Genetic susceptibility of glutathione S-transferase genes (GSTM1/T1 and P1) to coronary artery disease in Asian Indians.

Genetic polymorphisms in glutathione S-transferase (GST) genes may modulate the risk of cardiovascular diseases. The objective of present study was to investigate the potential association between the polymorphisms of GSTM1/T1 and P1 genes and their influence on diverse clinical parameters and oxidative stress biomarkers in coronary artery disease (CAD) patients in Asian Indians. The present study includes 562 angiographically confirmed CAD patients and 564 healthy control subjects from the north Indian population. Anthropometric and clinical measurements were performed for all the participants. The oxidative stress biomarkers including malondialdehyde and total antioxidant capacity were also measured. The genotyping of the GSTM1/T1 and P1 genes was performed using the multiplex-PCR and PCR-RFLP methods. The CAD patients exhibit significantly high values of waist circumference, waist-to-hip ratio, body fat (%), glucose, triglycerides, and very low-density lipoprotein, and reduced high-density lipoprotein levels compared to control subjects (P < 0.001). Malondialdehyde levels were significantly enhanced, and the total antioxidant capacity was reduced in CAD patients compared to controls (P < 0.001). However, no significant difference in body mass index and total cholesterol levels were observed in CAD patients and control subjects. The frequencies of the GSTM1 and GSTM1/T1 null genotypes in the CAD patients were significantly higher than the control subjects. In contrast, the GSTT1(-) genotype frequencies were significantly lower in CAD patients than the controls. Logistic regression analysis of the data revealed the null genotype of GSTM1 and the GG genotype of the GSTP1 (313A/G) gene were associated with an approximately twofold enhanced risk of developing CAD, whereas GSTT1(-) plays a defensive role against CAD development in north Indians. Upon stratification of data according to the genotypes of the GSTM1/T1 and P1 genes, we did not find significant a difference among the various metabolic traits in CAD patients and controls. Our results suggest that oxidative damage induced by lipid peroxidation with reduced antioxidant capacity and genetic variants in GST genes (GSTM1/T1 and P1) may modify the risk of CAD development in Asian Indian population.

Implications of ACE (I/D) Gene Variants to the Genetic Susceptibility of Coronary Artery Disease in Asian Indians.

Angiotensin-1-converting enzyme (ACE) gene has established substantial attention in the recent years as a candidate gene for hypertension, cardiovascular diseases and type 2 diabetes. The aim of the present study was to investigate the association of ACE (I/D) polymorphism with coronary artery disease (CAD) in a north Indian population. A total of 662 subjects (330 CAD patients and 332 healthy controls) were examined for association of ACE gene (I/D) polymorphism and environmental risk factors. The mean age of the CAD patients and control subjects was 60.53 ± 8.6 years and 56.55 ± 7.7 years, respectively (p = 0.000). Anthropometric and demographic data showed BMI values significantly higher among CAD patients and control subjects (26.98 ± 4.9 vs 24.04 ± 4.7, p = 0.000). We observed pronounced central obesity in both CAD patients and controls, even at the lowest BMI values (<23 kg/m2). Dyslipidemia was highly prevalent in CAD patients compared to control subjects. Genotypic data showed significantly higher frequency of DD genotype in CAD patients than that of control subjects (40 vs 28.3 %). No significant difference was observed in the distribution of ID genotypes between CAD patients and control subjects. Logistic regression analysis of data demonstrate that DD genotype was associated with 1.8 fold increased risk of development of CAD in Asian Indians (OR 1.8; 95 % CI 1.22-2.66; p = 0.003). The frequency of D allele was significantly higher in CAD patients (p = 0.001). No significant difference was observed in the clinical and biochemical characteristics of CAD patients and controls when the data was stratified according to the genotypes of ACE gene. In conclusion, DD genotype of ACE gene may be associated with increased risk of CAD in Asian Indian population.

Ameliorative action of melatonin on oxidative damage induced by atrazine toxicity in rat erythrocytes.

