Carboxylesterases (CESs) play important roles in the metabolism of endogenous and foreign compounds in physiological and pharmacological responses. The aim of this study was to investigate the effect of dexamethasone at different doses on the expression of CES1 and CES2. Imidapril and irinotecan hydrochloride (CPT-11) were used as special substrates for CES1 and CES2, respectively. Rat hepatocytes were cultured and treated with different concentrations of dexamethasone. The hydrolytic activity of CES1 and CES2 was tested by incubation experiment and their expression was quantitated by real-time PCR. A pharmacokinetic study was conducted in SD rats to further evaluate the effect of dexamethasone on CESs activity in vivo. Western blotting was performed to investigate the regulatory mechanism related to pregnane X receptor (PXR) and glucocorticoid receptor (GR). The results showed that exposure of cultured rat hepatocytes to nanomolar dexamethasone inhibited the imidapril hydrolase activity, which was slightly elevated by micromolar dexamethasone. For CES2, CPT-11 hydrolase activity was induced only when dexamethasone reached micromolar levels. The real-time PCR demonstrated that CES1 mRNA was markedly decreased by nanomolar dexamethasone and increased by micromolar dexamethasone, whereas CES2 mRNA was significantly increased by micromolar dexamethasone. The results of a complementary animal study showed that the concurrent administration of dexamethasone significantly increased the plasma concentration of the metabolite of imidapril while the ratio of CPT-11 to its metabolite SN-38 was significantly decreased. PXR protein was gradually increased by serial concentrations of dexamethasone. However, only nanomolar dexamethasone elevated the level of GR protein. The different concentrations of dexamethasone required suggested that suppression of CES1 may be mediated by GR whereas the induction of CES2 may result from the role of PXR. It was concluded that dexamethasone at different concentrations can differentially regulate CES1 and CES2.

Objective:To evaluate the inhibitory effect of 5 Chinese herbal medicinal ingredients baicalin, andrographolide, hes-peridin, polyphenols and daidzein on the activity of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2). Methods: The spe-cial probes respectively for CES1 and CES2, namely imidapril and CPT-11, imidaprilat and SN-38, were used to investigate the poten-tial effect of the above drugs on CES1 and CES2 in rat liver microsomes incubation system. Results:Compared with that in the control group, the activity of CES1 and CES2 was not significantly influenced by the above 5 Chinese herbal medicinal ingredients ( P <0. 05). Conclusion:Baicalin, andrographolide, hesperidin, polyphenols and daidzein exhibit no inhibitory effect against CES1 and CES2, and further studies should be conducted to confirm the effect in vivo.

Objective To explore the influence of different administration time on antidepressant effect of seven clinical common antidepressants. Methods Male mice were randomly divided into eight groups:venlafaxine (75 mg/kg), sertraline (20 mg/kg), fluoxetine (20 mg/kg), doxepin (15 mg/kg), mirtazapine (15 mg/kg), citalopram (40 mg/kg), trazodo?ne (50 mg/kg) and control (saline) groups. Each group contained 36 mice. Drugs were administered to 6 mice per group 30 min before forced swimming test at the 6 time points (9:00, 13:00 and 17:00 as light phase and 21:00, 1:00 and 5:00 as dark phase). Forced swimming test was applied to determine the influence of dosing time on anti-immobility effect of seven antidepressants at each time point. Results Immobility time in venlafaxine group and sertraline group significant?ly decreased compared with that of control group at all time points(all P<0.05). Moreover, anti-immobility effects of ven?lafaxine, fluoxetine, mirtazapine and doxepin were better during the dark phase than during the light phase (all P<0.05). In addition, immobility time in sertraline group decreased at the late part of dark phase (5:00) and the early part of light phase (9:00) compared with other phases (P<0.05). Conclusions Most antidepressants show 24-h rhythm dependent an?ti-immobility effects, but rhythmic patterns are not completely consistent among different antidepressants. Further study is needed to explore the chronopharmacological mechanism and clinical applications of these antidepressants.

Carboxylesterases (CESs) play important roles in the metabolism of endogenous and foreign compounds in physiological and pharmacological responses. The aim of this study was to investigate the effect of dexamethasone at different doses on the expression of CES1 and CES2. Imidapril and irinotecan hydrochloride (CPT-11) were used as special substrates for CES1 and CES2, respectively. Rat hepatocytes were cultured and treated with different concentrations of dexamethasone. The hydrolytic activity of CES1 and CES2 was tested by incubation experiment and their expression was quantitated by real-time PCR. A pharmacokinetic study was conducted in SD rats to further evaluate the effect of dexamethasone on CESs activity in vivo. Western blotting was performed to investigate the regulatory mechanism related to pregnane X receptor (PXR) and glucocorticoid receptor (GR). The results showed that exposure of cultured rat hepatocytes to nanomolar dexamethasone inhibited the imidapril hydrolase activity, which was slightly elevated by micromolar dexamethasone. For CES2, CPT-11 hydrolase activity was induced only when dexamethasone reached micromolar levels. The real-time PCR demonstrated that CES1 mRNA was markedly decreased by nanomolar dexamethasone and increased by micromolar dexamethasone, whereas CES2 mRNA was significantly increased by micromolar dexamethasone. The results of a complementary animal study showed that the concurrent administration of dexamethasone significantly increased the plasma concentration of the metabolite of imidapril while the ratio of CPT-11 to its metabolite SN-38 was significantly decreased. PXR protein was gradually increased by serial concentrations of dexamethasone. However, only nanomolar dexamethasone elevated the level of GR protein. The different concentrations of dexamethasone required suggested that suppression of CES1 may be mediated by GR whereas the induction of CES2 may result from the role of PXR. It was concluded that dexamethasone at different concentrations can differentially regulate CES1 and CES2.
Animals ; Carboxylic Ester Hydrolases ; genetics ; Dexamethasone ; pharmacology ; Gene Expression ; drug effects ; immunology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Cytoplasmic and Nuclear ; metabolism

Calculus bovis(CB) exerts potencial pharmacological effects through anti-oxidation, anti-inflammatory, and anti-hypoxic injury. We reviewed the published literature about CB and its substitutes in the treatment of central nervous system diseases, in order to provide a reference for the deeper application and study in the future.