Association of single nucleotide polymorphisms of cytochrome P450 gene with susceptibility to gout in ethnic Han males from coastal regions of Shandong province / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association of cytochrome P450 gene single nucleotide polymorphisms (SNPs) with susceptibility to gout in ethnic Han males from coastal regions of Shandong province.</p><p><b>METHODS</b>Four hundred and eighty male patients with gout and 480 healthy male controls were included. Genotyping was carried out with a custom Illumina GoldenGate Genotyping assay to detect SNP rs2275620 of CYP2C8 gene, SNP rs2070676 of CYP2E1 gene, SNP rs837395 of CYP4B1 gene, and SNP rs194150 of TBXAS1 gene. The association was assessed with chi-square test.</p><p><b>RESULTS</b>No significant difference has been found between the two groups in regard to the genotypic and allelic frequencies of the TT, AT, AA genotypes and A, T alleles of the SNP rs2275620 of the CYP2C8 gene (P=0.88; P=0.97), the CC, CG, GG genotypes and C,G alleles of SNP rs2070676 of the CYP2E1 gene (P=0.24; P=0.09), the TT, AT, AA genotypes and A, T alleles of SNP rs837395 of the CYP4B1 (P=0.88; P=0.97), and TT, AT, AA genotypes and the A,T alleles of SNP rs194150 of TBXAS1 gene (P=0.15; P=0.06).</p><p><b>CONCLUSION</b>This study has identified no association of SNP loci rs2275620(A/T) of CYP2C8, rs2070676(C/G) of CYP2E1, rs837395(A/T) of CYP4B1 and rs194150(A/T) of TBXAS1 with gout in ethnic Han males from coastal regions in Shandong province. However, our result needs to be replicated in larger sets of patients collected from other regions and populations.</p>

O endotélio disfuncionante na hipertensão arterial e no tabagismo / Dysfunctional endothelium in hypertension and smoking

Disfunção endotelial (DE) caracteriza qualquer alteração de atividadenormal do endotélio incluindo atividade vasomotora, proliferaçãocelular, adesão/agregação plaquetária, permeabilidade vascular e a interaçãoleucócitos/parede vascular. Contudo, em repouso o leito arterialexibe um estado basal de vasoconstrição (tônus vascular) modulado pormecanismos de controle centrais (sistema nervoso-simpático), periféricos(sistema renina-angiotensina-aldosterona) e um mecanismo local(endotelial) cuja potência é superior às anteriores. DE na hipertensãoestá relacionada à diminuição da biodisponibilidade de NO por reduçãoda síntese e liberação pela sintase endotelial do óxido nítrico (eNOS)influenciada por fatores genéticos e ambientais como hipóxia, hipofluxo,forças de cisalhamento, redução do substrato L-arginina e seuscofatores, ou inativação do NO resultado da sua ligação com diferentesmoléculas hemoglobina, albumina e, principalmente, sua interação comespécies reativas de oxigênio (estresse oxidativo). DE na hipertensãopode, ainda, estar associada à liberação de substâncias vasoconstritorasderivadas do endotélio como trornboxano-Aç, prostaglândina-Hj,endotelina-l e angotensina-Il. Tabagismo aumenta o risco de eventoscardiovasculares, principalmente quando associado à hipertensão.Nicotina estimula a liberação de catecolarninas e promove lesões noendotélio vascular. Radicais livres e compostos aromáticos diminuema síntese de NO, prejudicando a vasodilatação endotélio-dependente.Tabagismo favorece o crescimento celular por estimulação de fatoresde crescimento do endotélio vascular e inativação do NO por aumentodo estresse oxidativo. Aumento da oxidação das lipoproteínas debaixa densidade (LDL) em fumantes tem efeito sinérgico na adesão emigração de monócitos. Todos esses efeitos deletérios do tabagismono leito vascular também são observados, embora em menor extensão,em tabagistas passivos...

