Inhibition of SND1 overcomes chemoresistance in bladder cancer cells by promoting ferroptosis.

Chemotherapy remains one of the most important adjuvant treatments for bladder cancer (BC). However, similar to other malignancies, BC is prone to chemotherapy resistance and only approximately half of muscle­invasive patients with BC respond to chemotherapy. The present study aimed to reveal the mechanisms underlying chemoresistance in BC cells. Cell viabilities were assessed by CCK­8 assay. The differentiated expression of genes in chemoresistant and their parental BC cells were examined by RNA sequencing. Cell death was determined by flow cytometry. Different cell death inhibitors were used to determine the types of cell death. Levels of reactive oxygen species, iron, glutathione and malondialdehyde were assessed using the corresponding commercial kits. ChIP and dual luciferase activity assays were performed to investigate the interaction between staphylococcal nuclease and tumour domain containing 1 (SND1) and glutathione peroxidase 4 (GPX4) mRNA. RNAi was used to knockdown SND1 or GPX4. The results revealed that SND1 in BC cells were insensitive to cisplatin, and inhibition of SND1 overcame this resistance. Silencing of SND1 enhanced cell death induced by cisplatin by promoting ferroptosis in BC cells. Mechanistically, SND1 was revealed to bind to the 3'UTR region of GPX4 mRNA and stabilise it. Knockdown of GPX4 could also overcome chemoresistance, and overexpressing GPX4 reversed the effects of silencing of GPX4 on the chemosensitivity of BC cells. Thus, targeting the SND1­GPX4 axis may be a potential strategy to overcome chemoresistance in BC cells.

Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells.

Targeting the phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway is a promising strategy for the treatment of various cancers, including bladder cancer (BC). PF-04691502 is a relatively novel dual PI3K/mTOR inhibitor that exerts inhibitory effects against various cancer cells. However, the effects of PF-04691502 in BC cells have not been clarified thus far. This study aimed to evaluate the antitumour effects of PF-04691502 and the mechanisms underlying these antitumour effects in BC cells. The effects of PF-04691502 on the viabilities of BC cells were examined using the cell counting kit 8 (CCK-8) assay. Cell migration and invasion were measured using the wound healing assay and transwell assay, respectively. Cellular apoptosis was determined using flow cytometry. The change in the cellular protein levels was measured using western blotting. siRNA was used to study the role of PTEN in the antitumour effects of PF-04691502. PF-04691502 inhibited the proliferation, migration, and invasion of BC cells. Additionally, PF-04691502 induced apoptosis of BC cells via the intrinsic pathway. PF-04691502 inhibited the expression of Mcl-1 and the PI3K/Akt/mTOR pathway in BC cells. In addition, PF-04691502 increased the apoptosis induced by various chemotherapeutic agents in BC cells. Taken together, PF-04691502 could be used alone or in combination with other chemotherapeutic agents in the treatment of BC.

Baicalein Inhibits the Proliferation of Cervical Cancer Cells Through the GSK3ß-Dependent Pathway.

Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to possess multiple pharmacological activities, such as anticancer and anti-inflammatory properties. This study investigated the effect of baicalein in cervical cancer cells. Cell growth curve and MTT assay were performed and revealed that baicalein inhibited the proliferation of SiHa and HeLa cells in a dose-dependent manner. We further found that baicalein arrested the cell cycle of SiHa and HeLa cells at the G0/G1 phase by suppressing the expression of cyclin D1 through the downregulation of phosphorylated protein kinase B (p-AKT) and phosphorylated glycogen synthase kinase 3ß (p-GSK3ß) according to FACS assays and Western blotting. Moreover, when CHIR-99021, a GSK3ß inhibitor, was added to baicalein-treated SiHa cells, the expression of cyclin D1 was recovered, and cell proliferation was promoted. In conclusion, these data indicated that baicalein suspended the cell cycle at the G0/G1 phase via the downregulation of cyclin D1 through the AKT-GSK3ß signaling pathway and further inhibited the proliferation of SiHa and HeLa cervical cancer cells.

Effect of transcutaneous electrical nerve stimulation therapy for the treatment of primary dysmenorrheal.

BACKGROUND: This study aimed to investigate the effect and safety of transcutaneous electrical nerve stimulation (TENS) therapy for relieving pain in women with primary dysmenorrhea (PD). METHODS: In this study, 134 participants with PD were randomly divided into the intervention group and the sham group, with 67 participants in each group. Participants in the intervention group received TENS, whereas those in the sham group received sham TENS. The primary outcome was measured by the Numeric Rating Scale (NRS). The secondary outcomes were measured by the duration of relief from dysmenorrheal pain, number of ibuprofen tablets taken, and the World Health Organization quality of life (WHOQOL)-BREF score, as well as the adverse events. RESULTS: A total of 122 participants completed the study. Compared to sham TENS, TENS showed a greater effect in pain relief with regard to the NRS (P < .01), duration of relief from dysmenorrheal pain (P < .01), and number of ibuprofen tablets taken (P < .01). However, no significant differences in the quality of life, measured by the WHOQOL-BREF score, were found between 2 groups. The adverse event profiles were also similar between 2 groups. CONCLUSION: TENS was efficacious and safe in relieving pain in participants with PD.