Zachariah Bobby

Antioxidants preserve redox balance and inhibit c-Jun-N-terminal kinase pathway while improving insulin signaling in fat-fed rats: evidence for the role of oxidative stress on IRS-1 serine phosphorylation and insulin resistance

The oxidative stress-sensitive c-Jun-N-terminal kinase (JNK) pathway is known to be activated in diabetic condition and is involved in the progression of insulin resistance. However, the effect of antioxidants on JNK pathway and insulin resistance has not been investigated. The present study was aimed to investigate the effect of antioxidants on redox balance, insulin sensitivity, and JNK pathway in high-fat-fed rats. Male Wistar rats were divided into four groups: the control group - received a rodent chow; control+antioxidant group - fed with rodent chow supplemented with 0.2% (w/w) vitamin E, 0.3% (w/w) vitamin C, and 0.5% (w/w) alpha-lipoic acid; high-fat group - received high-fat diet; and high fat+antioxidant group - fed with high-fat diet supplemented with above antioxidants. Fat feeding to rats for 9 weeks significantly increased IRS-1 serine phoshorylation, reduced insulin-stimulated IRS-1 tyrosine phosphorylation and insulin sensitivity. High-fat diet also impaired redox balance and activated the redox-sensitive serine kinase - JNK pathway. Antioxidant supplementation along with high-fat diet preserved the free radical defense system, inhibited the activation of JNK pathway, and improved insulin signaling and insulin sensitivity. The present study shows for the first time that antioxidants inhibit JNK pathway and IRS-1 serine phosphorylation while improving insulin sensitivity in fat-fed rats. These findings implicate the beneficial effect of antioxidants in obesity-/dyslipidemia-induced insulin resistance in humans.

An evaluation of level of oxidative stress and protein glycation in nondiabetic undialyzed chronic renal failure patients.

BACKGROUND Chronic renal failure (CRF) patients on prolonged dialysis and with diabetes have been found to have significant alteration in their antioxidant status and protein glycation, but little is known about the same in nondiabetic undialyzed CRF patients. This study was performed to evaluate (a) the levels of oxidative stress and protein glycation in nondiabetic undialyzed CRF patients and (b) the possible influence of oxidative stress on protein glycation. DESIGN AND METHODS A case control study was performed on 23 nondiabetic undialyzed CRF patients and 17 control subjects. The concentrations of total plasma ascorbic acid, whole blood reduced glutathione (GSH) and plasma lipid peroxides were measured to evaluate the antioxidant status and oxidative stress. The protein glycation was measured from plasma fructosamine normalized for albumin concentrations. A partial correlation analysis was carried out to analyze the effect of oxidative stress parameters on protein glycation. RESULTS A compromised nonenzymatic defense against free-radical generation was evidenced by decreased concentrations of whole blood GSH and plasma ascorbic acid. The concentrations of lipid peroxides, fructosamine and fructosamine/albumin ratio were significantly (p<0.05) higher in the CRF group when compared with controls. The partial correlation analysis revealed that oxidative stress influences protein glycation in CRF patients. CONCLUSIONS Increased oxidative stress might have a role in promoting protein glycation in nondiabetic undialyzed CRF patients. The reduction of oxidative stress and protein glycation might open new therapeutic approaches in treating CRF patients.

Oxidative stress and protein glycation in primary hypothyroidism. Male/female difference

Oxidative stress (OS) has recently been documented in hypothyroidism, a disease more prevalent in women. In general, OS is reported to be more prevalent in males. However, the effect of gender on OS and protein glycation in hypothyroidism has not been addressed. Blood samples from 37 recently diagnosed primary hypothyroid patients were collected before initiation of thyroxine therapy. Serum glucose, thyroid and lipid profiles were estimated. Glutathione (GSH), malondialdehyde (MDA), protein carbonylation (PCO) and fructosamine levels were analysed. GSH was found to be lower, whereas MDA, fructosamine and PCO levels were higher in male than in female patients. Level of MDA was significantly correlated with fructosamine, protein carbonyls, cholesterol, low-density and high-density lipoprotein cholesterol, triglyceride and GSH in hypothyroid patients. We found OS to be more prevalent in male hypothyroid patients. The positive association of MDA with fructosamine indicates that enhanced lipid peroxidation could be a plausible contributor for accelerated glycation of protein. Considering the negative influence of OS on health, extra attention should be paid to male hypothyroid patients in spite of the low prevalence of this disease in them.

