Repeated-dose toxicity (RDT) studies in rats are crucial for assessing the risks of chemicals, including pesticides, by elucidating their toxicological properties. In this study, we collected and comprehensively analyzed the results of rat RDT studies on pesticides. For over 350 pesticides across more than 400 studies, all toxicological findings observed in 90-day and 2-year RDT/carcinogenicity studies in rats were organized into 1,092 endpoints using our previously established three-level categorization system. The liver, kidney, thyroid gland, and spleen were identified as the primary non-tumor targets in both the 90-day and 2-year studies. In the 2-year study, the liver, thyroid gland, testis, and uterus were found to be the primary tumor targets, with significant sex differences in liver and thyroid tumors. We also identified findings observed at the lowest observed adverse effect level (LOAEL) for each study. Finally, analyses by pesticide class, based on their mode of action classification, demonstrated class effects on the toxicological findings observed and the LOAEL values. Taken together, these results provide valuable insights into toxicological endpoints that should be evaluated in further mechanistic studies and considered for the safety assessment of each class of pesticides.

Venlafaxine was the first serotonin/noradrenaline reuptake inhibitor used to treat major depressive disorders. Its overdose can cause cardiovascular toxicity and life-threatening cardiogenic shock. We present the case of a 48-year-old woman who experienced venlafaxine overdose-induced cardiogenic shock. Initial treatment included gastric lavage, blood purification therapy, and ventricular assist device use. The serum venlafaxine concentration was 21.4 μg/mL at 12–24 hr after ingestion, which subsequently decreased to 11.0 and 8.4 μg/mL after 1 and 2 days, respectively. This trend in blood concentration exhibited a biphasic elimination pattern. In addition to venlafaxine-induced cardiotoxicity, the patient exhibited peripheral vascular unresponsiveness to catecholamines. Notably, this vascular dysfunction resolved more rapidly than the cardiotoxic effects. Ultimately, the patient was transferred to a psychiatric ward without sequelae. Although venlafaxine overdose-induced cardiotoxicity has been reported, reports on the unresponsiveness of peripheral blood vessels to catecholamines remain lacking. In cases of venlafaxine overdose-induced cardiogenic shock, both left ventricular function may be impaired and peripheral blood vessels may also be unresponsive to catecholamines. Therefore, rapid initiation of extracorporeal life support and multimodal removal of venlafaxine tailored to the clinical situation may contribute to patient survival.

Sepsis-associated acute kidney injury (AKI) remains a critical clinical challenge with limited therapeutic options. This study investigated the renoprotective effects of spermidine using sepsis-associated AKI models. In vitro, HK-2 cells were challenged with lipopolysaccharide (LPS) to establish an inflammatory injury model, followed by spermidine treatment (25–100 μM). In vivo, a cecal ligation and puncture (CLP)-induced septic AKI mouse model was employed. Key methodologies included CCK-8 viability assay, flow cytometry apoptosis analysis, western blotting (apoptotic proteins: Bcl-2/Bax/cleaved caspase-9; TLR4/MyD88/TRAF6/p-p65), ELISA (TNF-α/IL-6/IL-1β), TUNEL staining, and histopathological assessment, with spermidine doses of 25–100 μM (cells) and 50 mg/kg (mice). We found that spermidine treatment significantly mitigated renal histopathological damage and improved functional markers, including blood urea nitrogen, serum creatinine, and neutrophil gelatinase-associated lipocalin. Spermidine administration attenuated oxidative stress by restoring antioxidant enzyme activities while reducing lipid peroxidation in renal tissues. Spermidine suppressed apoptosis in both LPS-challenged HK-2 and CLP-injured kidneys, evidenced by reduced apoptotic markers and caspase activation. Furthermore, spermidine inhibited systemic and intrarenal inflammatory cytokine production through modulation of the TLR4/MyD88/NF-κB signaling axis. These findings collectively establish that spermidine alleviates sepsis-induced AKI through coordinated suppression of apoptosis and inflammation mediated by TLR4/MyD88/NF-κB pathway inhibition.

Age-related macular degeneration is a leading cause of vision loss and is characterized by the accumulation of drusen in the retinal pigment epithelium. N-retinylidene-N-retinylethanolamine (A2E), a major component of drusen, induces phototoxicity upon exposure to blue light. Given that blue light activates the MAPK pathway and triggers apoptosis, the present study aimed to determine the role of signaling via the activator protein-1 (AP-1) transcription factor in A2E-laden ARPE-19 cells. RNA-sequencing identified significant upregulation of the UV response and p53 pathways. In silico analysis predicted that JUN was a key upstream transcriptional regulator, and experimental validation confirmed increased JUN phosphorylation and AP-1 target gene expression upon blue light exposure. Furthermore, blue light treatment decreased BCL2 and increased BAX protein levels, thereby promoting apoptosis via caspase activation and PARP cleavage, as also confirmed by flow cytometry. These findings suggest that blue light induces apoptosis via JUN, which activates AP-1 in A2E-laden ARPE-19 cells. The present study provides new insights into the molecular mechanisms underlying blue light-induced retinal damage and its potential contribution to the progression of age-related macular degeneration.

Dihydropyrazines (DHPs) are glycation intermediates produced by nonenzymatic glycation reactions in vivo and in foods. We previously reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) activates endoplasmic reticulum (ER) stress and inhibits autophagy, although its effect on autophagy initiation remained unclear. In this study, we examined the effect of DHP-3 on the autophagy initiation pathway in HepG2 cells. DHP-3 exposure resulted in activation of UNC-51-like kinase 1 (ULK1), the catalytic subunit of the ULK complex essential for autophagy initiation. Notably, phosphorylation of AMP-activated protein kinase (AMPK), an upstream activator of ULK1, was enhanced without a corresponding increase in the ADP/ATP ratio. Among the upstream kinases regulating AMPK, phosphorylation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was increased, whereas that of liver kinase B1 (LKB1) remained unchanged. These findings suggest that DHP-3 activates the CAMKK2–AMPK–ULK1 signaling pathway, thereby inducing autophagy initiation.

Purinergic signaling plays an important role in vascular biology by vascular tone, inflammation, and remodeling through extracellular nucleotides that activate the P1 and P2 receptors. However, the expression patterns of these receptors in commonly used vascular cell models are not well characterized. In this study, we examined purinergic receptor expression in bovine aortic endothelial cells (BAECs), bovine aortic smooth muscle cells (BASMCs), and human vascular endothelial EA.hy926 cells. In BAECs, ADORA2A, ADORA2B, P2X4R, P2X7R, P2Y1R, P2Y2R, P2Y4R, P2Y6R, and P2Y11R were expressed, whereas the other purinergic receptors were not. BASMCs expressed ADORA2A, ADORA2B, P2X4R, P2X5R, P2Y1R, P2Y2R, P2Y6R, and P2Y11R. EA.hy926 cells expressed ADORA2A, ADORA2B, P2X4R, P2Y2R, P2Y6R, and P2Y11R. These results showed distinct expression profiles of purinergic receptors across different cell types. BAECs exhibited a purinergic receptor expression pattern similar to that of primary human vascular endothelial cells, suggesting that BAECs are a suitable model for studying purinergic signaling in vascular endothelial cells.