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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.
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Background: Diffuse lower-grade gliomas (LGGs) are infiltrative and heterogeneous neoplasms. Gene signature including multiple protein-coding genes (PCGs) is widely used as a tumor marker. This study aimed to construct a multi-PCG signature to predict survival for LGG patients. Methods: LGG data including PCG expression profiles and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Survival analysis, receiver operating characteristic (ROC) analysis, and random survival forest algorithm (RSFVH) were used to identify the prognostic PCG signature. Results: From the training (n = 524) and test (n = 431) datasets, a five-PCG signature which can classify LGG patients into low- or high-risk group with a significantly different overall survival (log rank P < 0.001) was screened out and validated. In terms of prognosis predictive performance, the five-PCG signature is stronger than other clinical variables and IDH mutation status. Moreover, the five-PCG signature could further divide radiotherapy patients into two different risk groups. GO and KEGG analysis found that PCGs in the prognostic five-PCG signature were mainly enriched in cell cycle, apoptosis, DNA replication pathways. Conclusions: The new five-PCG signature is a reliable prognostic marker for LGG patients and has a good prospect in clinical application.
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BACKGROUND: Research has shown that the progression of clear cell renal cell carcinoma (ccRCC) is modulated by long non-coding RNAs (lncRNAs). However, the roles of specific lncRNAs in the malignancy of ccRCC are still unknown. METHODS: TCGA and GSE66272 datasets were used to predict differentially expressed genes (DEGs) in ccRCC. ENCORI database was employed to display BIRC5 miRNA network and potential lncRNA interactions for miRNAs. KM plotter and correlation analyses were performed to identify the overall survival (OS)- and BIRC5-related miRNAs. Quantitative real-time PCR (qRT-PCR) was used to verify the BIRC5 mRNA in the seventy paired clinical samples of ccRCC tissues. The ccRCC A498 and 786-O were individually transfected with lncRNA SNHG3 and LINC00997 and then western blotting was used to detect the BIRC5 protein expression. The Dual-luciferase reporter assay was used to examine the regulatory interaction between lncRNA SNHG3 and microRNA (miRNA/miR)-10b-5p. RESULTS: BICR5 is associated with the progression of ccRCC. The two novel lncRNAs (LINC00997, SNHG3) were up-regulated in ccRCC tissues and positively with the BICR5 protein expression. However, Suppressing SNHG3 expression reduced BIRC5 protein expression compared with the LINC00997, most importantly, Suppressing SNHG3 expression suppressed tumor progression in vitro. In addition, SNHG3 promotes the expression of BIRC5 protein by sponging microRNA-10b-5p. CONCLUSIONS: Our findings suggest that SNHG3 plays a vital role in promoting ccRCC via the microRNA-10b-5p/BIRC5 axis and may serve as a novel therapeutic target for the treatment of patients with ccRCC.
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Di-n-butyl phthalate (DBP), a plastic-derived, endocrine-disrupting chemical, is regarded as a male reproductive toxicant. In this study, we investigated the in vitro actions of DBP and mono-n-butyl phthalate (MBP, the main metabolite of DBP) on human sperm functions. Human sperm were treated with DBP (2 nM-6 µM), MBP (1 nM-3 µM), and a mixture of DBP and MBP in vitro. The results showed that only DBP at 6 µM, a dose reported in semen of infertile men, MBP at 3 µM (three times of the reported maximum MBP concentration in semen), and their mixture, had obvious adverse effects on sperm motility, penetration ability and capacitation. In addition, these doses of phthalates suppressed human sperm tyrosine phosphorylation, a key signaling pathway that regulates sperm functions. Our findings indicate that DBP and MBP may compromise human sperm functions by inhibiting sperm tyrosine phosphorylation once they accumulate in semen at high levels.