Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

The transcription factor NAC102 confers cadmium tolerance by regulating WAKL11 expression and cell wall pectin metabolism in Arabidopsis.

Cadmium (Cd) toxicity severely limits plant growth and development. Moreover, Cd accumulation in vegetables, fruits, and food crops poses health risks to animals and humans. Although the root cell wall has been implicated in Cd stress in plants, whether Cd binding by cell wall polysaccharides contributes to tolerance remains controversial, and the mechanism underlying transcriptional regulation of cell wall polysaccharide biosynthesis in response to Cd stress is unknown. Here, we functionally characterized an Arabidopsis thaliana NAC-type transcription factor, NAC102, revealing its role in Cd stress responses. Cd stress rapidly induced accumulation of NAC102.1, the major transcript encoding functional NAC102, especially in the root apex. Compared to wild type (WT) plants, a nac102 mutant exhibited enhanced Cd sensitivity, whereas NAC102.1-overexpressing plants displayed the opposite phenotype. Furthermore, NAC102 localizes to the nucleus, binds directly to the promoter of WALL-ASSOCIATED KINASE-LIKE PROTEIN11 (WAKL11), and induces transcription, thereby facilitating pectin degradation and decreasing Cd binding by pectin. Moreover, WAKL11 overexpression restored Cd tolerance in nac102 mutants to the WT levels, which was correlated with a lower pectin content and lower levels of pectin-bound Cd. Taken together, our work shows that the NAC102-WAKL11 module regulates cell wall pectin metabolism and Cd binding, thus conferring Cd tolerance in Arabidopsis.

New indolequinazoline alkaloids from the fruits of Tetradium ruticarpum.

In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.