Methionine challenge paradoxically induces a greater activation of the antioxidant defence in subjects with hyper- vs. normohomocysteinemia

To determine whether hyperhomocysteinemia induced post-methionine loading (PML) is associated with different response in the aminothiol redox state and oxidative stress vs. normohomocysteinemia, we assessed PML plasma thiols, vitamins, free malondialdehyde (MDA), and blood reduced glutathione (GSH) in 120 consecutive subjects (50 [35-56] years, 83 males), divided into two groups according to PML plasma total Hcy < 35 microM (Group 1, n = 65) or > or = 35 microM (Group 2, n = 55).In the group as a whole, plasma reduced cysteine and cysteinylglycine, blood reduced GSH (all p for time = 0.0001) and plasma total GSH (p for time = 0.001) increased from baseline to PML. MDA values were unchanged. Group 1 and 2 differed in blood reduced GSH (p for group = 0.004, higher in Group 2), and MDA levels (p for group = 0.024, lower in Group 2).The oxidative stress induced by methionine challenge seems to be opposed by scavenger molecules activation, namely GSH, and lipid peroxidation does not increase. This mechanism paradoxically appears to be more efficient in hyperhomocysteinemic subjects.     

Age- and gender-related oxidative status determined in healthy subjects by means of OXY-SCORE, a potential new comprehensive index.

Oxidative stress has been related to various diseases, gender and ageing, and has been measured by various markers. The authors developed a procedure to compute a global oxidative stress index (OXY-SCORE), reflecting both oxidative and antioxidant markers in healthy subjects. Its performance was tested in relation to age and gender and in coronary artery disease (CAD) patients. Eighty-two healthy subjects and 20 CAD patients were enrolled. Plasma free and total malondialdehyde (F- and T-MDA), glutathione disulphide/reduced form ratio (GSSG/GSH) and urine isoprostanes (iPF2alpha-III) levels were combined as oxidative damage markers (damage score). GSH, alpha- and gamma-tocopherol (TH) levels, and individual antioxidant capacity were combined as antioxidant defence indexes (protection score). The OXY-SCORE was computed by subtracting the protection score from the damage score. Among single parameters, T-MDA and iPF2alpha-III significantly correlated with age; only GSH and both tocopherols correlated with male gender in healthy subjects. The OXY-SCORE was positively associated with age (p=0.004) and male gender (p=0.03). As expected, the OXY-SCORE was higher in CAD with a very significant p-value (<0.0001), after adjusting for age, gender and smoking. Combining different markers can potentially provide a powerful index in the evaluation of oxidative stress related to age, gender and CAD status.     

Gender Differences in the Risk Factors for Endothelial Dysfunction in Chinese Hypertensive Patients: Homocysteine Is an Independent Risk Factor in Females

ObjectivesEndothelial dysfunction plays a key role in the pathogenesis of cardiovascular disease. However, the gender-related differences in risk factors for endothelial dysfunction are controversial. We investigated the gender differences in the risk factor profiles for endothelial dysfunction in Chinese hypertensive patients.MethodsVascular endothelial functions in 213 hypertensive patients were measured by digital reactive hyperemia peripheral arterial tonometry (RH-PAT). Peripheral blood samples were collected, and the self-reported smoking and alcohol consumption status, age, body mass index, heart rate, blood pressure and drug administrations were recorded.ResultsRH-PAT indexes were attenuated in both male and female hypertensive patients [1.60 (1.38-2.02) vs. 1.63 (1.44-1.98)]. Multivariate logistic regression analysis identified plasma creatinine (p < 0.001), total cholesterol (p = 0.001), homocysteine (p = 0.002) and smoking (p < 0.001) as the independent factors correlated with gender (male). Multivariate linear regression analysis further identified homocysteine as the factor that is significantly and independently correlated with the decrease in the RH-PAT indexes in female patients (odds ratio: -0.166, 95% confidence interval: -0.292 to -0.040, p = 0.01). However, none of these four factors were correlated with the RH-PAT indexes in male patients.ConclusionsThere are gender-related differences in the risk factors for endothelial dysfunction in Chinese hypertensive patients. Homocysteine is an independent factor for endothelial dysfunction in female hypertensive patients.     

Antioxidant status,lipid peroxidation,mixed function oxidase and UDP-glucuronyl transferase activities in livers from control and DOCA salt-hypertensive male Sprague Dawley rats

The effects of DOCA-salt hypertensive treatment on hepatic glutathione-dependent defense system, antioxidant enzymes, lipid peroxidation, mixed function oxidase and UDP-glucuronyl transferase activities were investigated in male Sprague Dawley rats.Compared with controls, DOCA-salt hypertensive rats had lower body weights (linked to liver hypertrophy). Mixed function oxidase and p-nitrophenol-UGT activities were not affected by the treatment but a significant lower rate of the glucuronoconjugation rate of bilirubin (p < 0.001) was observed in DOCA-salt hypertensive rats. While cytosolic glutathione contents and glutathione reductase activity were not affected, glutathione peroxidase (p < 0.001), glutathione transferase (p < 0.001) and catalase (p < 0.01) activities were decreased and associated with higher malondialdehyde contents (p < 0.001) in treated rats. The imbalance in liver antioxidant status (increasing generation of cellular radical species), associated with increases in lipid peroxidation, suggests that oxidative stress might be directly related to arterial hypertension in DOCA-salt treated male Sprague Dawley rats.     

