OBJECTIVE CYP2 family including CYP2C and CYP2J is the predominant arachidonic acid(AA)epoxygenase,and the epoxidation of AA produces four regioisomeric cis-epoxyeicosatrienoic acids(5,6-,8,9-,11,12-,and 14,15-EET).Hu...OBJECTIVE CYP2 family including CYP2C and CYP2J is the predominant arachidonic acid(AA)epoxygenase,and the epoxidation of AA produces four regioisomeric cis-epoxyeicosatrienoic acids(5,6-,8,9-,11,12-,and 14,15-EET).Human CYP2J2 is one of the main CYP isoforms expressed in brain,but CYP2C8 was present at a low level.The aim of this study is to investigate the roles of brain CYP2J in Parkinson disease.METHODS Rats received the right-unilateral y injection with concentrated LV-CYP2J3 or LV-EGFP in the substantia nigra(SN)at 3 d before LPS or 6-OHDA treatment.The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 14 and 21 d after LPS injection.The influence of CYP2J-dependent derivative,14,15-EET,on the genes related with oxidative stress was assayed in SH-SY5Y cells.RESULTS CYP2J overexpression or 14,15-EET treatment significantly increased the levels of SOD1,CAT,GPX1,NRF2 and KEAP1 in neurons.TLR4-My D88 signaling pathway was involved the down-regulation of CYP2J by LPS.The binding of p-CREB with the promoter of CYP2J was inhibited by the LPS treatment.The loss of dopaminergic neurons in the right SN induced by LPS or 6-OHDA was significantly decreased by CYP2J3 transfection at 21 d after LPS injection.Compared with LPS or 6-OHDA group,the number of the rotation of rats was decreased by 42.6% and 60.7%by CYP2J3 transfection at 14 d after LPS or 6-OHDA injection;meanwhile,the rotation number was decreased by 12.7%and 21.3%at 21 d.The accumulation of alpha synuclein induced by LPS was significantly decreased by CYP2J3 transfection.The mR NA levels of SOD1,CAT,GPX1,NRF2 and KEAP1 in SN were decreased by LPS,which was attenuated by the injection of LV-CYP2J3.CONCLUSION Brain CYP2J can play a protective role in the damage of the inflammation and oxidative stress to the dopaminergic neurons.Brain CYP2J-dependent derivatives from AA may have therapeutic effects in Parkinson disease via the up-regulation of the antioxidant system in neurons.展开更多
The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450...The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.展开更多
基金supported by New Century Excellent Talents in University(NCET-11-0399)National Natural Science Foundation of China(81673503)
文摘OBJECTIVE CYP2 family including CYP2C and CYP2J is the predominant arachidonic acid(AA)epoxygenase,and the epoxidation of AA produces four regioisomeric cis-epoxyeicosatrienoic acids(5,6-,8,9-,11,12-,and 14,15-EET).Human CYP2J2 is one of the main CYP isoforms expressed in brain,but CYP2C8 was present at a low level.The aim of this study is to investigate the roles of brain CYP2J in Parkinson disease.METHODS Rats received the right-unilateral y injection with concentrated LV-CYP2J3 or LV-EGFP in the substantia nigra(SN)at 3 d before LPS or 6-OHDA treatment.The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 14 and 21 d after LPS injection.The influence of CYP2J-dependent derivative,14,15-EET,on the genes related with oxidative stress was assayed in SH-SY5Y cells.RESULTS CYP2J overexpression or 14,15-EET treatment significantly increased the levels of SOD1,CAT,GPX1,NRF2 and KEAP1 in neurons.TLR4-My D88 signaling pathway was involved the down-regulation of CYP2J by LPS.The binding of p-CREB with the promoter of CYP2J was inhibited by the LPS treatment.The loss of dopaminergic neurons in the right SN induced by LPS or 6-OHDA was significantly decreased by CYP2J3 transfection at 21 d after LPS injection.Compared with LPS or 6-OHDA group,the number of the rotation of rats was decreased by 42.6% and 60.7%by CYP2J3 transfection at 14 d after LPS or 6-OHDA injection;meanwhile,the rotation number was decreased by 12.7%and 21.3%at 21 d.The accumulation of alpha synuclein induced by LPS was significantly decreased by CYP2J3 transfection.The mR NA levels of SOD1,CAT,GPX1,NRF2 and KEAP1 in SN were decreased by LPS,which was attenuated by the injection of LV-CYP2J3.CONCLUSION Brain CYP2J can play a protective role in the damage of the inflammation and oxidative stress to the dopaminergic neurons.Brain CYP2J-dependent derivatives from AA may have therapeutic effects in Parkinson disease via the up-regulation of the antioxidant system in neurons.
基金Supported by Kaohsiung Medical University"Aim for the Top Universities Grant,grant No.KMU-TP103G01 and No.KMUTP103 G04(partially)
文摘The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.
