Toxicology and applied pharmacology最新文献

Increasing evidence links exposure to fine particulate matter (PM2.5) with an elevated risk of kidney disease. In this study, we investigated the effect of PM2.5 exposure on human proximal tubular epithelial (HK-2) cells and found that it elevated ferroptotic stress markers, including increased iron, reactive oxygen species (ROS), and malondialdehyde (MDA), along with reducing glutathione (GSH) levels. PM2.5 promotes the epithelial-to-mesenchymal transition (EMT) in these cells, which is associated with the loss of epithelial morphology, lowered expression of E-cadherin, and elevated expression of α-smooth muscle actin (α-SMA). Notably, a reduction in PM2.5-induced EMT characteristics was observed using either a ferroptosis-specific inhibitor (Fer-1) or a mitochondrial ROS scavenger (Mito-Tempo). Moreover, Fer-1 effectively counteracted ferroptotic stress and restored glutathione peroxidase 4 (GPX4) expression in PM2.5-exposed cells, which may explain its efficacy in inhibiting EMT induced by PM2.5. In contrast, GPX4 knockdown exacerbated EMT features in PM2.5-treated cells. Further studies showed that GPX4 overexpression alleviated EMT markers in mouse tubular cells following PM2.5 exposure, indicating the role of GPX4 in reducing ferroptotic stress and may prevent tubular injury caused by PM2.5 exposure. Our study highlights that PM2.5 may induce GPX4-regulated ferroptotic stress in tubular cells, potentially triggering the EMT process and contributing to kidney injury.

Although it has been recognized that females are more susceptible to chemical-induced liver injury, the effects of dibutyl phthalate (DBP), a widely used synthetic chemical, on female liver structure and function are under-researched. Here, we sought to investigate the effects of DBP on histological, stereological, and biochemical parameters, as well as global gene expression in female rat liver. Female Wistar rats were exposed to 100, 500, and 5000 mg DBP/kg diet for 28 days, corresponding to 8.6, 41.43, and 447.33 mg DBP/kg body weight (B.W.)/day, respectively. The highest dose (447.33 mg DBP/kg B.W./day) was between the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level for liver toxicity, whereas two lower doses (8.6 and 41.43 mg DBP/kg B.W./day) were below the NOAEL. Analysis of hematoxylin and eosin-stained sections revealed an increased volume of hepatocytes, their nuclei and cytoplasm, while the volume of sinusoids decreased in DBP-exposed groups compared to the control. Examination of Periodic acid-Schiff-stained sections showed reduced glycogen content, which was the most prominent in the highest dose group. Increased glutathione S-transferase and catalase activities, and decreased GSH content and superoxide dismutase activity were observed in DBP-exposed groups. The mRNA sequencing revealed DBP-induced dose-specific changes in various genes and biological functions in female rat liver. The highest number of deregulated genes was observed in the 500 mg DBP/kg diet group. In summary, exposure to DBP caused significant liver microstructural changes, decreased glycogen content, disturbed the redox status, and affected global gene expression in female rat liver.

The lncRNA CALML3 antisense RNA 1 (CALML3-AS1) is a biomarker for various cancers, including non-small cell lung cancer (NSCLC). However, the role of CALM3-AS1 in small cell lung cancer (SCLC) is still unclear. Here, we found that the CALML3-AS1 was upregulated in SCLC tissues and cells. SCLC cells (NCI-H69 and NCI-H466 cells) were transfected with small interfering RNA of CALML-AS1 (si-CALML3-AS1) and Death domain-associated protein (DAXX) (si-DAXX) or an overexpression vector of CALML-AS1 (dCas9-CALML3-AS1) and DAXX (dCas9-DAXX). The results showed that silencing CALML3-AS1 inhibited SCLC cell proliferation, colony formation, migration, invasion, and spheroid formation, and reduced the expression of stemness marker proteins (Nanog. Oct4, and Lin28). Moreover, silencing CALML3-AS1 reduced glycolysis rate, glucose utilization, and lactate production, and decreased the levels of key glycolytic regulatory proteins (GLUT1, GLUT4, HK2, and PKM2) in SCLC cells, while overexpression of CALML3-AS1 promoted malignant growth and stemness and enhanced glucose transporters type 4 (GLUT4)-mediated aerobic glycolysis by interacting with DAXX in NCI-H69 and NCI-H466 cells. Silencing DAXX or GLUT4, or treatment with 2-Deoxy-d-glucose (2-DG, a glycolysis inhibitor) reversed the effects of CALML3-AS1 overexpression on aerobic glycolysis, malignant growth, and stemness of SCLC cells. Finally, NCI-H69 cells transfected with CALML3-AS1, sh-CALML3-AS1, and sh-DAXX lentiviral vectors were subcutaneously injected into nude mice to construct xenograft models. Knockdown of CALML3-AS1 or DAXX inhibited tumor growth in SCLC in vivo. In conclusion, CALML3-AS1, an oncogene, promotes the malignancy and stemness of SCLC cells by interacting with DAXX to enhance GLUT4-mediated aerobic glycolysis, thereby promoting SCLC progression.

