Tris(2-butoxyethyl) phosphate (TBOEP) and tris( n-butyl) phosphate (TNBP) are the most commonly used alkyl organophosphate esters (alkyl-OPEs), and they increasingly accumulate in organisms and create potential health hazards. This study examined the metabolism of TNBP and TBOEP in Carassius carassius liver and intestinal microsomes and the production of their corresponding monohydroxylated and dealkylated metabolites. After 140 min of incubation with fish liver microsomes, the rapid depletion of TNBP and TBOEP were both best fitted to the Michaelis-Menten model (at administrated concentrations ranging from 0.5 to 200 μM), with a CL (intrinsic clearance) of 3.1 and 3.9 μL·min·mg protein, respectively. But no significant ( P > 0.05) biotransformation was observed for these compounds in intestinal microsomes at any administrated concentrations. In fish liver microsomes assay, bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) and bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate (3-OH-TBOEP) were the most abundant metabolites of TBOEP, and dibutyl-3-hydroxybutyl phosphate (3-OH-TNBP) was the predominant metabolite of TNBP. Similarly, the apparent V values (maximum metabolic rate) of BBOEHEP and 3-OH-TNBP were also respectively highest among those of other metabolites. Further inhibition studies were conducted to identify the specific cytochrome P450 (CYP450) isozymes involved in the metabolism of TNBP and TBOEP in liver microsomes. It was confirmed that CYP3A4 and CYP1A were the significant CYP450 isoforms catalyzing the metabolism of TNBP and TBOEP in fish liver microsomes. Overall, this study emphasized the importance of hydroxylated metabolites as biomarkers for alkyl-OPEs exposure, and further research is needed to validate the in vivo formation and toxicological implications of these metabolites.

Cerebrovascular disease is the main cause of death in the world. Here, we explored whether circulating serum miR-148b-3p, miR-151b and miR-27b-3p could be as potential diagnostic biomarkers for diagnosing acute ischemic stroke. Seventy-seven IS patients and forty-two healthy controls matched for age and sex were enrolled in the present study. Blood samples were drawn from IS patients within the 24 h. The correlation analysis was performed by Spearman. The ability to distinguish patients from healthy controls was determined by receiver operating characteristic (ROC) curve. The expression of circulating serum miR-148b-3p was significantly decreased, whereas miR-151b and miR-27b-3p were elevated significantly compared with controls. ROC analysis showed area under the ROC curve (AUC) of miR-148b-3p, miR-151b and miR-27b-3p to be 0.6647, 0.6852 and 0.6657, respectively. While the AUC increased to 0.8103 for the combination of miR-148b-3p and miR-27b-3p. Blood miR-151b level was negatively correlated with insulin-like growth factor-1 (IGF-1), and miR-27b-3p level was negatively correlated with IGF-1 and insulin-like growth factor binding protein-3, respectively. Our findings suggest that miR-148b-3p, miR-151b and miR-27b-3p may serve as blood-based biomarkers for diagnosing ischemic stroke patients, and the combination of miR-148b-3p and miR-27b-3p may be more powerful.

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Phenanthrene (Phe) is one of the most abundant low-molecular-weight polycyclic aromatic hydrocarbons (PAHs). Widespread human and aquatic organism exposure to Phe has been reported, but the toxic effects of Phe and potential mechanisms are unclear. We focused on the chronic hepatotoxicity of Phe in adult Chinese rare minnows (Gobiocypris rarus) and the underlying mechanisms. The chronic effects of exposing Chinese rare minnows to 8.9, 82.3, or 510.0 μg/L Phe for 30 days were examined by histopathological observation, TUNEL assays, caspase activity assays, and gene expression profiles. The liver lesion frequency and hepatocyte apoptosis were increased in Phe-exposed groups. Caspase 9 and caspase 3 enzyme activity in liver tissues was markedly increased. The expression of miR-17/92 cluster members was significantly increased in the 82.3 and 510.0 μg/L groups. Moreover, the response of primary hepatocytes indicated a significant decrease in the mitochondrial membrane potential (MMP) after a 48 h exposure to Phe. Interestingly, miR-18a was significantly decreased in primary hepatocytes in all treatments. Moreover, molecular docking indicated that Phe might have the same binding domain as pri-miR-18a, forming pi-pi and pi-σ interactions with heterogeneous nuclear ribonucleoprotein (hnRNP) A1. Given the above, Phe caused liver lesions and induced hepatocyte apoptosis through the intrinsic apoptosis pathway, and the interaction of Phe with hnRNP A1 contributes to the suppression of miR-18a expression and hepatocyte apoptosis.