الملخص
Cardiovascular disease is a principal cause of morbidity and death in the world. Although drug therapy has made great progress in the past few decades, there are still many deficiencies in the prevention and treatment of cardiovascular disease. Dyslipidemia is still a common risk feature and is not sufficiently controlled. A growing body of evidence suggests that the occurrence and development of cardiovascular disease is associated with many associated risk factors, such as higher low-density lipoprotein levels, lower high-density lipoprotein levels and high triglyceride levels. A number of clinical trials in patients with dyslipidemia have shown that actively decreasing low density lipoprotein cholesterol can significantly decrease cardiovascular events. ATP citrate lyase (ACLY) is a cytoplasmic homo-tetrameric enzyme. In the presence of adenosine triphosphate (ATP), ACLY catalyzes the conversion of citric acid and coenzyme A to acetyl-CoA and oxalyl acetate. ACLY is the main enzyme for the production of cytoplasmic acetyl-CoA, and cytoplasmic acetyl-CoA is the precursor required for de novo synthesis of cholesterol and fatty acids. Therefore, it is possible to reduce the production of acetyl-CoA and reduce the levels of cholesterol and triglycerides by inhibiting ACLY. ACLY can be used as a molecular target for reducing blood lipids, and there are an increasing number of studies on ACLY inhibitors. In this paper, the structure and mechanism of ACLY and its relationship with lipid metabolism are briefly introduced, and we review some current ACLY inhibitors.
الملخص
Aim To study the effect of resveratrol on the metabolism of tryptophan to kynurenine in human liver microsomes.Methods High performance liquid chromatography-tandem mass spectrometry ( LC-MS/ MS) was used to detect the concentration of tryptophan and kynurenine in the microsome incubation system, and the incubation time, tryptophan concentration, and microsomal protein concentration were investigated respectively.The optimal tryptophan incubation system obtained above was used to explore the effect of resveratrol on the kynurenine pathway.Results The optimal incubation time of tryptophan in human liver mi-crosomes in vitro was 90 min,the concentration of tryptophan and liver microsomal protein was 8 mg • L"1 and 1 g • L"1, respectively.The enzyme reaction rate constant Km was 95.91 ±22.29 jxmol • L'1, and the maximum reaction rate V
الملخص
Coronary artery disease (CAD)is a major cause of death and disability worldwide, and consumes a considerable amount of medical resources every year.Clopidogrel is a first-line antiplate-let therapy for CHD, butit is associated with substantial variability in PK and pharmacodynamics re-sponse. To date, gene variants explain only a smallproportion of the variability.The study aimed to identify new genetic loci-modifying antiplatelet response to clopidogrel in Chinese patients with CAD by a systematic analysis combining antiplatelet effects and PK, and further to investigate the PON1 gene promoter DNA methylation and genetic variations possibly influencing clinical outcomes in pa-tients undergoing PCI. We identified novel variants in two transporter genes (SLC14A2rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reac-tion unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically im-proved the predictability of PRU variability to 37.7%. The associations between these loci and PK pa-rameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P<0.05). Rs2254638 was further identified to exert a marginal risk effect formajor adverse cardiac events in an independent cohort.Multivariate logistic regression analysis indicated that PON1methylation level at CpG site-161 (OR=0.95; 95% CI=0.92–0.98;P<0.01)and the use of angiotensin converting enzyme inhibitors(OR=0.48;95% CI=0.26–0.89;P<0.01) were associated with decreased risk of bleeding events. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.The ab-normal expression of DNA methylation-regulating key genes in the pharmacokinetic and pharmacody-namics pathways of clopidogrel and aspirin may modify clinical outcomes in dual antiplatelet-treated pa-tients undergoing PCI.
