中国汉族人群谷胱甘肽硫转移酶M1及T1基因多态性与先天性心脏病发病风险的关系

目的探讨中国汉族人群谷胱甘肽硫转移酶(glutathione S-transferases,GST)M1及T1基因(GSTM1/GSTT1)多态性与先天性心脏病(先心病)发病风险的关系。方法采用病例-对照研究(病例组365例,对照组372例),运用多重聚合酶链反应检测先心病患者及健康对照GSTM1/GSTT1基因型;并利用多因素非条件logistic回归模型,进行先心病发病风险影响因素关联强度及交互作用分析。结果 GSTM1/GSTT1基因多态性及研究对象母亲围孕期吸烟、饮酒、化学物质接触、孕前体质量指数、教育程度、定期产检以及怀孕知情时间在病例组和对照组之间分布存在明显差异(P<0.05)。GSTM1/GSTT1基因缺失与先心病发病风险显著正相关(OR=1.56,P=0.049;OR=1.73,P=0.036)。经logistic回归分析,GSTM1(-)/GSTT1(-)基因型和研究对象母亲围孕期吸烟、饮酒、化学物质接触以及孕前高体质量指数是先心病发病的高危因素,研究对象母亲围孕期定期产检以及摄入充足的叶酸是先心病的保护因素。研究对象母亲围孕期吸烟与GSTM1(-)/GSTT1(-)基因型之间具有正相加交互作用,与母亲围孕期不吸烟且GSTM1/T1基因未缺失的研究对象相比,其母亲围孕期吸烟且携带GSTM1(-)和(或)GSTT1(-)基因型的先心病发病风险显著上升(OR=9.01,3.87,3.01;95%CI:1.73～39.69,1.21～19.57,1.13～9.69)。结论 GSTM1/GSTT1基因缺失是先心病发病风险的独立危险因素;GSTM1(-)/GSTT1(-)基因型与孕母围孕期吸烟在先心病的发生中具有协同作用。     

Lovastatin reduces postprandial lipoprotein levels in hypercholesterolaemic patients with mild hypertriglyceridaemia

Drugs that inhibit cholesterol synthesis have recently been released for lowering LDL-cholesterol levels. The current study examines the effect of one of these drugs, lovastatin, alone and in combination with cholestyramine on postprandial fat metabolism in five patients with severely elevated LDL-cholesterol and normal triglyceride levels (less than 1.8 mmol l-1) and in five patients with similarly elevated LDL-cholesterol and mildly elevated triglyceride levels (1.8 to 2.7 mmol l-1). In the group of patients with normal triglyceride levels, neither lovastatin alone nor in combination with cholestyramine had any effect on postprandial lipoprotein levels, while profoundly decreasing LDL-cholesterol levels. This provides evidence that LDL and postprandial lipoproteins are cleared by different mechanisms. In the group of five patients with mildly elevated triglyceride levels, in addition to LDL-cholesterol lowering, lovastatin significantly lowered VLDL-cholesterol, fasting triglyceride and postprandial lipoprotein levels. Thus in patients with mild hypertriglyceridaemia, lovastatin may have another favourable effect on the lipoprotein system in addition to LDL-cholesterol lowering.     

Altered status of glutathione and its metabolites in cystinotic cells.

