Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability.

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.

Electrical stimulation accelerates neurite regeneration in axotomized dorsal root ganglion neurons by increasing MMP-2 expression.

Electrical stimulation (ES) can be useful for promoting the regeneration of injured axons, but the mechanism underlying its positive effects is largely unknown. The current study aimed to investigate whether ES could enhance the regeneration of injured neurites in dorsal root ganglion explants and regulate the MMP-2 expression level, which is correlated with regeneration. Significantly increased neurite regeneration and MMP-2 expression was observed in the ES group compared with the sham group. However, an MMP inhibitor significantly decreased this ES-induced neurite regeneration. Our data suggest that the positive effect of ES on neurite regeneration could likely be mediated by an increase in MMP-2 expression, thereby promoting the regeneration of injured neurites.

Characterization of Soybean Germinated Embryo Extract as an Estrogen Receptor Subtype-Selective and Tissue-Specific Modulator.

Phytoestrogens possess beneficial effects in the management of menopausal symptoms with few side effects. Soybeans are major natural sources of isoflavones, with high estrogen receptor (ER)-ß selectivity. The objective of this study therefore was to develop a solvent-mediated extraction method for soybean germinated embryos (SGEs) and to investigate the biological activities of the extract. Ethanolic extraction yielded the SGE extract (SGEE), which had a unique composition of biologically active aglycones and soyasaponins. SGEE showed a proliferative effect in MCF7 cells and ERß-selective transcriptional activities in human embryonic kidney cells. In addition, oral administration of SGEE to ovariectomized rats resulted in the induction of ERß and estrogen-responsive genes in the uterus and a decrease in tail skin temperature and uterus weight. Our data suggest that germination and ethanolic extraction are effective measures for producing isoflavone-rich food supplements, which may be useful as alternative menopausal hormone therapy.