الملخص
<p><b>BACKGROUND</b>Sequence variants in the β-adrenergic receptor (ADRB) genes have a close relationship with the development of coronary artery disease (CAD) and the patient's prognosis. However, there is a lack of data on the role of the variants in ADRBs genes in Han Chinese patients with CAD. We aimed to investigate the association of genetic variants in the ADRB1 and ADRB2 genes with the incidence of major adverse cardiac event (MACE) in Han Chinese patients with CAD.</p><p><b>METHODS</b>A total of 545 Han Chinese patients with CAD undergoing percutaneous coronary intervention (PCI) were recruited to the study and followed for one year. Three variant sites in ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) were genotyped. The effect of the ADRB1 and ADRB2 genotypes on MACE within one year was assessed.</p><p><b>RESULTS</b>There were 47 cases of MACE during follow-up. There was no significant difference in the incidence of MACE among patients carrying different genotypes of the three variants in ADRB1 and ADRB2 (Log-rank, all P > 0.05). Cox regression analysis showed no association between three variants in ADRB1 and ADRB2 genes and the incidence of MACE during one-year follow-up, the adjusted hazard ratios (95% confidence interval) for rs1801253, rs1042713 and rs1042714 were 1.05 (0.54-2.02), 1.24 (0.58-2.64) and 1.66 (0.81-3.42), respectively.</p><p><b>CONCLUSION</b>Our data did not support a relationship between the three polymorphisms of ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) genes and risk of subsequent cardiovascular events after PCI in Han Chinese patients with CAD.</p>
الموضوعات
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Asian People , Genetics , Coronary Artery Disease , Genetics , Genotype , Incidence , Polymorphism, Genetic , Genetics , Polymorphism, Single Nucleotide , Genetics , Receptors, Adrenergic, beta , Genetics , Receptors, Adrenergic, beta-1 , Genetics , Receptors, Adrenergic, beta-2 , Geneticsالملخص
<p><b>OBJECTIVES</b>To investigate if there is altered microRNAs (miRNAs) expression in aortic dissection (Debakey Type A) and normal aorta tissue.</p><p><b>METHODS</b>Total RNA was exacted from aorta of 5 patients with aortic dissection (AD) and four patients without aortic diseases (NA). miRNAs of the aortic tissues were analyzed by miRNA microarray. Reverse transcription polymerase chain reaction (RT-PCR) was performed to verify the expression of miRNAs in larger sample size (AD = 11 and NA = 9).</p><p><b>RESULTS</b>hsa-miR-146b-5p_st, hsa-miR-19a_st and hsa-miR-505_st were significantly upregulated while hsa-miR-1268_st and hsa-miR-939_st were significantly downregulated [fold change > 2, q-value (%) ≤ 5] in AD group compared with NA group. RT-PCR verified hsa-miR-146b-5p_st miRNAs change in AD group.</p><p><b>CONCLUSIONS</b>Altered miRNAs expression might play an essential role in the pathogenesis of aortic dissection formation and hsa-miR-146b-5p_st might serve as a new diagnosis biomarker of aortic dissection.</p>
الموضوعات
Humans , Aortic Dissection , Genetics , Gene Expression Profiling , MicroRNAs , Genetics , Metabolism , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reactionالملخص
Coronary heart disease is one of the most important causes of death in human, and consumes vast medical resources. Percutaneous coronary intervention (PCI) has been a significant breakthrough for its treatment. However, clinical application has been hampered by in-stent restenosis (ISR). Although drug eluting stent (DES) has reduced the occurrence of restenosis, incidence of ISR is still about 5% to 10%. The main reasons for restenosis after PCI are hyperplasia of vascular endothelial cells and smooth muscle cell migration. The exact mechanism of personalized differences in restenosis is not clear yet, but there may be a variety of risk factors. In addition to aging, smoking and diabetes, an increasing number of studies have found that genetic and epigenetic factors play an important role in ISR. In this article, authors have reviewed genetic and epigenetic factors on the progression of ISR, which may help to determine the genetic risk factors in patients with ISR after PCI.
