Effect of antimalarials treatment on rat liver lysosomal function—Anin vivo study

Effects of treatmentin vivo with the antimalarials:chloroquine (CQ), primaquine (PQ) and quinine(Q) on lysosomal enzymes and lysosomal membrane integrity were examined. Treatment with the three antimalarials showed an apparent increase in the membrane stability. CQ treatment resulted in increase in both the ‘free’ and ‘total’ activities of all the enzymes i.e. acid phosphatase, RNase II, DNase II and cathepsin D. PQ treatment lowered the ‘free’ and ‘total’ activities of acid phosphatase and cathepsin D, but the DNase II activities increased. Treatment with Q resulted in increased ‘free’ and ‘total’ activities of RNase II and DNase II. While ‘free’ activities of acid phosphatase and cathepsin D were low; the ‘total’ activities increased significantly. Our results suggest that a generalized increase in free nucleases activities following prolonged treatment with antimalarials may lead to cell damage and/or necrosis.     

Putative Role of Cardio Metabolic Risk Among Poorly Controlled Asthmatics in South Indian Population

Mortality and morbidity attributed to asthma remains to be the biggest nightmare worldwide. Hence, the study was aimed to compare the cardio metabolic risk factors as assessed by Body mass index (BMI), waist hip ratio (WHR), serum triacylglycerol and uric acid in well controlled and poorly controlled asthmatics and to correlate these parameters with the severity of asthma. A case control study was conducted on 90 subjects who were segregated into well controlled asthmatics (n = 30) and poorly controlled asthmatics (n = 30) who were diagnosed based on Global initiative for Asthma management guidelines and healthy volunteers (n = 30). Centrifuged fasting venous blood samples were used for biochemical analysis, pulmonary function test, BMI, and waist hip ratio (WHR) were measured. The statistical analysis was done using SPSS version 17. There was a significant increase in BMI, WHR, lipid profile, serum uric acid and decrease in forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC in poorly controlled asthmatics. There was a significant association between FEV1 and serum uric acid, BMI and Triacylgycerol in poorly controlled asthmatics. Poorly controlled asthmatics have greater risk of developing cardiometabolic problems. Serum uric acid can be used as one of the severity markers in asthma to assess cardio metabolic risk.     

Altered Kinetics Properties of Erythrocyte Lactate Dehydrogenase in Type II Diabetic Patients and Its Implications for Lactic Acidosis

Recent studies have been noted that the erythrocytes from Type II diabetic patients show significantly altered structural and functional characteristics along with the changed intracellular concentrations of glycolytic intermediates. More recent studies from our laboratory have shown that the activities of enzymes of glycolytic pathway changed significantly in RBCs from Type II diabetic patients. In particular the levels of lactate dehydrogenase (LDH) increased significantly. Lactic acidosis is an established feature of diabetes and LDH plays a crucial role in conversion of pyruvate to lactate and reportedly, the levels of lactate are significantly high which is consistent with our observation on increased levels of LDH. Owing to this background, we examined the role of erythrocyte LDH in lactic acidosis by studying its kinetics properties in Type II diabetic patients. Km, Vmax and apparent catalytic efficiency were determined using pyruvate and NADH as the substrates. With pyruvate as the substrate the Km values were comparable but Vmax increased significantly in the diabetic group. With NADH as the substrate the enzyme activity of the diabetic group resolved in two components as against a single component in the controls. The Apparent Kcat and Kcat/Km values for pyruvate increased in the diabetic group. The Ki for pyruvate increased by two fold for the enzyme from diabetic group with a marginal decrease in Ki for NADH. The observed changes in catalytic attributes are conducive to enable the enzyme to carry the reaction in forward direction towards conversion of pyruvate to lactate leading to lactic acidosis.     

利用预执行的预取来并行应用程序隐藏I／O延迟

并行程序通常用来提高计算性能,但却受到I／O存取过程中的大延迟的影响。鉴于处理器与I／O之间差距越来越大,数据存取延迟成为主要的性能瓶颈。我们认为是时候重新审视“I／O墙”的问题并用额外的计算能力换取数据存取速度。我们提出一种新的用于掩盖I／O延迟的预执行策略。我们介绍了这种预执行的I／O预取框架,这种预取线程的构造方法,底层支持库,     

Diabetic cardiomyopathy and reactive oxygen species (ROS) related parameters in male and female rats: A comparative study

Studies were carried out to examine and compare the effects of alloxan-diabetes on reactive oxygen species (ROS) related parameters in the heart from male and female rats. Effects of insulin treatment were also evaluated. The diabetic state severely compromised the ROS defense mechanism in the cardiac tissue and the effects were more pronounced in the female than in the male rats. There was several fold increase in the xanthine oxidase (XO) activity in general and the magnitude of increase was higher in the females; insulin treatment resulted in further increase in the XO activity. The glucose-6-phosphate dehydrogenase (G6PDH) and catalase activities decreased and the reduced glutathione (GSH) content in mitochondria was completely depleted in diabetic state with significant decrease in the GSH levels in the post-mitochondrial fraction; the effect was more pronounced in the females. The superoxide dismutase (SOD) and glutathione peroxidase (GPox) activities increased in the diabetic state to a greater extent in male rats. Insulin treatment had restorative action only on some parameters. In conclusion, our results suggest that diabetic state may further compromise the weak ROS defense systems in the heart thus initiating a lesion at the level of mitochondria which ultimately leads to cardiomyopathy and the effects are especially more pronounced in the females. Our results also pointed out that insulin treatment was ineffective in restoring ROS related parameters.     

