapy response was explored.Discussion: These results suggest a novel research direction for precision therapy of bladder cancer and demonstrate that copper-related genes can play a promising role in predicting prognosis and may serve as therapeutic targets for bladder cancer.