The peroxisome proliferator‐activated receptor gamma (PPARγ) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer's disease. However, the molecular mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation. Treatment with troglitazone decreased tau‐Thr²³¹ phosphorylation and p35, the specific activator of cyclin‐dependent kinase 5 (CDK5), in a dose‐ and time‐dependent manner. Troglitazone also decreased CDK5 enzymatic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone‐induced decrease in tau‐Thr²³¹ phosphorylation. Treatment with either MG‐132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the observed inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPARγ antagonist, did not alter the observed inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone‐induced inhibitions of tau‐Thr²³¹ phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3β, protein kinase A, and protein phosphatase 2A signaling pathways. Finally, we also found that the same observed inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau‐Thr²³¹ phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degradation of p35 and a PPARγ‐independent signaling pathway. image Thiazolidinediones (TZDs) decrease tau‐Thr²³¹ phosphorylation via the inhibition of CDK5 enzymatic activity, which is mediated by the enhanced proteasomal degradation of p35 and a PPARγ‐independent signaling pathway. This molecular mechanism implies a role for TZD drugs in the prevention and treatment of Alzheimer's disease.

Hwang YJ, et al. J Korean Med Sci. 2023 Oct;38:e335. https://doi.org/10.3346/jkms.2023.38.e335

Hwang YJ, et al. J Korean Med Sci. 2020 Aug;35(35):e289. https://doi.org/10.3346/jkms.2020.35.e289

Zearalenone (ZEN) is a non-steroidal mycotoxin that has various toxicological impacts on mammalian health. Here, we found that ZEN significantly affected the production of nitric oxide (NO) and the expression of endothelial NO synthase (eNOS) of bovine aortic endothelial cells (BAECs). A promoter analysis using 5′-serially deleted human eNOS promoter revealed that the proximal region (−135 to +22) was responsible for ZEN-mediated reduction of the human eNOS promoter activity. This effect was reversed by mutation of two specificity protein 1 (Sp1) binding elements in the human eNOS promoter. A chromatin immunoprecipitation assay revealed that ZEN increased Sp1 binding to the bovine eNOS promoter region (−113 to −12), which is homologous to −135 to +22 of the human eNOS promoter region. We also found that ZEN promoted the binding of the pregnane X receptor (PXR) to Sp1 of the bovine eNOS, consequently decreasing eNOS expression. This reduction of eNOS could have contributed to the decreased acetylcholine-induced vessel relaxation upon ZEN treatment in our ex vivo study using mouse aortas. In conclusion, our data demonstrate that ZEN decreases eNOS expression by enhancing the binding of PXR-Sp1 to the eNOS promoter, thereby decreasing NO production and potentially causing vessel dysfunction.