FOXM1 transcriptional regulation of RacGAP1 activates the PI3K/AKT signaling pathway to promote the proliferation, migration, and invasion of cervical cancer cells.

BACKGROUND: Cervical cancer (CC) is the most common gynecological tumor disease in women, which occurs at the junction of cervical squamous columnar epithelium. We investigated the effect and mechanism of transcription factor FOXM1 synergizing RacGAP1 in the proliferation, migration, and invasion of CC cells. METHODS: Here, we analyzed the correlation between FOXM1 and RacGAP1 and the clinicopathological features of 68 CC patients. RT-qPCR was used to assess FOXM1 and RacGAP1 mRNA expression in CC tissues and cells. Cell proliferation was assessed by CCK-8 and EDU assays. Transwell assay was applied to test migration and invasion. Cell apoptosis was evaluated utilizing flow cytometry. ChIP and dual-luciferase reporter assays confirmed the interaction of FOXM1 and RacGAP1. Protein levels of FOXM1 and RacGAP1, as well as PI3K/AKT, were analyzed by Western blot. RESULTS: FOXM1 expression was correlated with FIGO stage and histological grade, and RacGAP1 expression was correlated with histological grade. FOXM1 and RacGAP1 levels were increased in CC tissues, and higher expressed in human CC cell lines than that in an immortalized HPV-negative skin keratinocyte line (HaCaT). Depleted RacGAP1 suppressed CC cell proliferation, migration and invasion, and promoted apoptosis. RacGAP1 was a target gene of FOXM1, and FOXM1 positively regulated RacGAP1 expression. FOXM1 had a synergistic effect with RacGAP1 to exert oncogenic function in CC by activating the PI3K/AKT signaling. CONCLUSION: FOXM1 cooperates with RacGAP1 to induce CC cell proliferation, migration and invasion, inhibit apoptosis, and regulate PI3K/AKT signaling to promote CC progression.

Occurrence and Health Risks of Organic Micropollutants in Tap Water in Dalian.

Organic micropollutants (OMPs) in tap water may pose risks to human health. Previous studies on the potential health risks of OMPs in tap water may have underestimated the potential health risks of OMPs due to their limited coverage in target pollutants and incomplete toxicity data. In this study, tap water samples were collected in 37 sampling sites in Dalian, China. More than 1,200 target pollutants were screened by combining screening analysis and target analysis. A total of 93 OMPs were detected, with concentration summation ranging from 157 to 1.7 × 104 ng/L among different sampling sites. A total of 17 OMPs (12 agrochemicals, 3 pharmaceuticals and personal care products, and 2 other compounds) were detected in over 80% of the sampling sites. Especially, imidacloprid, tebuconazole, and atrazine-desethyl were found in all the sampling sites. Computational toxicology models were adopted to predict the missing toxicity threshold values of the identified chemicals. Noncarcinogenic risks were estimated to be negligible among all the sampling sites, while carcinogenic risks at six sites were above 10-6 but below 10-4, indicating non-negligible risks. Griseofulvin contributed the most to the carcinogenic risk. This study offers valuable insights that can guide future initiatives to safeguard tap water safety.

An Efficient UPLC-MS/MS Method Established to Detect Relugolix Concentration in Rat Plasma.

Relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, has been well studied in the treatment of endometriosis symptomatic. It is mainly metabolized by the CYP3A subfamily of P450 enzymes, while minorly metabolized by CYP2C8. Daidzein in different dose groups exhibited a certain induction on the mRNA expression level of CYP3A4 and resulted in the potent induction of CYP3A4. However, it is still unknown whether daidzein and relugolix interact. We developed an effective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to study the effect of daidzein on the pharmacokinetics of relugolix in rats after oral administration of 12 mg/kg relugolix in a single or mixed of 50 mg/kg daidzein. The results showed that the method had respectable linearity (r 2 > 0.999) on the scale of 0.7-1000 ng/mL. The intra-day precision was between 3.0% and 8.4% in this assay, and the inter-day was between 4.0% and 11.7%. The intra-day accuracy was from -4.3% to 6.1%, and the inter-day was 2.9% to 12.1%. Another three key indicators, including the stability, the recovery rate of extraction and the new technique's matrix effect, were perfectly in accord with the test verification rule in the biological medium by the United States Food and Drug Administration. Meanwhile, treatment with daidzein led to a decrease in Cmax and AUC0-t of relugolix by about 15.56% and 21.36%, respectively. Although there was no statistical difference in pharmacokinetic parameters, it reflected the induction trend of daidzein on relugolix metabolism for food-drug interaction. It would provide reference and improvement value for subsequent experiments.

Effects of lomefloxacin on survival, growth and reproduction of Daphnia magna under simulated sunlight radiation.

Lomefloxacin, an antibacterial agent with known photo-induced toxicity in clinical studies, is frequently detected in aquatic environments. Investigating the photo-induced toxicity of lomefloxacin in aquatic organisms is therefore of importance for assessing its ecological risks. In this study, the effects of lomefloxacin on survival, growth and reproduction of Daphnia magna under simulated sunlight radiation (SSR) were investigated, and the mechanism of action was revealed. Results indicated that SSR containing UV radiation increased the acute toxicity of lomefloxacin to Daphnia magna relative to white fluorescent light irradiation. Under SSR, 100 µM lomefloxacin significantly enhanced reactive oxygen species (ROS) generation and lipid peroxidation, and decreased activities of superoxide dismutase and catalase. The biochemical observations and apparent effects on the organism indicate that oxidative stress plays a central role in the acute photo-induced toxicity. Chronic toxicity results showed that SSR significantly affected growth and reproduction of Daphnia magna, whereas lomefloxacin reduced the damage of UV radiation in SSR through light shielding. This study provides insight into the mechanism of photo-induced toxicity and can support the risk assessment of chemicals in the aquatic environment by including the impacts of sunlight irradiation on toxicity.