Increased Glycation of Hemoglobin in Chronic Renal Failure Patients and Its Potential Role of Oxidative Stress

Among the various mechanisms proposed, the process of non-enzymatic glycation of proteins is believed to play an important role in the pathogenesis of chronic complications associated with renal failure. The two traditional factors found to modulate the early glycation of proteins are the prevailing concentration of glucose and half life of the protein. Among the various proteins that are known to undergo nonenzymatic glycation in vivo, hemoglobin has been the most thoroughly investigated. Determination of glycated hemoglobin in diabetic patients is currently acknowledged as the most reliable indicator for assessment of retrospective glycemic control and the planning of clinical management. The clinical utility of glycated hemoglobin measurements, however, in renal failure is controversial, given the numerous earlier studies showing no correlation between glycated hemoglobin and other indicators of blood glucose control in uremic subjects. With few exceptions, previous studies have suggested that the concentration of glycated hemoglobin was increased in uremic patients. There is documented evidence that increased glycated hemoglobin levels are found in certain non-diabetic states. So it stands to reason that hyperglycemia, although clearly being the culprit in diabetes, does not provide the complete answer to the etiology of increased early glycated products in non-diabetic conditions including chronic renal failure. This article reviews available evidence supporting increased glycation of hemoglobin in patients with chronic renal failure. Potential mechanisms for this increase are examined with special emphasis on the potential role of oxidative stress.

Association of thyroid stimulating hormone and coronary lipid risk factors with lipid peroxidation in hypothyroidism.

Abstract Background: Hypothyroidism is the second most prevalent disorder in India and most cases require lifelong treatment. Disordered myocardial function is one of the complications of overt hypothyroidism. Dyslipidemia and lipid peroxidation are two biochemical derangements of hypothyroidism and both have been found to be associated. Still uncertainty remains regarding the origin of lipid peroxidation in this clinical condition. Besides, thyroid stimulating hormone or thyrotropin at a higher concentration can induce secretion of inflammatory cytokines and decrease the antioxidant status. Methods: Hence, we analyzed the association of lipid risk factors and thyrotropin in hypothyroidism with the extent of lipid peroxidation. A total of 42 primary hypothyroid patients volunteered to give fasting blood samples prior to therapy for the analysis of oxidative stress, thyroid and lipid profiles. Results: Oxidative stress was confirmed by the increased levels of malondialdehyde and protein carbonylation and decreased levels of reduced glutathione. Simple correlation analyses revealed the association of lipid peroxidation with both thyrotropin and lipid risk factors. Partial correlation analyses showed that thyrotropin and lipid risk factors mutually influence their association with the higher malondialdehyde levels in these patients. Conclusions: Hyperthyrotropinemia may be considered not only as an index of the severity of hypothyroidism but also of the extent of the associated lipid peroxidation. Clin Chem Lab Med 2008;46:674–9.

