Aristolochic acid I (AA I) is one of the most abundant and toxic aristolochic acids that is reported to cause Aristolochic acid nephropathy (AAN). This paper was designed to assess whether mitochondrial Uncoupling Protein 2 (UCP2), which plays an antioxidative and antiapoptotic role, could protect human renal proximal tubular epithelial (HK-2) cells from toxicity induced by AA I. In this study, HK-2 cells were treated with different concentrations of AA I with or without UCP2 inhibitor (genipin). To upregulate the expression of UCP2 in HK-2 cells, UCP2-DNA transfection was performed. The cell viability was evaluated by colorimetric method using MTT. A series of related biological events such as Reactive Oxygen Species (ROS), Glutathione peroxidase (GSH-Px), and Malondialdehyde (MDA) were evaluated. The results showed that the cytotoxicity of AA I with genipin group was much higher than that of AA I alone. Genipin dramatically boosted oxidative stress and exacerbated AA I-induced apoptosis. Furthermore, the increased expression of UCP2 can reduce the toxicity of AA I on HK-2 cells and upregulation of UCP2 expression can reduce AA I-induced oxidative stress and apoptosis. In conclusion, UCP2 might be a potential target for alleviating AA I-induced nephrotoxicity.

Background: As GLP-1 receptor agonists (GLP-1 RAs) are increasingly used worldwide, concerns about their association with mood disorders have grown. Yet real-world observational studies have produced conflicting findings. This study aims to fully examine the link between GLP-1 RAs and emotional/behavioral outcomes. Methods: Disproportionality analysis of GLP-1 RA adverse events was conducted using FAERS data. Mendelian randomization (MR) employed GLP1R cis-eQTLs as instrumental variables to assess links with mood/behavior-related disorders. Summary-data MR (SMR) was then performed using GLP1R cis-eQTL data. Results: 275,718 adverse events (AEs) associated with GLP-1 RAs were retrieved and analyzed. A mild signal for suicide-related AEs was observed only in the obesity indication subgroup (ROR:1.65, 95% CI: 1.28–2.12). Genetic evidence showed that GLP-1 RAs were likely associated with reduced risks of anxiety, depression, emotional lability, bipolar disorder, and suicide. Mediational analysis indicated that weight loss partially mediated the causal effects of GLP-1 RAs on depression and emotional lability, accounting for 18.28% (95% CI: 9.46–27.10%, P = 0.038) and 7.65% (95% CI: 5.66–9.64%, P < 0.001) of the total effects, respectively. SMR analysis showed that genetically predicted GLP1R expression was negatively associated with anxiety (OR: 0.79, 95% CI: 0.64–0.98, P = 0.031), with no significant associations for other emotional or behavioral outcomes. Conclusions: Both observational and MR analyses showed that patients treated with GLP-1 RAs may have no increased risk of emotional and behavioral disorders. Instead, genetic proxy activation of GLP-1 RAs may reduce the risk of anxiety, depression, and emotional lability.