Endothelial dysfunction (ED) characterizes ali changes in the normalactivity ofthe endothelium including vasomotor activity, cell proliferation,platelet adhesion and aggregation, vascular permeability andleukocyte-vascular wall interactions. However, at rest, the arterialbed exhibits a baseline state of vasoconstriction (vascular tone) whichis modulated by central control (sympathetic nervous system) andperipheral mechanisms (Renin angiotensin-aldosterone system) anda local mechanism (endothelial); the latter is the most potent. ED inhypertension is related to decreased bioavailability of nitric oxide(NO) due to its reduced synthesis and release by endothelial nitricoxide synthase (eNOS) regarding genetic and environmental factorssuch as hypoxia, decreased blood flow, shear forces, diminishedL-arginine substrate and its cofactors and NO inactivation as a resultof its binding to different molecules including hemoglobin, albuminand, mainly, its interaction with reactive oxygen species (oxidativestress). ED in hypertension can also be linked to the release of endothelium-derived vasoconstricting substances such as thromboxane-Ai,prostaglandin-H2, endothelin-l and angiotensin-Il. Smoking increasesthe risk of cardiovascular events especially when associated withhypertension. Nicotine stimulates catecholamine release and causesvascular endothelium injury. Free radicais and aromatic compoundsreduce NO synthesis, impairing endothelium-dependent vasodilation.Smoking promotes cell growth by stimulating vascular endotheliumgrowth factors and NO inactivation by increasing oxidative stress.The increased oxidation of low-density lipoproteins ir smokers hasa synergistic effect on monocyte adhesion and migration. All thesedeleterious effects of smoking on the vascular bed are also observed,albeit at a lesser extent, in passive smokers...

Thromboxane A2 Synthetase Inhibitor Plus Low Dose Aspirin : Can It Be a Salvage Treatment in Acute Stroke Beyond Thrombolytic Time Window

OBJECTIVE: There is no proven regimen to reduce the severity of stroke in patients with acute cerebral infarction presenting beyond the thrombolytic time window. Ozagrel sodium, a selective thromboxane A2 synthetase inhibitor, has been known to suppress the development of infarction. The antiplatelet effect is improved when aspirin is used together with a thromboxane synthetase inhibitor. METHODS: Patients with non-cardiogenic acute ischemic stroke who were not eligible for thrombolysis were randomly assigned to two groups; one group received ozagrel sodium plus 100 mg of aspirin (group 1, n=43) and the other 100 mg of aspirin alone (group 2, n=43). Demographic data, cardiovascular risk factors, initial stroke severity [National Institute of Health Stroke Scale (NIHSS) and motor strength scale] and stroke subtypes were analyzed in each group. Clinical outcomes were analyzed by NIHSS and motor strength scale at 14 days after the onset of stroke. RESULTS: There were no significant differences in the mean age, gender proportion, the prevalence of cardiovascular risk factors, stroke subtypes, and baseline neurological severity between the two groups. However, the clinical outcome for group 1 was much better at 14 days after the onset of stroke compared to group 2 (NIHSS score, p=0.007, Motor strength scale score, p<0.001). There was one case of hemorrhagic transformation in group 1, but there was no statistically significant difference in bleeding tendency between two groups. CONCLUSION: In this preliminary study, thromboxane A2 synthetase inhibitor plus a low dose of aspirin seems to be safe and has a favorable outcome compared to aspirin alone in patients with acute ischemic stroke who presented beyond the thrombolytic time window.

