Background: Prostate cancer is the second leading cause of cancer-related death among males in America. The patients’ survival time is significantly reduced after prostate cancer develops into castration-resistant prostate cancer (CRPC). It has been reported that AKR1C3 is involved in this progression, and that its abnormal expression is directly correlated with the degree of CRPC malignancy. Genistein is one of the active components of soy isoflavones, and many studies have suggested that it has a better inhibitory effect on CRPC. Objective: This study aimed to investigate the antitumor effect of genistein on CRPC and the potential mechanism of action. Design: A xenograft tumor mouse model established with 22RV1 cells was divided into the experimental group and the control group, and the former was given 100 mg/kg.bw/day of genistein, with 22RV1, VCaP, and RWPE-1 cells cultured in a hormone-free serum environment and treated with different concentrations of genistein (0, 12.5, 25, 50, and 100 μmol/L) for 48 h. Molecular docking was used to elucidate the molecular interactions between genistein and AKR1C3. Results: Genistein inhibits CRPC cell proliferation and in vivo tumorigenesis. The western blot analysis confirmed that the genistein significantly inhibited prostate-specific antigen production in a dose-dependent manner. In further results, AKR1C3 expression was decreased in both the xenograft tumor tissues and the CRPC cell lines following genistein gavage feeding compared to the control group, with the reduction becoming more obvious as the concentration of genistein was increased. When the genistein was combined with AKR1C3 small interfering ribonucleic acid and an AKR1C3 inhibitor (ASP-9521), the inhibitory effect on the AKR1C3 was more pronounced. In addition, the molecular docking results suggested that the genistein had a strong affinity with the AKR1C3, and that it could be a promising AKR1C3 inhibitor. Conclusion: Genistein inhibits the progression of CRPC via the suppression of AKR1C3.

Retinal photochemical damage (RPD) can be the main cause of various ophthalmic diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Patients' vision can be severely impaired in the late stages of these eye diseases. Delphinidin, one of the major functional components of anthocyanins, has shown preventive effects on RPD and ophthalmic diseases induced by RPD, but the underlying mechanisms are complex and unclear. This study investigated the protective effect of delphinidin on photochemically damaged retinal photoreceptors in vivo and in vitro and characterized the underlying mechanisms. In vivo experiments showed that delphinidin downregulated the expression levels of caspase-3, and reduced the apoptosis rate of retinal photoreceptor cells in SD rats, thus protecting the structural integrity of the retina. In vitro experiments showed that delphinidin could maintain the normal ultrastructure of the mitochondrial endoplasmic reticulum membrane, reduce the apoptosis rate caused by light injury and improve the survival rate of light-damaged 661W cells. In addition, we found that delphinidin increased the mRNA and activated protein expression of NF-κB p65, NF-κB p50, and IκBα in photochemically injured 661W cells, and decreased the mRNA and protein expression of AP-1 (c-fos/c-jun) and Caspase-3/-8/-9. Compared with the model group, phospho-NF-κB p65 in delphinidin-treated cells was translocated into the nucleus, and the nuclear phospho-NF-κB p65 expression was increased, while nuclear c-jun expression was decreased. These results suggested that delphinidin resisted RPD-induced apoptosis of retinal photoreceptors by regulating the expression of factors involved in the NF-κB/AP-1/caspase-3 pathway.

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