NLRP3 inhibitors(Bengbu Medical College)

The subchronic cardiotoxicity of 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), an unregulated disinfection byproduct with high environmental detection rates, remains poorly characterized. Using integrated multi-omics (transcriptomics, proteomics, phosphoproteomics) and histopathological analyses in zebrafish, this study systematically elucidated its dose-dependent (low-dose, 10 nM; medium-dose, 100 nM; high-dose, 1000 nM) cardiotoxicity, from adaptive remodeling to failure, over a 35-day exposure period. A reduction in atrioventricular inflow ranging from 81.4 % to 93.9 %, along with lipid droplet accumulation and Z-disc rupture, indicate a dose-dependent cardiac crisis induced by 2,6-DCBQ. Multi-omics analyses, revealed that the kinase cascade involving braf (Myhpc2_T1545), camk2a (Mybpc3_S291), and mark3b (Ttn.1_S28131) arranged dose-dependent cytoskeletal remodeling. High-dose exposure initiated an inflammation-cytoskeleton vicious cycle, wherein chemokine-driven collagen degradation exacerbated Z-disc rupture, while lipotoxic lipid droplets recruit inflammatory infiltrates, collectively escalating irreversible cardiac decompensation. These findings demonstrate that subchronic exposure to 2,6-DCBQ initiates cardiac remodeling, escalating cardiovascular susceptibility in exposed populations.

2,6-dichloro-1,4-benzoquinone (DCBQ) is the most frequently detected and highly toxic halobenzoquinones, a class of aromatic disinfection byproducts (DBPs), yet its renal toxicity and underlying mechanisms largely remain unknown. In this research, we utilized a dual-omics strategy to explore the toxicological impact of DCBQ on human renal proximal tubular epithelial (RPTEC/TERT1) cells. After the cytotoxicity of DCBQ was uncovered by CCK-8 and cell cycle tests, the significantly changed biological events associated with cell adhesion, extracellular matrix (ECM) remodeling, and organelle lumen homeostasis were highlighted as mechanistic cues primarily by integrated transcriptomic and metabolomics analysis. Our subsequent experiments confirmed that DCBQ significantly disrupted mitochondrial membrane potential and led to anoikis, a unique type of programmed cell death distinguished by cell separation from the ECM. Notably, DCBQ exposure significantly suppressed the PI3K/AKT and Ras/ERK signaling pathways, which may have contributed to reduced cell viability, G1 phase cell cycle arrest and induction of anoikis. These results offered new perspectives on the nephrotoxic mechanisms of DCBQ, highlighting its potential to impair cell-ECM interaction and even induce future cancer progression. Our study also proved the benefits of dual-omics application and integrated data analysis for understanding the comprehensive health risks of those poorly-studied emerging contaminants.