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1.
CYP2C9 gene polymorphisms are widely studied in several ethnic groups, however they are less known in the Roma population. The aim of this work was to study the ethnic differences of the CYP2C9 allele distribution in a healthy Roma population in order to compare them with a healthy Hungarian population. A total of 535 Hungarian and 465 Roma volunteers were genotyped for the CYP2C92 (Arg144Cys) and CYP2C93 (Ile359Leu) allelic variants by PCR-RFLP assay. The frequencies of the CYP2C91, 2 and 3 alleles in the Hungarian population were 0.787, 0.125, and 0.088 and in Roma 0.727, 0.118, and 0.155, respectively. We found a significant difference in CYP2C93 prevalence between the Hungarian and Roma populations, which have therapeutic consequences ( p < 0.005). The distribution of 1/1, 1/2, 1/3, 2/2, 2/3, and 3/3 genotypes in Hungarians were 0.620, 0.195, 0.139, 0.021, 0.015, and 0.011, while in Roma were 0.533, 0.168, 0.219, 0.011, 0.047, and 0.022, respectively. A significant difference was found between the Hungarian and Roma populations regarding the 1/1, 1/3 and the 2/3 ( p < 0.005) genotypes. This is the first study to investigate the polymorphisms of CYP2C9 gene in the two largest populations in Hungary, healthy Hungarians and Roma. The prevalence of variant CYP2C9 alleles in the Hungarian population is similar to that observed in other European populations. In contrast, the Roma population differs from Hungarians, from most of other Caucasian groups, and from Indians in the incidence of CYP2C9 common variants. The difference in allele distribution patterns between the two populations studied has therapeutic implications as it influences the optimization of therapies. 相似文献
2.
Maternal cocaine administration during gestation caused a down-regulation of PKC expression in the heart of adult offspring resulting in an increased sensitivity to ischemia and reperfusion injury. The present study investigated the direct effect of cocaine in epigenetic modification of PKC gene repression in the fetal heart. Hearts were isolated from gestational day 17 fetal rats and treated with cocaine in an ex vivo organ culture system. Cocaine treatment for 48 h resulted in significant decreases in PKC protein and mRNA abundance and increases in CpG methylation at two SP1 binding sites in the PKC promoter region (− 346 and − 268). Electrophoretic mobility shift assays demonstrated that CpG methylation of both SP1 sites inhibited SP1 binding. Consistently, chromatin immunoprecipitation assays showed that cocaine treatment significantly decreased binding of SP1 to the SP1 sites in the intact fetal heart. Reporter gene assays revealed that site-directed mutations of CpG methylation at both SP1 sites significantly reduced the PKC promoter activity while methylation of a single site at either − 346 or − 268 did not have a significant effect. The causal effect of increased methylation in the cocaine-induced down-regulation of PKC was demonstrated with the use of DNA methylation inhibitors. The presence of either 5-aza-2′-deoxycytodine or procainamide blocked the cocaine-induced increase in SP1 sites methylation and decrease in PKC mRNA. The results demonstrate a direct effect of cocaine in epigenetic modification of DNA methylation and programming of cardiac PKC gene repression linking prenatal cocaine exposure and pathophysiological consequences in the heart of adult offspring. 相似文献
3.
We have recently shown that a novel endothelial mitogen netrin-1 potently stimulates nitric oxide (NO ) production via a DCC-ERK1/2 dependent mechanism. In view of the well-established cardioprotective role of NO , the present study investigated whether netrin-1 is cardioprotective via NO signaling in the heart. Netrin-1 receptor DCC was abundantly expressed in the C57BL/6J mouse hearts. Perfusion of heart with netrin-1 (100 ng/mL) using a Langendorff system significantly increased NO production. Under ischemia/reperfusion (I/R), netrin-1 induced a substantial reduction in infarct size (21.8 ± 4.9% from 42.5 ± 3.6% in the controls), which was accompanied by an augmented production of NO . Pre-perfusion with DCC-antibody, U0126 (MEK1/2 inhibitor), L-NAME or PTIO (NO scavenger) attenuated protective effects of netrin-1 on infarct size and NO production, indicating upstream roles of DCC and ERK1/2 in NO production, as well as an essential role of NO in cardioprotection. Netrin-1 induced reduction in infarct size was significantly attenuated in DCC+/− mice, confirming an intermediate role of DCC. In additional experiments we found netrin-1 increased ERK1/2 and eNOS s1177 phosphorylation, and DCC protein expression, which was diminished by I/R. Furthermore, netrin-1-induced DCC upregulation was NO and ERK1/2-dependent, implicating a feed-forward mechanism. DAF-AM staining revealed enhanced NO production in both cardiac endothelial cells (ECs) and myocytes. In primarily isolated cardiomyocytes, netrin-1 also increased NO production, DCC abundance and ERK1/2 phosphorylation. Of note, cardiac apoptosis was significantly attenuated by netrin-1, which was reversed by DCC-antibody, U0126, L-NAME or PTIO. In summary, our data clearly demonstrate that netrin-1 potently protects the heart from I/R injury by stimulating NO production from cardiac ECs and myocytes. This potent effect is mediated by a DCC/ERK1/2/eNOS s1177/NO /DCC feed-forward mechanism in both cell types. 相似文献
4.