الموضوعات
Humans , Angioplasty, Balloon, Coronary , Methods , Coronary Restenosis , Genetics , Disease Progression , Epigenomics , Methods , Stents , Treatment Outcomeالملخص
<p><b>OBJECTIVE</b>To investigate potential contributions of genetic variants of cytochrome P-450 2C9 (CYP2C9) and vitamin K expoxide reductase (VKORC1) to the anticoagulation response during the initiation of warfarin therapy in the Han Chinese population.</p><p><b>METHODS</b>A total of 798 Han Chinese patients received long-term warfarin anticoagulant therapy orally after valve replacement in our hospital between 2000 and 2008 were included in this study. Nine single nucleotide polymorphism (SNP) loci [rs12572351 G > A, rs9332146 G > A, rs4917639 G > T, rs1057910 A > C (CYP2C9(*)3), rs1934967 G > T, rs1934968 G > A, rs9923231 C > T (VKORC1-1639 G > A), rs2359612 G > A and rs10871454 C > T] in 2 genes including CYP2C9 and VKORC1, which were possibly correlated with warfarin pharmacokinetics and pharmacodynamics through literature retrieval, were selected and analyzed. Warfarin steady-state dose requirement, time to the INR (the international normalized ratio) within the therapeutic range and percent of the INR of more than 3.5 were compared among genotype subgroups. SNaPshot technique was used to detect gene SNPs; Hardy-Weinberg genetic equilibrium test was used to test population representativeness.</p><p><b>RESULTS</b>CYP2C9(*)3 genotype did not affect the required warfarin dose while it was associated with increased risk of bleeding when treated with routine dosage regimen during the initiation of treatment. The allelic mutation frequency at VKORC1 gene rs10871454G > A and VKORC1-1639G > A SNP loci was 92.04% and 88.03%, respectively and rs10871454 was in perfect linkage disequilibrium with-1639. Patients with VKORC1 rs10871454 genetic mutation required lower warfarin dose in the first 28 days of therapy. VKORC1-1639 genetic polymorphism was also associated with shorter time to the INR within the therapeutic range and increased risk of over-anticoagulation.</p><p><b>CONCLUSION</b>Detecting genetic polymorphism of CYP2C9 and VKORC1 could guide clinical use of warfarin to reduce the risk of adverse reactions including bleeding in patients receiving chronic anticoagulation therapy.</p>
الموضوعات
Aged , Humans , Anticoagulants , Pharmacology , Therapeutic Uses , Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 CYP2C9 , Genetics , Gene Frequency , Genes , Genetic Variation , Genotype , Hemorrhage , International Normalized Ratio , Linkage Disequilibrium , Mixed Function Oxygenases , Polymorphism, Single Nucleotide , Vitamin K Epoxide Reductases , Genetics , Warfarin , Pharmacology , Therapeutic Usesالملخص
<p><b>OBJECTIVE</b>To investigate the clinical application of anticoagulation treatment with warfarin after prosthetic heart valve replacement and compare the effect and safety of different anticoagulant intensities.</p><p><b>METHODS</b>A total of 845 Chinese patients receiving oral warfarin for anticoagulant treatment after prosthetic heart valve replacement in Guangdong General Hospital between 2000 and 2008 were enrolled in this survey. The general data, clinical data, medications, international normalized ratio (INR) and results of echocardiogram of these patients were followed up to observe the incidence of complication of thrombo-embolism and such adverse effect as hemorrhage.</p><p><b>RESULTS</b>All the patients were of Han nationality, and Cantonese accounted for 88.04%. The daily mean maintenance dose of warfarin was 2.92∓0.88 mg in these patients with a median INR of 2.09∓0.39. Of these patients, 44.62% received low-intensity anticoagulant treatment with warfarin with the INR maintained between 1.5 and 2.0, and 56.45% had standard anticoagulant intensity with the INR maintained between 2.0 and 3.0. The total incidence of thrombo-embolism was 4.14%. Severe hemorrhage occurred in 14 cases (1.66%), most frequently in the alimentary tract. The events of hemorrhage were correlated to the type of prosthetic heart valve replacement, occurring more frequently in patients with mechanical prosthetic heart valve replacement than in those with biological ones. No significant difference was found in the incidence of thrombo-embolism and server hemorrhage between the two groups receiving low and standard intensity therapy anticoagulant.</p><p><b>CONCLUSION</b>The effect and safety of low-intensity anticoagulant treatment are comparable to that of standard intensity treatment in Chinese Han patients, and anticoagulation treatment with warfarin is effective and safe to maintain the INR between 1.8-3.0.</p>