Ginkgo Biflavones Cause p53 Wild-Type Dependent Cell Death in a Transcription-Independent Manner of p53.

Ginkgo biloba, as a medicinal plant in both traditional and western medicine, emerged as a potential therapeutic agent for the management of a variety of diseases, but ginkgo biflavones (bilobetin, isoginkgetin, and ginkgetin) application in cancer therapy and underlying mechanisms of action remained elusive. In the present study, we identified ginkgo biflavones as potential p53 activators that could enhance p53 protein expression level by inhibiting MDM2 protein expression. At the same time, they induced cell death independent of p53 transcriptional activity. Moreover, ginkgetin was a standout among ginkgo biflavones that reduced the survival of HCT-116 cells by induction of apoptosis and G2/M phase arrest. Furthermore, ginkgo biflavones induced ROS generation significantly, which resulted in ferroptosis. Finally, we provide evidence that ginkgetin strengthened the antitumor effect of fluorouracil (5-FU) in the HCT-116 colon cancer xenograft model. To sum up, ginkgo biflavones represent a new class of p53 activator that depends on the p53 wild-type status and warrants further exploration as potential anticancer agents.

Virtual screening and activity evaluation of human uric acid transporter 1 (hURAT1) inhibitors.

Hyperuricemia is a disease caused by disorder of purine metabolism, mainly due to insufficient renal excretion of uric acid. Urate transporter 1 (URAT1) is the most widely studied target of urate transporters, and used for uric acid (UA) reabsorption. This study used the AlphaFold2 algorithm to predict the structure of URAT1. Virtual screening and biological evaluation were used to discover novel URAT1 inhibitors that target the critical amino acids. Seven compounds were screened from the T2220 database and validated as URAT1 inhibitors by cell biology experiments. The IC50 values of benbromarone, NP023335, TN1148, and TN1008 were 6.878, 18.46, 24.64, and 53.04 µM, respectively. Molecular dynamics simulation was used to investigate the binding mechanism of URAT1 to NP023335, which forms stable contact with Ser35, Phe365, and Arg477. These interactions are essential for maintaining the biological activity of NP023335. The three compounds' pharmacokinetic characteristics were predicted, and NP023335's properties matched those of an empirical medication with the benefits of high solubility, low cardiotoxicity, good membrane permeability, and oral absorption. The natural product NP023335 will serve as a promising hit compound for facilitating the further design of novel URAT1 inhibitors.