BACKGROUND: Cystinosis is an autosomal recessive disorder, caused by mutations of the lysosomal cystine carrier cystinosin, encoded by the CTNS gene (17p13). The concomitant intralysosomal cystine accumulation leads to multi-organ damage, with kidneys being the first affected. Altered mitochondrial oxidative phosphorylation has been demonstrated in animal proximal tubules loaded with cystine dimethyl ester, mimicking cystine accumulation in cystinosis, but has not been confirmed in cells of patients with cystinosis. Furthermore, the link between cystine accumulation and mitochondrial damage is also missing. We hypothesized that cytosolic cysteine deficiency resulting in intracellular glutathione (GSH) shortage might be involved in cellular dysfunction in cystinosis. METHODS: Components of the gamma-glutamyl cycle were measured in cultured skin fibroblasts (n = 9) and polymorphonuclear (PMN) leukocytes (n = 15) derived from patients with cystinosis and compared with the values in cultured fibroblasts (n = 9) and PMN cells (n = 18) of healthy controls. RESULTS: Cystine content in cystinotic fibroblasts and PMN cells was significantly elevated compared with the controls, consistent with the lysosomal cystine accumulation in these cells. Although no reduction of total intracellular GSH content was found in cystinotic cells, it inversely correlated with cystine levels. Furthermore, GSH disulfide (GSSG) was elevated in cystinotic cells, resulting in an increased GSSG/total GSH (%) ratio. No relationship between intracellular cystine and GSH was found in control fibroblasts and PMN cells. CONCLUSION: An elevated GSSG/total GSH (%) ratio might indicate increased oxidative stress present in cystinotic cells. Inverse correlation between cystine accumulation and intracellular GSH content indicates that under stress conditions such as intensive energy demand or increased oxidative insult, cystinotic cells may be more prone to GSH depletion.     

Substituted spiro[chroman-4,5′-thiazolidine]-2′,4′-diones as aldose reductase inhibitors

Aldose reductase (EC 1.1.1.21) is believed to be involved in the pathogenesis of diabetic complications. Inhibitors of this enzyme could be useful for the treatment of diabetic cataracts and neuropathies. A series of spiro[chroman-4,5′-thiazolidine]-2′,4′-diones, substituted at the aromatic ring, has been synthesized as potential inhibitors of this enzyme. Their activity was determined with in vitro and in vivo tests. The compounds are very potent inhibitors of aldose reductase. Activity in galactosemic rats was found, especially for derivatives bearing alkyl-carbamate substituents. Drug levels in plasma, lens and nerve were determined with radioactively labelled compounds and by high performance liquid chromatography. The latter method was also used to determine in vivo degradation of the carbamates.     

矽尘作业者血抗脂质过氧化活性变化

作者测定了矽尘作业者和对照组血超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的活性变化,结果是矽尘作业者和健康对照组SOD、GSH-Px的活性分别为2.396±0.413(×10~3u/gHb)、35.06±6.94(μmol GSH被氧化量/min·gHb)和2.098±0.591(×10~3u/gHb)、27.41±9.20(μmol GSH被氧化量/min·gHb),前者均显著高于后者,同时SOD、GSH-Px活性高尘龄组也显著高于低尘龄组,揭示长期接触矽尘机体内的脂质过氧化和抗过氧化活性均处于亢奋状态。抗脂质过氧化活性的增强,可能是机体的一种防御性机制,是矽尘作业者机体对二氧化硅细胞毒性作用的不同阶段的反应。     

Sulfhydryl drugs reduce neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridime (MPTP) in the mouse

Summary Striatal levels of dopamine and its metabolites 3-methoxy-4-hydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased 7 days after subcutaneous injection of MPTP (20 mg/kg) to the mouse. Striatal GSH contents decreased and GSSG/GSH ratios increased one hour after subcutaneous administration of MPTP. Pretreatments of both cysteamine (200 mg/kg, s.c.) and dimercaprol (20 mg/kg, i.m.) reduced the MPTP-induced decreases in striatal dopamine, DOPAC and HVA, and also prevented the MPTP-induced decreases in GSH levels and increases in GSSG/GSH ratios. On the other hand, injection of cysteamine did not modify the MPTP-induced decreases in striatal levels of dopamine and its metabolites when it was done 2 hours after MPTP administration. Moreover, pretreatment of cysteamine did not affect striatal concentrations of MPP⁺ in MPTP-treated mice. These results suggest that sulfhydryl drugs such as cysteamine and dimercaprol may reduce neurotoxity of MPTP probably via changes in redox cycle of glutathione in the brain.     

