Meiotic Cell Cycle Progression in Mouse Oocytes: Role of Cyclins.

All eukaryotic cells, including oocytes, utilize an engine called cyclin-dependent kinase (Cdk) to drive the cell cycle. Cdks are activated by a co-factor called cyclin, which regulates their activity. The key Cdk-cyclin complex that regulates the oocyte cell cycle is known as Cdk1-cyclin B1. Recent studies have elucidated the roles of other cyclins, such as B2, B3, A2, and O, in oocyte cell cycle regulation. This review aims to discuss the recently discovered roles of various cyclins in mouse oocyte cell cycle regulation in accordance with the sequential progression of the cell cycle. In addition, this review addresses the translation and degradation of cyclins to modulate the activity of Cdks. Overall, the literature indicates that each cyclin performs unique and redundant functions at various stages of the cell cycle, while their expression and degradation are tightly regulated. Taken together, this review provides new insights into the regulatory role and function of cyclins in oocyte cell cycle progression.

Investigation of pharmacokinetic parameters of bakuchicin isolated from Psoralea corylifolia in mice.

Bakuchicin is a furanocoumarin isolated from the seeds of Psoralea corylifolia, which is used in oriental medicine. However, limited information on the pharmacokinetics of bakuchicin is available and in addition, no determined method has been devised to quantify bakuchicin levels in the plasma. In the present study, we developed and validated a quantification method using liquid chromatography (LC) coupled with tandem mass spectrometry (LC-MS/MS), which was applied to a pharmacokinetic investigation in mouse plasma. LC was performed using an ACE 5 C18 column, and a mixture of acetonitrile and water containing 0.1% formic acid was used as the mobile phase at a flow rate of 220µL/min. Bakuchicin transition ions in multiple reaction-monitoring modes using positive ionization were observed at m/z 187.0 to m/z 131.0. Bakuchicin and the internal standard (reserpine) had retention times of 4.5 and 4.3min, respectively. Acceptable linearity (r2=0.996) was observed over the concentration range of 20-1000ng/mL, with a lower quantification limit of 20ng/mL in mouse plasma. This method was successfully applied to determine the pharmacokinetic parameters of bakuchicin in mouse plasma and showed that the bioavailability of bakuchicin was 58.3% at 5mg/kg oral administration.

Investigation of the Regulatory Effects of Saccharin on Cytochrome P450s in Male ICR Mice.

Saccharin, the first artificial sweetener, was discovered in 1879 that do not have any calories and is approximately 200~700 times sweeter than sugar. Saccharin was the most common domestically produced sweetener in Korea in 2010, and it has been used as an alternative to sugar in many products. The interaction between artificial sweeteners and drugs may affect the drug metabolism in patients with diabetes, cancer, and liver damage, this interaction has not been clarified thus far. Here, we examined the effects of the potential saccharin-drug interaction on the activities of 5 cytochrome P450 (CYPs) in male ICR mice; further, we examined the effects of saccharin (4,000 mg/kg) on the pharmacokinetics of bupropion after pretreatment of mice with saccharin for 7 days and after concomitant administration of bupropion and saccharin. Our results showed saccharin did not have a significant effect on the 5 CYPs in the S9 fractions obtained from the liver of mice. In addition, we observed no differences in the pharmacokinetic parameters of bupropion between the control group and the groups pretreated with saccharin and that receiving concomitant administration of saccharin. Thus, our results showed that saccharin is safe and the risk of saccharin-drug interaction is very low.

Identification of absolute conversion to geraldol from fisetin and pharmacokinetics in mouse.

Fisetin (3,3',4',7-tetrahydroxyflavone) is a flavonoid found in several fruits, vegetables, nuts, and wine and has anti-oxidant, anti-inflammatory, and anti-angiogenic properties. Geraldol is the 3'-methoxylated metabolite of fisetin (3,4',7-trihydroxy-3'-methoxyflavone). The concentration of fisetin and geraldol in mouse plasma was determined by LC-MS/MS, following direct protein precipitation. These concentrations were determined after administration of fisetin at doses of 2mg/kg (i.v.) and 100 and 200mg/kg (p.o.). The method was validated in terms of linearity, accuracy, precision, matrix effect, and stability. The pharmacokinetics parameters of fisetin and geraldol were successfully determined using a validated method in mice. Results indicated that fisetin was very rapidly methylated to geraldol in vivo. Following administration of fisetin, it was observed that the Cmax and AUC values for geraldol were higher than those of fisetin. The absolute bioavailability of fisetin was calculated as 7.8% and 31.7% after oral administration of 100 and 200mg/kg fisetin, respectively. This method was successfully applied to determine the pharmacokinetic parameters of fisetin and its main metabolite geraldol in mouse plasma. Geraldol was the dominant circulating metabolite after fisetin administration in vivo.

Decreased absorption of midazolam in the stomach due to low pH induced by co-administration of Banha-sasim-tang.

OBJECTIVES: Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb-drug interactions and may modify the clinical safety profile of therapeutic drugs. METHODS: We investigated the potential herb-drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1ʹ-hydroxymidazolam (1ʹ-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). RESULTS: It was found that the AUC of MDZ and 1ʹ-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. CONCLUSIONS: The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.

Roles of plant hormones and anti-apoptosis genes during drought stress in rice (Oryza sativa L.).

We previously identified the rice (Oryza sativa) senescence-associated gene OsSAP which encodes a highly conserved protein involved in anti-apoptotic activity. This novel Bax suppressor-related gene regulates tolerance to multiple stresses in yeast. Here, we show the effects of drought stress on leaf and root tissues of plants over-expressing OsSAP in relation to the levels of phytohormones, abscisic acid (ABA), jasmonic acid (JA), indole-3-carboxylic acid (ICA), gibberellic acid (GA3), and zeatin. Results showed that rice plants over-expressing SAP were tolerant to drought stress compared to wild type and the plants over-expressing AtBI-1, which is a homolog of the human Bax inhibitor-1 in Arabidopsis. ABA and JA levels in OsSAP and AtBI-1 transgenic plants consistently increased up to at least 3 days after drought treatment, whereas lower GA3 levels were recorded during early drought period. Comparison between control and transgenic plants overexpressing anti-apoptosis genes OsSAP and AtBI-1 resulted in different patterns of hormone levels, indicating that these genes are involved in the plant responses to drought stress and present an opportunity for further study on drought stress tolerance in rice and other plant species.