Aims: There has been an unprecedented rise in electronic cigarette (EC) usage likely because of its perception of being safer than smoking. Recent studies show that EC exposures impact heart rate (HR) and heart rate variability (HRV), but how they are affected by the timing and frequency of exposures remain unclear. We examined the electrocardiographic (EKG) effects induced by brief EC exposures over time, their relation to EC aerosol particle and mass concentrations, and potential to promote prooxidative effects in the lungs.

Methods & results: Six 10-week-old C57BL/6J mice, implanted with telemetry devices to monitor EKG activity continuously, were exposed once per week for three weeks to two EC exposures, each lasting 15-min followed by 45-min post-exposure periods. Filtered air (primary) and PBS aerosol (secondary) were used as controls. After combining weeks, EC aerosol induced bradycardia and increased time domain parameters during EC exposures with significant reductions in the post-exposure periods. Log-transformed frequency domain parameters were significantly elevated during and after exposures (p < 0.001). HRV changes occurred within minutes with similar trends observed in particle number and mass concentrations of EC aerosol. HR and HRV varied by week and parameter, with Week 2 and 3 effects overshadowing those in Week 1. ECs induced prooxidative effects in the lungs as evidenced by elevated potential for hydroxyl radical generation in bronchoalveolar lavage fluid of exposed mice (p = 0.003).

Conclusion: Short-term EC exposures altered murine HR and HRV within minutes during and after exposures, effects that were modulated by the timing and frequency of EC exposures.

Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the S-adenosylmethionine (SAM)-dependent methylation of inorganic arsenic (iAs), yielding monomethyl‑arsenic (MAs) and dimethyl‑arsenic (DMAs) metabolites. The formation of DMAs in this pathway is considered a key mechanism for iAs detoxification. Availability of SAM for iAs methylation depends in part on dietary intake of folate. Results of population studies suggest that supplementation with folate stimulates iAs methylation, increasing DMAs and decreasing iAs and MAs proportions in urine and/or blood. The goal of the present study was to determine if folate intake affects methylation and clearance of iAs in a recently established mouse strain that expresses human AS3MT and exhibits a human-like pattern of iAs metabolism. The humanized male and female mice were fed folate-deficient (FD) or folate-supplemented (FS) diet for 6 weeks, followed by exposure to 0 ppb or 400 ppb iAs in drinking water for 5 weeks, while on the same types of diet. The concentrations and proportions of iAs, MAs and DMAs were determined in urine, liver, kidneys, and spleen. The diet-, sex- and dose-related differences were assessed by t-test or a non-parametric test; Bonferroni test was used to correct for multiple comparisons. In general, proportions of DMAs were greater and proportions of iAs were smaller in urine and tissues of FS mice as compared to FD mice. However, folate supplementation also increased MAs proportions. Notably, the folate intake had no effect on the concentrations of total arsenic either in the urine or the tissues. These results suggest that, similar to humans, folate supplementation stimulates iAs methylation in the humanized mice. However, the stimulation of iAs methylation is not associated with clearance of arsenic from tissues, possibly due to an inefficient conversion of MAs to DMAs.