Association of Rs10487667 genetic polymorphism of thromboxane synthase with myocardial infarction in Uigur population of Xinjiang / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the association between the polymorphism of thromboxane synthase gene (CYP5A1) and myocardial infarction (MI) of Uigur nationality patients in Xinjiang.</p><p><b>METHODS</b>Rs10487667 site polymorphism in CYP5A1 gene of 318 patients with MI (MI group) and 232 healthy control subjects (control group) were analyzed by polymerase chain reaction and restriction fragment length polymorphism. The serum thromboxane B(2)(TXB(2)) concentration was also detected in all subjects. The relationship of multiple factors and myocardial infarction was evaluated comprehensively by non-condition logistic regression analysis.</p><p><b>RESULTS</b>The frequencies of CYP5A1 gene Rs10487667 site polymorphism in MI group and control group were: GG type 0.204 (65/318) and 0.155 (36/232), GT type 0.553 (176/318) and 0.466 (106/232), TT type 0.242 (77/318) and 0.379 (88/232), respectively. There was significant difference in frequencies of GG genotype (χ(2) = 12.193, P = 0.002) between two groups and G allele frequency in MI group (0.481 (306/636)) was significant higher than control group (0.388 (180/464)) (χ(2) = 9.449, P = 0.021), but no difference in frequencies of GT and TT genotypes (χ(2) = 0.699, P > 0.05)between controls and MI cases. There was significant difference in serum TXB(2) level between MI ((184.3 ± 34.7) pg/ml) and control ((124.3 ± 28.1) pg/ml) groups (t = 5.503, P = 0.034). In the case and control group, the serum TXB(2) level of the person with GT + GG genotype ((164.21 ± 22.56) and (134.26 ± 19.83) pg/ml)) was significant higher than those of TT genotypes ((113.67 ± 54.23) and (98.54 ± 13.11) pg/ml) (t values were 5.433 and 5.108, respectively, both P values < 0.05). Logistic regression analysis showed that the T allele of the CYP5A1 gene was one independent risk factor of MI (OR = 1.673, 95%CI: 1.020 - 2.156) after adjustment of risk factors.</p><p><b>CONCLUSION</b>Rs10487667 polymorphism in CYP5A1 gene might be a risk factor of MI in Uigur population in Xinjiang, which maybe related with the significant high serum TXB(2) level.</p>

Association of the Pro1770Leu polymorphism in CYP5A1 gene with myocardial infarction in Uigur population of Xinjiang / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the association between the polymorphism of the thromboxane synthase gene and Uigur patients with myocardial infarction (MI) in Xinjiang.</p><p><b>METHODS</b>Three hundred and fifteen patients with MI and 218 healthy control subjects were detected by polymerase chain reaction and restriction fragment length polymorphism. The serum thromboxane B2 (TXB2) in all subjects was detected with radioimmunoassay kit.</p><p><b>RESULTS</b>The genotype distributions of the MI group and control group were in Hardy-Weinberg equilibrium (Chi-square=0.375,0.029, P>0.05). The frequencies of CC and TC were 0.933 and 0.067 in MI group while they were 0.977 and 0.023 in controls. There was significant difference in frequencies of the TC genotype and T allele but no difference in frequencies of CC genotype between controls and MI cases. There was significant difference in serum TXB2 level between the MI and control group (P<0.05), and between individuals of the TC and CC genotypes (P<0.05). The serum TXB2 level in the MI cases with TC genotype was increased compared with that of other genotypes (P<0.05).</p><p><b>CONCLUSION</b>The TC genotype and T allele of thromboxane synthase gene might be risk factors of MI in Uigur population in Xinjiang, which might result from the increased serum TXB2 level.</p>

Effects of cyclo-oxygenase and thromboxane synthetase inhibitors on right atrial prostaglandins.