Folate supplementation improves endothelial function in patients with hyperhomocysteinemia. Mechanistic insights into potential benefits of folate on vascular function in general population however, remain mysterious. Expression of dihydrofolate reductase (DHFR) was markedly increased by folic acid (FA, 50 μmol/L, 24 h) treatment in endothelial cells. Tetrahydrofolate (THF) is formed after incubation of purified DHFR or cellular extracts with 50 μmol/L of substrate dihydrofolic acid. THF could then be detected and quantified by high performance liquid chromatography (HPLC) with a fluorescent detector (295/365 nm). Using this novel and sensitive assay, we found that DHFR activity was significantly increased by FA. Furthermore, FA improved redox status of Ang II treated cells by increasing H 4B and NO bioavailability while decreasing superoxide (O 2−) production. It however failed to restore NO levels in DHFR siRNA-transfected or methotrexate pre-treated cells, implicating a specific and intermediate role of DHFR. In mice orally administrated with FA (15 mg/kg/day, 16 days), endothelial upregulation of DHFR expression and activity occurred in correspondence to improved NO and H 4B bioavailability, and this was highly effective in reducing Ang II infusion (0.7 mg/kg/day, 14 days)-stimulated aortic O 2− production. 5′-methyltetrahydrofolate (5′-MTHF) levels, GTPCH1 expression and activity remained unchanged in response to FA or Ang II treatment in vitro and in vivo. FA supplementation improves endothelial NO bioavailability via upregulation of DHFR expression and activity, and protects endothelial cells from Ang II-provoked oxidant stress both in vitro and in vivo. These observations likely represent a novel mechanism (intermediate role of DHFR) whereby FA induces vascular protection. 相似文献
5.
The family of selenoproteins have a broad range of functions, including protection against oxidative damage. Previous studies have shown that elevated levels of oxidative damage can induce accelerated loss of telomeric DNA during proliferation of mammalian cells. The incorporation of selenocysteine (Sec) into proteins in mammalian cells requires the Sec insertion sequence (SECIS) binding protein 2 (SBP2). Thus in the present study we have assessed the effect of knocking down the expression of SBP2 on telomere length. Following knock-down of SBP2 expression in two different human cell lines, the MSTO mesothelioma cell line (5 Kb average telomere length) and SY5Y neuroblastoma cell line (4.2 Kb average telomere length), we observed a significant reduction (−0.6 to −1.1 Kb; P 0.01) in telomere length as compared to control cells. This reduction in telomere length was independent of affects on telomerase, since both telomerase activity levels and Tert mRNA expression levels were not altered by knock-down of SBP2 expression. Furthermore, telomeres were particularly sensitive to S1 nuclease digestion following SBP2 knock-down, indicating an increased frequency of oxidative damage-induced lesions in the telomeric DNA in these cells. Together, these observations imply that selenoproteins may help protect telomeric reserve in mammalian cells. 相似文献
6.
Currently used electrocardiographic criteria for identifying patients with ST-elevation myocardial infarction (STEMI) perform with high specificity but low sensitivity. Our aim was to enhance ischemia-detection ability of conventional STEMI criteria based on 12-lead electrocardiogram (ECG) by adding new criteria using 3 vessel-specific leads (VSLs) derived from 12-lead ECG. Study data consisted of 12-lead ECGs acquired during 99 ischemic episodes caused by balloon inflation in, respectively, left anterior descending coronary artery (LAD; n = 35), right coronary artery (RCA; n = 47), and left circumflex coronary artery (LCx; n = 17). ST deviation was measured at J point in 12 standard leads, and for 3 VSLs, its value was derived from 12-lead ECG by using 8 independent predictor leads or just a pair of precordial leads combined with a pair of limb leads. Mean values of sensitivity (SE) and specificity (SP) of ischemia detection achieved with conventional STEMI vs VSL criteria were then obtained from bootstrap trials. We found that the detection of ischemic state by conventional criteria achieved the mean SE/SP of 60%/96% in the total set of ischemic episodes, 74%/97% in the LAD subgroup, 60%/94% in the RCA subgroup, and 36%/100% in the LCx subgroup. In comparison, the mean SE/SP values of VSLs derived from 8 independent leads of 12-lead ECG were, at 125- μV threshold, 76% /96% in the total set, 91% /97% in the LAD subgroup, 70%/94% in the RCA subgroup, and 71% /100% in the LCx subgroup (with asterisk denoting a statistically significant increase). The mean SE/SP of VSLs derived from some of the 4-predictor lead sets (namely, those including lead V 3) matched or exceeded values achieved by VSLs derived from 8 predictors; for instance, with predictor leads I, II, V 3, V 6 derived VSLs attained at 125- μV threshold the mean SE/SP of 80% /95% in the total set, 91% /97% in the LAD subgroup, 74%/92% in the RCA subgroup, and 71% /100% in the LCx subgroup. Based on these results, we conclude that, in our data set, 3 VSLs derived from the complete standard 12-lead ECG—and even from its subsets—can identify acute ischemia better than existing STEMI criteria. 相似文献
7.
