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OBJECTIVE To demonstrate the long-or short-term impacts of neonatal Pxr(pregnane X receptor) agonists exposureon DMEs (drug metabolism enzymes) expression in adulthood. METHODS C57BL/6 mice(day 5,postnatal)were injected with different doses(0,50,100,150,200 mg·kg-1·d-1, constitutive 4 d)of PCN(pregnenolone-16a-carbonitrile).Mice at different ages(day 5,10,15,25,postna-tal)were administrated with 200 mg·kg-1·d-1PCN in constitutive 4 d.All mice were sacrificed at day 60 after birth. Liver samples were collected for detecting the expression of Pxr target genes. RESULTS Compared with vehicle group, the significant inductions of Cyp2b10, Cyp3a11 and Pxrwere observed in high dose groups (150, 200 mg·kg-1·d-1, 5-8 d after birth) both in male and female mice (n=4-9/group,P<0.05).Furthermore,high dose groups(200 mg·kg-1·d-1,5-8 d after birth)were found to have higher mRNA expression levels of Cyp2a4,Ugt1a1,Abcc4,and Oatpla4 in female mice,while Papss2 in male mice compared with vehicle groups (n= 4-9/group, P<0.05). Interestingly, a decreased mRNA expression of Sult2a1 was identified in 200 (5-8 d) groups (n=4-9/group, P<0.05). Consistent with these results, the protein expression of Cyp3a11 was only increased in 200 (5-8 d) groups compared with the vehicle groups(n=3/group,P<0.05).Importantly,the persistent impacts on DMEs only occurred in day 5 and day 25 treatment groups,not day 10 and day 15 groups(n=4/group).CONCLUSION Neonatal Pxr activation has a long-term effect on the expression of DMEs in C57BL/6 mice.Dose and treatment exposure time are two key factors involved in this permanent alteration procedure.
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OBJECTIVE To explore the effects of perinatal inflammation on the expression of proin-flammatory cytokines and DMEs (drug metabolism enzymes) in offspring mice. METHODS C57BL/6 maternal mice were administrated with single dose 100 μg·kg-1LPS(lipopolysaccharide)or saline(vehicle) during gestation (day 10 after fertilization). Offspring mice were sacrificed at 30 d after birth and liver samples were collected.Real-time PCR was adopted to test the mRNA expression of proinflammatory cytokines (Nrlp3 and IL-1β), nuclear receptors (Pxr and Car), and DMEs (Cyp3a11, 2b10, 1a2, and Ugt1a1).RESULTS Gender different expression of candidate genes was observed.The expression of Car,in the maternal injection of LPS groups,was significantly decreased in both female and male offspring (n=3-8/group, P<0.01). Concomitantly, a significantly lower expression of Cyp3a11 was found in both female and male offspring (P<0.01, P<0.05, respectively). Furthermore, the expression of Ugt1a1 was reduced in male offspring following maternal administration of LPS (P<0.01). In male offspring, Nrlp3 expression was specially decreased(P<0.05).Interestingly,there was an approximately 66% reduction in mRNA level of Cyp1a2 in female offspring (P<0.01), while in male offspring Cyp1a2 expression showed an increased trend (P>0.05) compared with vehicle group. The expression of Pxr, Cyp2b10, and IL-1β was no difference between LPS treatment group and vehicle group(P>0.05).CONCLUSION Maternal LPS administration affects the expression of proinflammatory cytokines, nuclear receptors and DMEs in mouse offspring.
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OBJECTIVE To observe the effects of glycogen synthase 3β (GSK-3β) in the regula-tion of NLRP3 inflammasome activation after acute myocardial infarction (MI) in Sprague Dawley(SD) rats. METHODS Ligation of the left anterior descending (LAD) in SD rats was used to establish an acute myocardial infarction model. SD rats were randomly divided into 3 groups (n=10, each group):sham group,MI group,and MI+SB group:the GSK-3β inhibitor(SB216763)was given 1 h by intrave-nous injection(0.6 mg·kg-1·d-1)before surgery.The serum and heart tissue were collected to measure lactate dehydrogenase (LDH) and IL-1β content and mRNA and protein levels of NLRP3, ASC, Cas-pase-1,IL-1β and GSK-3β after 2 days and 7 days operation,respectively.RESULTS The serum levels of LDH and IL-1β in the MI group were significantly higher than those in the sham group(P<0.01),and the MI+SB group was obviously lower than the MI group(P<0.01).In addition,mRNA and protein levels of NNLRP3, ASC, Caspase-1, IL-1β and GSK-3β expressions in MI group were clearly increased (P<0.01) compared with those in sham group.These indicators were significantly decreased in SB+MI group (P<0.01). Interestingly, the indicators were all higher at 7 days than 2 days. CONCLUSION GSK-3β inhibition induces cardioprotection via attenuating the activation of NLRP3 inflammasome after the acute myocardial infarction in rats.
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<p><b>OBJECTIVE</b>To investigate the effect of midazolam on human ether-a-go-go (hERG) K+ channels exogenously expressed in human embryonic kidney cells (HEK-293) and the underlying molecular mechanisms.</p><p><b>METHODS</b>Whole-cell patch clamp technique was used to record WT, Y652A and F656C hERG K+ current expressed in HEK-293 cells.</p><p><b>RESULTS</b>Midazolam inhibited hERG K+ current in a concentration-dependent manner, the half-maximum block concentrations (IC50) values were (1.31 ± 0.32) µmol/L. The half-activation voltage (V1/2) were (2.32 ± 0.38) mV for the control and (-1.96 ± 0.83) mV for 1.0 µmol/L midazolam. The half-inactivation voltage (V1/2) was slightly shifted towards negative voltages from (-49.25 ± 0.69) mV in control to (-57.53 ± 0.53) mV after 1.0 µmol/L midazolam (P < 0.05). Mutations in drug-binding sites (Y652A or F656C) of the hERG channel significantly attenuated the hERG current blockade by midazolam.</p><p><b>CONCLUSION</b>Midazolam can block hERG K+ channel and cause the speed of inactivation faster. Mutations in the drug-binding sites (Y652 or F656) of the hERG channel were found to attenuate hERG current blockage by midazolam.</p>
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Humans , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels , HEK293 Cells , Midazolam , Pharmacology , Mutation , Patch-Clamp Techniques , Potassium Channel Blockers , PharmacologyABSTRACT
<p><b>AIM</b>To learn the electrophysiological interference of levofloxacin (LVFX) to heart in guinea pig.</p><p><b>METHODS</b>High, moderate and low doses of LVFX were given to the anesthetic guinea pig via i.p., and QT interval span and corrected QT-interval span in the II leading lines of ECG were recorded and analyzed from 5 min to 360 min after the drug administration. Single ventricular myocytes were obtained and impacted by LVFX solution of different concentrations. Then delayed rectifier potassium currents (I(K)) on single cells were recorded with whole-cell patch clamp technique, and compared with control group(without impact of LVFX).</p><p><b>RESULTS</b>(1) After the administration of LVFX, at the dose of 200 mg/kg. QT-interval span was significantly elongated, and the increasing rate is 19.38% +/- 3.15% (P < 0.05). While at the relatively lower doses of 50 mg/kg and 100 mg/kg, the elongation is of low/no significance (P > 0.05). (2) LVFX inhibited I(K) dose-dependently and time-dependently.</p><p><b>CONCLUSION</b>LVFX might prolong the QT-interval span by the mechanism of inhibiting I(K), which implies a potential risk in clinical application.</p>