OBJECTIVES: The aim of this study was to find out the effects of cyclo-oxygenase and thromboxane synthetase inhibitors on right atrial prostacyclin and thromboxane A2 levels. METHODS: The study consisted of a total of 50 patients subjected to coronary bypass surgery. These patients were divided into two groups, Group I and Group II each consisting of 25 patients. In Group I patients, the right atrial tissues were studied for effects of indomethacin and U63557A on the prostaglandin levels. In Group II patients, the right atrial tissues were studied for effects of Aspirin and U63557A on the prostaglandin levels. RESULTS: In Group I patients, the atrial tissues pretreated with indomethacin showed a fall in the levels of 6 keto PGF1 alpha from 153.5 +/- 28.4 pg/0.1 mg to 59.7 +/- 11.6 pg/0.1 mg and of TXB2 from 41.6 +/- 1.2 pg/0.1 mg to 17.2 +/- 3.2 pg/0.1 mg. In the atrial tissues of Group I treated with U63557A the levels of 6 keto PGF1 alpha fell to 145.4 +/- 26.8 pg/0.1 mg and the levels of TXB2 fell to 14.7 +/- 2.8 pg/0.1 mg. In Group II patients, the atrial tissues pretreated with aspirin, showed a fall in the levels of 6 keto PGF1 alpha from 142.1 +/- 2.8 pg/0.1 mg to 17.5 +/- 0.8 pg/0.1 mg. In the atrial tissues pretreated with U63557A, the levels of 6 keto PGF1 alpha fell to 131.2 +/- 2.9 pg/0.1 mg and the levels of TXB2 fell to 14.4 +/- 0.7 pg/0.1 mg. CONCLUSIONS: The study showed that human right atrial tissues are capable of producing TXA2 in addition to prostacyclin. Indomethacin and aspirin by inhibiting generation of cyclic endoperoxides inhibited synthesis of both prostacyclin and TXA2. In contrast a thromboxane synthethase inhibitor U63557A selectively inhibited TXA2 without significant effects on prostacyclin synthesis.

Newer orally active antiplatelet agents: Do they have an edge over aspirin?

An extensive body of research conducted in the past 25 years has helped foster understanding of the mechanisms and pathogenesis of the acute coronary syndromes and occlusive disease. The role of platelet and the endothelium in the pathogenesis of atherosclerosis and subsequent ischemic events is well established. The filed of antiplatelet therapy is rapidly expanding with the availability of newer antiplatelet agents. However, at the present time, there is no convincing data available that other antiplatelet drugs are superior to aspirin. Aspirin remains the cornrstone of therapy for various ischemic disorders and the foundation on which other therapies are added, both in the short and long term

The modulatory effect of antigen- and PAF-induced asthmatic reaction by aerosol administration of OKY-046 in guinea pigs.

The therapeutic effect of a thromboxane A2 (TXA2) synthetase inhibitor on asthma is still controversial. This study was aimed at clarifying its effect on asthmatic reactions in guinea pigs. Both ovalbumin (OVA)- and platelet activating factor (PAF)-induced dual phase airway spasm and hyperreactivity in guinea pigs were used as the asthma model. Our results demonstrated that aerosol administration of OKY-046 could inhibit both OVA- and PAF-induced late phase bronchoconstriction and airway hyperreactivity to methacholine in OVA sensitized guinea pigs. PAF administration could also induced dual phase bronchoconstriction in normal guinea pigs. Similarly, late phase airway spasm and airway hyperreactivity after PAF exposure was also blocked by OKY-046. In conclusion, aerosol administration of OKY-046 is a safe and effective way to modulate OVA- and PAF-induced asthmatic reactions. The protective effect of OKY-046 on OVA- and PAF-induced late phase bronchoconstriction and airway hyperreactivity indicates that TXA2 might play an important role in the late phase asthmatic reaction and airway hyperreactivity. The normalization of PAF-induced airway hyperreactivity by OKY-046 also indicates that PAF induced airway inflammation might be through the generation of TXA2.

Involvement of prostaglandins in chilli-induced early gastric vascular damage in adult Wistar rat.

OBJECTIVE: To explore the role of prostaglandins in protecting against chilli-induced early gastric vascular damage. METHODS: Early gastric vascular damage was induced in rats by oral administration of 8 mg/Kg chilli extract. The damage was assessed by estimating spectrophotometrically the amount of Evan's blue leaking into gastric tissue and luminal contents 10 min after exposure to chilli. Further groups of rats were pretreated with misoprostol (10, 25 or 50 micrograms/Kg) or dazmegrel (1, 5 or 25 mg) to evaluate their protective effects. RESULTS: Both misoprostol and dazmegrel were able to reduce gastric vascular damage induced by chilli in a dose-dependent fashion. CONCLUSION: Prostaglandins may play a role in protecting against chilli-induced early gastric vascular damage.