Effect of streptozotocin-induced diabetes on oxidative energy metabolism in rat liver mitochondria—A comparative study of early and late effects

The reports in the literature on effects of diabetes on mitochondrial energy-linked functions are conflicting. Hence we carried out systematic studies to evaluate the effects at the early and the late stages of the disease using STZ-diabetic rat as a model. At the end of one week, after induction of diabetes, respiration rates with glutamate and succinate as the substrates increased; respiration rates with other substrates e.g. β-hydroxybutyrate, pyruvate + malate and ascorbate + TMPD were not affected despite substantial decrease in the β-hydroxybutyrate dehydrogenase activity and cytochrome b and c+c₁ contents. Insulin treatment brought about increase in the cytochrome contents beyond control values. The ATPase activity was generally low in the diabetic animals and was not restored by insulin treatment. At the end of one month, the respiratory activities with all the substrates were generally low. Insulin treatment either restored or stimulated the respiration rates beyond control values. The content of cytochromes was differentially affected in the diabetic animals, but insulin treatment caused significant increase beyond control levels. The pattern for ATPase activity was similar to the early effects. At both the stages i.e. early and late stages of diabetes the mitochondria were tightly coupled. The ADP/O ratios were in normal expected ranges and the respiratory control ratios were comparable with the control groups. Insulin treatment resulted in apparent restoration of respiratory activity. However, the effects on the cytochromes and dehydrogenases activities were differential. Taken together the two observations would suggest that the mitochondria were not re-instated to normality despite apparent restoration of respiratory function.     

Thyroidal regulation of substrate kinetics properties of cytochrome oxidase in rat liver mitochondria

Effects of thyroidectomy (T_x) and subsequent treatment with 3,5,3’-triiodothyronine (T₃), and combined treatment (T_R) with T₃ + thyroxine (T₄) on substrate kinetics properties of cytochrome oxidase of rat liver mitochondria were examined. T_x resulted in lowering of cytochromes content with decrease in the enzyme activity, and K_m and V_max. T₃ and T_R regimens restored the cytochromes contents and the V_max values to normal. In control, T₃ and T_R groups the enzyme activity resolved in two kinetic components; in T_x group three kinetic components were evident. The K_m values for all components decreased significantly in the experimental groups with concomitant increase in catalytic efficiency, K_cat/K_m. Significant alterations in the contents of total phospholipid and of cholesterol were noted while the changes in the phospholipids composition were only of restricted nature. Regression analysis revealed that total phospholipid, cholesterol and phosphatidylcholine, phosphatidylethanolamine play significant role in fine tuning the enzyme activity.     

Pharmacogenetic Aspects of Coumarinic Oral Anticoagulant Therapies

Coumarinic oral-anticoagulants (COAs) are commonly used for treatment of thromboembolic events. However, these medications have a narrow therapeutic range and there are large inter-individual variations in drug response. This is especially important in the initial phases of oral-anticoagulant therapy. Recent advancements in pharmacogenetics have established that clinical outcomes in oral-anticoagulant therapy are affected by genetic factors. The allelic variants of genes like cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are closely associated with maintenance dose of oral anti-coagulants. In addition, GGCX (Gamma-glutamyl carboxylase) polymorphism at position 12970 (rs11676382), CYP4F2 (rs2108622; V433M; 1347 C > T) and Apolipoprotein E (APOE) variants have been shown to explain a small but significant influence on dose requirements. There are large differences in the frequencies of these polymorphisms between different world populations which are also related to the requirements of oral anticoagulants. However, the final drug dosage in an individual is determined by complex sets of genetic and environmental factors and several dosing algorithms which combine clinical and genetic parameters to predict therapeutic COA doses have also been developed. The algorithm based dose prediction shows the importance of pharmacogenetic testing in patients undergoing oral anticoagulant therapies.     

Altered Erythrocyte Glycolytic Enzyme Activities in Type-II Diabetes

The activity of enzymes of glycolysis has been studied in erythrocytes from type-II diabetic patients in comparison with control. RBC lysate was the source of enzymes. In the diabetics the hexokinase (HK) activity increased 50 % while activities of phosphoglucoisomerase (PGI), phosphofructokinase (PFK) and aldolase (ALD) decreased by 37, 75 and 64 % respectively but were still several folds higher than that of HK. Hence, it is possible that in the diabetic erythrocytes the process of glycolysis could proceed in an unimpaired or in fact may be augmented due to increased levels of G6P. The lactate dehydrogenase (LDH) activity was comparatively high in both the groups; the diabetic group showed 85 % increase. In control group the HK, PFK and ALD activities showed strong positive correlation with blood sugar level while PGI activity did not show any correlation. In the diabetic group only PFK activity showed positive correlation. The LDH activity only in the control group showed positive correlation with marginal increase with increasing concentrations of glucose.     

A comparative study of reactive oxygen species (ROS) related parameters in rat tissues

Reactive oxygen species (ROS) are believed to be responsible for pathogenesis of various diseases affecting tissues and systems. ROS generated by mitochondrial electron transport chain as well as extra-mitochondrially are eliminated by the respective defense mechanisms. We checked the activity of ROS generating system such as xanthine oxidase and also the parameter of ROS defense mechanism e.g. superoxide dismutase (SOD), catalase, glutathione peroxidase (GPox), reduced glutathione content (GSH) and glucose-6-phosphate dehydrogenase (G6PDH) in mitochondrial and post-mitochondrial fractions from various tissues (liver, kidney, brain and heart) of normal rats. Extent of lipid peroxidation (LPO) which is immediate consequence of ROS generation was also examined. Our results shows that significant tissue-specific differences exist in mitochondrial and cytosolic ROS generating systems and ROS defense mechanisms.