ABSTRACT
Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.
ABSTRACT
The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid (RA) on the expression of LINGO-1 and GAP-43, and the number of synapses, and to emplore the repressive effect of LINGO-1 on neural regeneration after cerebral ischemia. The model of permanent focal cerebral ischemia was established by the modified suture method of middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. The expression of LINGO-1 was detected by Western blotting and that of GAP-43 by immunohistochemistry. The number of synapses was observed by transmission electron microscopy. The SD rats were divided into three groups: sham operation (sham) group, cerebral ischemia (CI) group and RA treatment (RA) group. The results showed that the expression level of LINGO-1 at 7th day after MCAO in sham, CI and RA groups was 0.266±0.019, 1.215±0.063 and 0.702±0.081, respectively (P<0.01). The number of Gap-43-positive nerve cells at 7th day after MCAO in sham, CI and RA group was 0, 59.08±1.76 and 76.20±3.12 per high power field, respectively (P<0.05). The number of synapses at 7th day after MCAO was 8.42±0.13, 1.74±0.37 and 5.39±0.26 per μm(2), respectively (P<0.05). It is concluded that LINGO-1 expression is up-regulated after cerebral ischemia, and RA inhibits the expression of LINGO-1, promotes the expression of GAP-43 and increases the number of synapses. It suggests that LINGO-1 may be involved in the pathogenesis of cerebral ischemia, which may provide an experimenal basis for LINGO-1 antogonist, RA, for the treatment of cerebral ischemia.
ABSTRACT
The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid (RA) on the expression of LINGO-1 and GAP-43, and the number of synapses, and to emplore the repressive effect of LINGO-1 on neural regeneration after cerebral ischemia. The model of permanent focal cerebral ischemia was established by the modified suture method of middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. The expression of LINGO-1 was detected by Western blotting and that of GAP-43 by immunohistochemistry. The number of synapses was observed by transmission electron microscopy. The SD rats were divided into three groups: sham operation (sham) group, cerebral ischemia (CI) group and RA treatment (RA) group. The results showed that the expression level of LINGO-1 at 7th day after MCAO in sham, CI and RA groups was 0.266 ± 0.019, 1.215 ± 0.063 and 0.702 ± 0.081, respectively (P<0.01). The number of Gap-43-positive nerve cells at 7th day after MCAO in sham, CI and RA group was 0, 59.08 ± 1.76 and 76.20 ± 3.12 per high power field, respectively (P<0.05). The number of synapses at 7th day after MCAO was 8.42 ± 0.13, 1.74 ± 0.37 and 5.39 ± 0.26 per μm², respectively (P<0.05). It is concluded that LINGO-1 expression is up-regulated after cerebral ischemia, and RA inhibits the expression of LINGO-1, promotes the expression of GAP-43 and increases the number of synapses. It suggests that LINGO-1 may be involved in the pathogenesis of cerebral ischemia, which may provide an experimenal basis for LINGO-1 antogonist, RA, for the treatment of cerebral ischemia.
Subject(s)
Animals , Male , Rats , Blotting, Western , Brain Ischemia , Metabolism , GAP-43 Protein , Genetics , Metabolism , Gene Expression , Membrane Proteins , Genetics , Nerve Tissue Proteins , Genetics , Neurons , Metabolism , Rats, Sprague-Dawley , Tretinoin , PharmacologyABSTRACT
Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.
Subject(s)
Humans , Racial Groups , Cytochrome P-450 CYP2C19 , Genetics , Gene Frequency , Platelet Aggregation Inhibitors , Therapeutic Uses , Polymorphism, Genetic , Ticlopidine , Therapeutic Uses , Treatment OutcomeABSTRACT
Recent studies showed that Eph/Ephrin tyrosine kinase family plays an important role in the development and functional maintenance of the nervous system, but its function in the sympathetic nervous system is still obscure. In the present study, we examined the effect of Eph/Ephrin-B1 signaling on the whole-cell currents mediated by either alpha7 or alpha3-nicotinic acetylcholine receptors (nAChRs) in acutly dissociated ciliary ganglion (CG) neurons. Firstly, we detected the effect of Ephrin-B1 on nAChRs currents. The neurons were randomly divided into control group, Ephrin-B1Fc-treated group that was stimulated by recombinant Ephrin-B1Fc, IgG-treated group, and Ephrin-B1-treated group. Secondly, we studied the regulatory mechanism of Ephrin-B1Fc on nAChRs currents. The neurons were randomly divided into control group, Ephrin-B1Fc-treated group, PP2 (inhibitor of Src tyrosine kinase) or PD98095 (antagonist of mitogen-activated protein kinase)-treated group, Ephrin-B1Fc + PP2 or PD98095-treated group. The results showed that there was no significant difference between the currents in control group, IgG-treated group and Ephrin-B1-treated group, but Ephrin-B1Fc significantly suppressed both alpha3-nAChRs and alpha7-nAChRs-mediated currents (P=0.002, P=0.003). Pretreatment with PP2 or PD98095 could partially rescue the Ephrin-B1Fc-induced suppression of currents mediated by alpha3-nAChRs or alpha7-nAChRs respectively. These results suggest that the Eph/Ephrin-B1 signaling may inhibit alpha3-nAChRs and alpha7-nAChRs-mediated currents on CG neurons, involving Src tyrosine kinase and mitogen-activated protein kinase signaling in the regulation of sympathetic nervous system.