Short-Term Heart Variability and Oxidative Stress in Newly Diagnosed Essential Hypertension

We sought to evaluate oxidative stress parameters like malondialdehyde, total antioxidant status, and time, frequency domain heart rate variability indices in newly diagnosed untreated hypertension. We also sought to study the correlation between heart rate variability and oxidative stress parameters in normotensive and newly diagnosed untreated essential hypertensives. Fourteen normotensive males and 36 newly diagnosed male hypertensives were enrolled for the study. Malondialdehyde, total antioxidant status, and heart rate variability in the frequency and time domain were studied in the hypertensive and normotensive group. Malondialdehyde was significantly higher in the hypertensive group, whereas total antioxidant status was significantly higher in the control group. SDNN, RR triangular index, RMSSD, log 10 low-frequency power, log 10 high-frequency power, log 10 total power, and heart rate variability during deep breathing test was significantly lower in hypertensive patients compared to normotensive controls. SDNN, RMSSD, high-frequency power, and high-frequency power normalized had significant negative correlation with malondialdehyde. Low-frequency power normalized positively correlated with malondialdehyde. Total antioxidant status had a significant negative correlation with blood pressure. The study gives further evidence for a decreased heart rate variability and elevated oxidative stress in hypertension.

Cardiovagal Modulation, Oxidative Stress, and Cardiovascular Risk Factors in Prehypertensive Subjects: Cross-Sectional Study

BACKGROUND Hypertension, one of the modifiable risk factors for cardiovascular disease (CVD), is known to be associated with increased oxidative stress and reduced cardiovagal modulation. Similar to hypertension, prehypertension is associated with increased risk of adverse cardiovascular (CV) events. We planned this study to find the association between prehypertension, cardiovagal modulation, oxidative stress, and associated CV risk factors. METHODS We recruited 178 subjects through hypertension screening camps conducted in Puducherry, India. Subjects were grouped into prehypertensive (n = 97) and normotensive (n = 81) groups. They were further subdivided, based on age, as young (20-39 years) and middle-aged (40-60 years) adults. We measured basal physiological parameters, heart rate variability, oxidative stress (thiobarbituric acid reactive substance and total antioxidant capacity (TAC)), and CV risk factors. RESULTS We found significant increase in oxidative stress in prehypertensive subjects of both age groups but the cardiovagal modulation decreased significantly in young prehypertensive subjects when compared with normotensive subjects. Correlation of TAC with root mean square of the sum of successive R wave to R wave (RR) interval differences (RMSSD), a cardiovagal modulation parameter (r = 0. 437; P < 0.001), and mean arterial pressure (MAP) (r = -0.318; P < 0.001) was significant even after adjusting for CV risk factors. The correlation between MAP and RMSSD (r = 0.199; P = 0.009) was reduced after adjusting for CV risk factors. CONCLUSIONS Prehypertension in young adults is associated with increased oxidative stress and altered cardiovagal modulation. The risk factors for CVDs in prehypertensive young adults were found to be equivalent to that of middle-aged adults who are in the twilight zone for developing CV dysfunctions.

Oxidative stress induced changes in plasma protein can be a predictor of imminent severe dengue infection.

OBJECTIVES Oxidative stress in dengue viral infection has been suggested and severity of it was found to be associated with progress of illness. Hence assessing oxidative stress mediated changes in plasma proteins can be an early biomarker for prediction of severe dengue infection. DESIGN AND METHODS Thirty two dengue hemorrhagic fever (DHF), 21 dengue shock syndrome (DSS), 27 dengue fever (DF) and 63 age and sex matched controls, were included in this study. Blood samples were collected on the 3rd day of fever. Protein carbonylation (PCOs) and protein-bound sulphydryl (PBSH) group levels were determined by spectrophotometric method and analyzed as predictor of dengue hemorrhagic fever and dengue shock syndrome. RESULTS About 80-84% of cases presented with no signs of DHF/DSS at the time of sampling. Dengue infected individuals had significantly elevated PCOs and low PBSH group levels than the controls. Using one-way ANOVA we found a significant difference with high PCOs and low PBSH group levels between DHF and DSS when compared with DF (P<0.001). However, no difference was observed in PBSH group levels between DHF and DSS. A significant difference in PCOs to PBSH ratio was observed among DF, DHF and DSS (P<0.001). Linear regression analysis revealed that duration of hospitalization is dependent on PCOs and PBSH group levels. Receiver operator curve (ROC) analysis indicated that 5.22nmol/mg protein PCOs; 1.08 PCOs to PBSH group levels ratio were optimal cutoff value for predicting DHF with sensitivity and specificity of 87.5% and 74.1%; 96.9% and 81.5%, respectively. For DSS prediction, 6.13 nmol/mg protein PCOs; 1.16 PCOs to PBSH group levels ratio were found as effective cutoff with sensitivity and specificity of 81% and 71.9%; 95.2% and 56.2%, respectively. CONCLUSION Oxidative stress has been observed to develop since early days of onset of dengue infection. Plasma PCOs, PCOs to PBSH group ratio were found to very well predict DHF/DSS.