Recruitment of Several Neuroprotective Pathways after Permanent Focal Ischemia in Mice

After an ischemic episode induced by the electrocoagulation of the left middle cerebral artery (MCA) in mouse, neurons within the damaged territory die either by an apoptotic or by a necrotic process. Most of the cortical neurons within the ischemic area display both morphological and biochemical signs of programmed cell death: nuclear condensation, DNA degradation, formation of apoptotic bodies, and glutathione depletion. In fact, apoptosis essentially contributes to the expansion of the ischemic lesion and the maximum of damaged territory is reached 24 h postocclusion. Several potentially neuroprotective pathways have been evidenced in different experimental models of ischemia including the activation of antioxidant enzyme activities and/or the recruitment of neurotrophic as well as antiapoptotic factors. In our model of permanent focal ischemia induced by MCA occlusion, we measured the temporal synthesis of nerve growth factor (NGF) and examined the status of antioxidant enzymes as well as Bcl-2 antiapoptotic product. We detected in both cortices a transient increase of NGF which peaks at 6 h. Moreover, we reported that glutathione peroxidase is recruited with a time course which parallels NGF synthesis. Finally, we observed the induction of Bcl-2 in safe neurons; this may represent a self-protective response against ischemia-induced apoptosis. We provide evidence that in a model of permanent focal ischemia, several neuroprotective pathways could be coactivated.     

实验性动脉粥样硬化家兔血浆LPO与红细胞SOD,GSH—Px的活力观察

为了研究自由基在动脉粥样硬化过程中的作用,建立了家兔动脉粥样硬化模型。实验组随着TC,LDL-C的升高,LPO由0.30上升到2.12△D_(233)/ml,是对照组的14倍。TC,LDL-C与LPO呈明显正相关(r=0.69,r=0.67,P<0.05)。但是,随着LPO的上升,GSH-Px逐渐下降,是对照组的0.57,0.35倍。SOD在两组间差异无显著性(P>0.05)。结果表明,检测LPO和GSH-Px对由于动脉粥样硬化引起的心脑血管病的诊断、疗效评估和预后有重要意义。     

Brain glutathione reductase induction increases early survival and decreases lipofuscin accumulation in aging frogs

Brain catalase was continuously depleted throughout the life span starting with a large population of initially young and old frogs. Free radical-related parameters were measured in the brain tissue once per year after 2.5, 14.5, and 26.5 months of experimentation. Brain lipofuscin accumulation was observed after 14.5 and 26.5 months, and survival was continuously followed during 33 months. The age of the animal did not decrease endogenous antioxidants nor increase tissue peroxidation either in cross-sectional or longitudinal comparisons. Continuous catalase depletion similarly affected young and old animals, inducing glutathione reductase, tending to decrease oxidized glutathione/reduced glutathione (GSSG/GSH) ratio, decreasing lipofuscin accumulation in the brain, and increasing survival from 46% to 91% after 14.5 months. At 26.5 months of experimentation the loss of the glutathione reductase induction in catalase-depleted animals was accompanied by the presence of higher lipofuscin deposits than in controls and was followed by a great increase in mortality rate. Even though the maximal life span (7 years) was the same in the control and treated animals which were already old (4.2 years) at the beginning of the experiment, the treated animals showed a strong reduction in the rates of early death. It is proposed that the maintenance of a high antioxidant/prooxidant balance in the vertebrate brain greatly increases the probability of the individual to reach the final segments of its species-specific life span. © 1993 Wiley-Liss, Inc.     

Phenytoin-Folate Interactions: Differing Effects of the Sodium Salt and the Free Acid of Phenytoin

Chronic phenytoin (PHT) treatment has long been associated with folate deficiency. It has been suggested that pH changes in the gut associated with PHT ingestion may be responsible for decreased folate uptake either by direct inhibition of folate transport into the intestinal mucosa or by inhibition of folate conjugase activity. To examine these possibilities, rats were gavaged chronically with PHT using either the sodium salt (NaPHT) or the free acid (HPHT) in the presence of folic acid as the dietary source of folate. The NaPHT caused a greater depletion of folate in the liver and brain and a significant increase in methylenetetrahydrofolate reductase activity in the liver. The HPHT caused a significantly decreased weight gain over the 8 weeks of treatment and resulted in a much higher liver PHT concentration and a slightly lower plasma PHT concentration. These data support the hypothesis that PHT-induced changes in pH in the gut affect the enterohepatic circulation of folate.