The effects of the CYP1A12A genotype on susceptibility to leukemia have received particular attention in recent years because this enzyme plays a central role in the activation of carcinogens. Several polymorphisms at the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We evaluated the role of the CYP1A12A genotype in adults with acute lymphoblastic leukemia (ALL) by genotyping 210 patients and 228 healthy controls from the Mexican population. The frequency of the CC genotype was 8% (18/228) in the control group and 42% (88/210) in ALL patients; the frequency of the CT genotype was 39% (89/228) and 29.5% (62/210), respectively; and that of the TT genotype was 53% (121/228) and 28.5% (60/210), respectively. The odds ratio was 8.4 (95% CI, 4.7–15.5; P < 0.001). These data indicate that the CYP1A12A genotype contributes significantly to susceptibility to adult ALL in a sample of the Mexican population. 相似文献
8.
The adverse effects of iodine deficiency (ID) intellectual impairment, damaged reproduction, goiter and hypo- and hyperthyroidism are well known and easily corrected with salt iodization, but they continue to impair health and socioeconomic development, with more than two billion people at risk worldwide. During the major global expansion of salt iodization over the past four decades, much of Europe has remained iodine deficient. Although every European country endorsed the goal of eliminating iodine deficiency at the 1992 World Health Assembly, control of iodine deficiency has received low priority in much of Europe. However, there has been recent progress in the region and the number of children with low iodine intakes has decreased by ca. 30% since 2003. This paper presents an estimate of the prevalence of iodine deficiency in Europe in 2010, based on a systematic review to update the WHO Vitamin and Mineral Nutrition Information System (VMNIS) database. 相似文献
9.
Recent evidence has suggested that erythrocytes naturally deficient in glycophorin A (GPA) have a reduced Vmax for monovalent anion exchange. Unanswered is whether miss-folding of band 3 during biosynthesis, or the absence of GPA modulation of properly folded band 3 is responsible. Here, I determine the effect of selective depletion of GPA on the kinetics of reversible binding of the competitive transport inhibitor DIDS (4,4′-diisothiocyanato-2,2′-stilbenedisulfonate) to properly folded band 3. Reversible binding of DIDS follows biphasic kinetics: a fast phase {DIDS + band 3 (DIDS − band 3), k1, k− 1} and a slower phase {(DIDS − band 3) (DIDS − band 3), k2, k− 2}. Selective depletion of GPA was accomplished by pretreating membranes with Triton X-100, over a range where erythrocyte hemolysis is inhibited by the detergent (0% to 0.03%, v/v). Pretreatment with sublytic Triton X-100: (a) virtually completely depleted GPA, (b) did not deplete membrane-bound band 3, and (c) slowed the overall rate of reversible binding of DIDS to band 3. Data analysis and model simulation studies indicated that the decrease in the rate of binding of DIDS was due exclusively to a decrease in k− 2, with no change in the initial rate of binding. Thus, depletion of GPA does not alter the native conformation of band 3 at the DIDS binding site, but rather modulates a conformational equilibrium between two states of the binary complex formed by the competitive inhibitor DIDS, reversibly bound to properly folded band 3. 相似文献
12.
A survey of the litterature was made to precise the characteristics of infectious endocarditis (IE) in the elderly as defined by the diagnostic criteria of Von Reyn. The IE presents at times with a fallacious symptomatology where fever and cardiac bruit are often lacking. With regard to the cardiac disease, there is an increase in the incidence of calcifying degenerative valvulopathy responsible for IE. On the bacteriological point of view, streptococcal infections are still predominent in etiologgy for endocarditis but opportunistic infections dues to other bacterial species are increasing in frequency. Lastly, on the therapeutical side, there is a new trend to reduce the proeminence of curative treatment with aminoglycoside agents in favor of the antibiotic prophylaxis. RésuméLe but de ce travail est de préciser, par une revue de la littérature, les particularités de l'endocardite infectieuse (El) du sujet âgé (critères diagnostiques de Von Reyn). L'El se distingue par une symptomatologie clinique trompeuse, où fièvre et souffle sont inconstants. Au plan cardiaque, les valvulopathies dégénératives calcifiantes responsables d'El sont à prendre en considération. Sur le plan bactériologique, si les El à streptocoques dominent, les greffes d'origine nosocomiale, provoquées par d'autres espèces bactériennes, sont en augmentation. Enfin, en matière de thérapeutique, on tend à restreindre la place des aminosides en traitement curatif, et à majorer celle de l'antibioprophylaxie. PDF (355 K)
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