Attenuation of Oxidative Stress, Inflammation and Insulin Resistance by Allium Sativum in Fructose-Fed Male Rats

BACKGROUND Fructose is widely used as a food ingredient and has potential to increase oxidative stress. Moreover, the beneficial health effects of medicinal plants are frequently attributed to their potent antioxidant effects. OBJECTIVES The present study was aimed to explore the effects of garlic (Allium sativum) extract on insulin resistance, inflammation and oxidative stress in male wistar rats fed with high fructose diet. MATERIAL AND METHODS Diabetes was induced in male albino Wistar rats by feeding 60% fructose rich diet. The fasting plasma glucose, insulin, insulin resistance, tumour necrosis factor alpha, total antioxidant status and the whole blood reduced glutathione, erythrocyte antioxidant enzyme activities were measured. Differences between the groups were assessed by using One Way Analysis of Variance with (ANOVA) Tukey post-hoc test. RESULTS The diabetic rats showed a significant increase in plasma fasting glucose, insulin, insulin resistance, tumour necrosis factor alpha and malondialdehyde level and decreased levels of total antioxidant status, reduced glutathione, catalase and glutathione peroxidase. Treatment with garlic extract restored all these biochemical changes. CONCLUSION The garlic extract is effective in improving the high fructose induced oxidative stress, inflammation and insulin resistance in male wistar rats.

Association between cardiac autonomic function, oxidative stress and inflammatory response in impaired fasting glucose subjects: cross-sectional study.

Background The worldwide burden of diabetes in 2030 is projected around 552 million. Diabetes leads to higher risk for cardiovascular diseases (CVD). Altered cardiac autonomic function (CAF) measured by heart rate variability (HRV) is observed in early stages of diabetes but the relationship between impaired fasting glucose (IFG) and HRV is still debatable. The aim of the study was to evaluate the association between CAF, oxidative stress, insulin resistance (IR), and inflammatory response in IFG subjects. Subjects and Methods Cross-sectional blinded study. Volunteers recruited from health awareness camps underwent CAF and biochemical tests. Based on fasting plasma glucose (FPG) participants (n = 123) were divided into two groups, normal fasting glucose (n = 76) and IFG (n = 47). The comparison of parameters between the groups was carried out using student t test and Mann-Whitney U test for parametric and non-parametric data respectively. The correlation between the parameters was analyzed by Spearman’s rank correlation using SPSS 13.0. Results The resting cardiovagal modulation parameters, heart rate response to forced timed breathing, and orthostatic stress were reduced in IFG subjects. Fasting plasma lipid profile, coronary atherogenic lipid risk factors, IR, thiobarbituric acid reactive substance (TBARS), high sensitive C-reactive protein, and tumor necrosis factor alpha were increased and total antioxidant capacity (TAC) was decreased significantly in IFG group but no significant alteration was observed in high-density lipoprotein (HDL-c). Cardiovagal modulation parameters were negatively correlated with triglycerides, FPG, insulin, IR, TBARS, and inflammatory markers and positively with TAC. Conclusion There is a continuous interplay between the altered CAF, hyperinsulinemia, IR, oxidative stress parameters, inflammatory response, and IFG in which one factor perpetuates another leading to the progression of disease.