Excessive generation of reactive oxygen species (ROS) can induce oxidative damage to vital cellular molecules and structures including DNA, lipids, proteins, and membranes. Recently, melatonin has attracted attention because of their free radical scavenging and antioxidant properties. The aim of this study was to evaluate the possible protective role of melatonin against atrazine-induced oxidative stress in rat erythrocytes in vivo. Adult male albino rats of Wistar strain were randomly divided into four groups. Control group received isotonic saline; melatonin (10 mg/kg bw/day) group; atrazine (300 mg/kg of bw/day) group; atrazine + melatonin group. Oral administration of atrazine and melatonin was given daily for 21 days. Oxidative stress was assessed by determining the glutathione (GSH) and malondialdehyde (MDA) level, and alteration in antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione-S-transferase (GST), and glucose-6-phosphate dehydrogenase (G-6-PD) in the erythrocytes of normal and experimental animals. A significant increase in the MDA levels and decrease in the GSH was observed in the atrazine treated animals (P < 0.05). Also, significant increase in the activities of SOD, CAT, GPx, and GST were observed in atrazine treated group compared to controls (P < 0.05). Moreover, significant decrease in protein, total lipids, cholesterol, and phospholipid content in erythrocyte membrane were demonstrated in atrazine treated rats. Administration of atrazine significantly inhibits the activities of G-6-PD and membrane ATPases such as Na(+)/K(+)-ATPase, Mg(2+)-ATPase, and Ca(2+)-ATPase (P < 0.05). Scanning electron microscopic (SEM) examination of erythrocytes revealed morphological alterations in the erythrocytes of atrazine treated rats. Furthermore, supplementation of melatonin significantly modulates the atrazine-induced changes in LPO level, total lipids, total ATPases, GSH, and antioxidant enzymes in erythrocytes. In conclusion, the increase in oxidative stress markers and the concomitant alterations in antioxidant defense system indicate the role of oxidative stress in erythrocytes of atrazine-induced damage. Moreover, melatonin shows a protective role against atrazine-induced oxidative damage in rat erythrocytes.

Biochemical and morphological perturbations in rat erythrocytes exposed to ethion: protective effect of vitamin E.

Erythrocyte membranes are an excellent model system to study interaction of pro-oxidants with membranes. The aim of the present study is to examine the effect of vitamin E on ethion-induced biochemical and morphological alterations in erythrocytes. Ethion was administered to the rats orally at a daily dose of 2.7 mg/kg body weight for a period of 7, 14, 21 and 28 days. The results from the present study show that administration of ethion resulted in oxidative damage to erythrocyte membranes as evident by increased lipid peroxidation and decreased phospholipid content. This was accompanied by decrease in membrane cholesterol levels. In addition, ethion exposure inhibited the activities of membrane bound enzymes; Na+ K+ ATPase and Mg2+ATPase. Scanning electron micrographs of erythrocytes from animals exposed to ethion revealed morphological changes. Supplementation of vitamin E (50 mg/kg body weight) to ethion exposed animals ameliorated the ethion-induced oxidative stress, restored membrane lipid composition and activity of membrane bound enzymes along with erythrocyte shape. The results clearly demonstrate that ethion-induced damage involves increase in oxidative stress that results in alterations in erythrocyte membrane structure and function. Furthermore, supplementation with vitamin E reversed ethion induced alterations suggesting its beneficial role in individuals exposed to ethion.

ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes in North Indians.

Genetic susceptibility may be responsible for high prevalence of type 2 diabetes worldwide. A common missense single nucleotide polymorphism, K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene, has recently been associated with type 2 diabetes in Italian, South Indian, and American populations. The objective of this study was to investigate the possible role of K121Q polymorphism in ENPP1 gene with type 2 diabetes in North Indians. The genotype of the ENPP1/PC-1 K121Q polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism analysis for 328 T2DM patients and 326 non-diabetic participants. Anthropometric and clinical characteristics (Body mass index (BMI), glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), Creatinine, HbA1c, and insulin levels) were measured using standard protocols. Their Chi-square analyses were used to test the significance differences in genotypic and allelic frequencies. Association studies were undertaken using the t test and logistic regression analyses. Our results revealed there was no significant difference in the genotypic distribution between T2DM patients and control subjects. The KK and KQ genotype frequencies were similar in T2DM cases and controls (60.7 and 39.3% in T2DM and 59.8 and 40.2% in controls). No subjects with the QQ genotype were found. Binary logistic regression analysis of data did not show any association of K121Q polymorphism with type 2 diabetes (OR; 0.97, 95% CI; 0.7-1.32, P = 0.82). No significant correlation among the BMI, WHR, BP, TG, TC, HDL-C, LDL-C, Glucose, HbA1c, Creatinine, and insulin indices (HOMA-IR) was observed in the individuals carrying KK and KQ genotypes. In conclusion, our results showed that ENPP1/PC-1 K121Q polymorphism is not associated with type 2 diabetes and related quantitative metabolic traits in North Indian Punjabi population.

Therapeutic Strategies for Mitochondrial Dysfunction and Oxidative Stress in Age-Related Metabolic Disorders.

Mitochondria are complex, intercellular organelles present in the cells and are involved in multiple roles including ATP formation, free radicals generation and scavenging, calcium homeostasis, cellular differentiation, and cell death. Many studies depicted the involvement of mitochondrial dysfunction and oxidative damage in aging and pathogenesis of age-related metabolic disorders and neurodegenerative diseases. Remarkable advancements have been made in understanding the structure, function, and physiology of mitochondria in metabolic disorders such as diabetes, obesity, cardiovascular diseases, and stroke. Further, much progress has been done in the improvement of therapeutic strategies, including lifestyle interventions, pharmacological, and mitochondria-targeted therapeutic approaches. These strategies were mainly focused to reduce the mitochondrial dysfunction caused by oxidative stress and to retain the mitochondrial health in various diseases. In this chapter, we have highlighted the involvement of mitochondrial dysfunction in the pathophysiology of various disorders and recent progress in the development of mitochondria-targeted molecules as therapeutic measures for metabolic disorders.

Alterations in Ca²âº homeostasis and oxidative damage induced by ethion in erythrocytes of Wistar rats: ameliorative effect of vitamin E.

Organophosphate (OP) insecticides have been reported to induce oxidative stress due to lipid peroxidation and alteration in defense mechanisms. It is known that calcium content in erythrocytes plays a very important in normal physiology of cells. Erythrocytes are a very convenient model to understand the susceptibility of membrane to oxidative damage induced by various xenobiotic compounds. The aim of present study was to investigate the effects of ethion induced oxidative damage, alterations in membrane bound enzymes and Ca(2+) homeostasis and a possible protective role of vitamin E. Adult male albino rats of Wistar strain were orally administered ethion and vitamin E daily for 28 days. Animals were randomly divided into four groups: control; ethion treated (2.7 mg/kgbw/day); vitamin E treated (50mg/kg of bw/day); ethion+vitamin E treated. The animals were sacrificed after 7, 14, 21 and 28 days. Erythrocyte membranes were prepared and analyzed for protein, lipid peroxidation (LPO) and membrane bound ATPases. Furthermore, Ca(2+) homeostasis as function of time and concentration was evaluated in erythrocytes. The results from the present study show that in vivo administration of ethion resulted in oxidative damage to erythrocyte membranes as evident by increased lipid peroxidation. The increased LPO following ethion intoxication was accompanied by significant decrease in the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase and disturbed Ca(2+)homeostasis in erythrocytes. Furthermore, vitamin E treatment had a beneficial effect by decreasing lipid peroxidation; partially restoring activities of membrane bound ATPases and Ca(2+) homeostasis. The present study suggests that ethion exerts its toxic effect by increasing LPO, altering the activity of membrane bound enzymes and disturbing Ca(2+) homeostasis. Vitamin E treatment ameliorated the toxic effects of ethion suggesting its role as a potential antioxidant.