The Association of Plasma Cysteine and γ‐Glutamyltransferase With BMI and Obesity

We recently reported a strong positive association of plasma total cysteine (tCys) with fat mass in over 5,000 subjects. As γ‐glutamyltransferase (GGT) enzyme increases cysteine availability by catalyzing glutathione breakdown and is positively associated with BMI and adiposity, we hypothesized that GGT might explain the association of tCys with adiposity. To study whether the associations of tCys and serum GGT with BMI and obesity were interrelated we conducted a cross‐sectional study using data from 1,550 subjects recruited from nine European countries in the COMAC project. Multiple linear and logistic regression models and concentration‐response curves were used. In age and sex‐adjusted analyses, tCys showed strong positive associations with BMI (partial r = 0.19, P < 0.001), and obesity (odds ratio (OR) for 4th vs. 1st tCys quartile: 2.8; 95% confidence interval: 1.6–5.0, P < 0.001), both of which remained robust after adjustment for GGT and other metabolic and lifestyle confounders. Serum GGT was also a positive predictor of BMI (partial r = 0.17, P < 0.001) and obesity (OR for 4th vs. 1st GGT quartile: 4.8; 95% confidence interval: 2.5–9.2, P < 0.001), independent of tCys. However, the associations of GGT with BMI and obesity were weakened by adjustment for obesity‐related factors such as serum lipids and blood pressure. These results indicate that tCys is a strong positive predictor of BMI and obesity, independent of GGT and other obesity‐related factors. We also suggest that the association of serum GGT with BMI and obesity is unrelated to the role of GGT in cysteine turnover. The potential link between cysteine and fat metabolism should be further evaluated.     

Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes

The role of oxidative stress in the regulation of the copy number of mitochondrial DNA (mtDNA) in human leukocytes is unclear. In this study, we investigated the redox factors in plasma that may contribute to the alteration of mtDNA copy number in human leukocytes. A total of 156 healthy subjects of 25-80 years of age who exhibited no significant difference in the distribution of subpopulations of leukocytes in blood were recruited. Small-molecular-weight antioxidants and thiobarbituric acid reactive substances (TBARS) in plasma and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4,977bp deletion of mtDNA in leukocytes were determined. The mtDNA copy number in leukocytes was determined by real-time PCR. The results showed that the copy number of mtDNA in leukocytes was changed with age in a biphasic manner that fits in a positively quadratic regression model (P = 0.001). Retinol (P = 0.005), non-protein thiols (P = 0.001) and ferritin (P = 0.004) in plasma and total glutathione in erythrocytes (P = 0.046) were the significant redox factors that correlated with the mtDNA copy number in leukocytes in a positive manner. By contrast, alpha-tocopherol levels in plasma (P = 0.001) and erythrocytes (P = 0.033) were negatively correlated with the mtDNA copy number in leukocytes. Three oxidative indices including the incidence of 4,977 bp deletion of mtDNA (P = 0.016) and 8-OHdG content in leukocytes (P = 0.003) and TBARS in plasma (P = 0.001) were all positively correlated with the copy number of mtDNA in leukocytes. Taken these findings together, we suggest that the copy number of mtDNA in leukocytes is affected by oxidative stress in blood circulation elicited by the alteration of plasma antioxidants/prooxidants and oxidative damage to DNA.     

Plasma and erythrocytes antioxidant status and trace element levels in proteinuric patients with moderate glomerular function.

The objective of the study was to investigate the effect of moderate glomerular dysfunction on oxidative stress. We determined the plasma and erythrocyte malondialdehyde (MDA) levels, as a marker of lipid peroxidation, erythrocyte glutathione (GSH) levels and activities of GSH-Px, GSH Red and SOD as an antioxidant enzymes, and plasma trace element levels containing Fe, Cu and Zn in twenty proteinuric patients (6.8 +/- 5.1 g/day) with moderate glomerular function and in 20 anemic control subjects. We found that the erythrocyte and plasma MDA levels and erythrocyte GSH-Px activities were significantly higher (p < 0.001, p < 0.001, p < 0.001, respectively) and the erythrocyte GSH levels and activities of GSH-Red and SOD activities were significantly lower (p < 0.001, p < 0.001, p < 0.001, respectively) in the patients than in the anemic subjects. Plasma Fe and Zn levels were not to be found significantly different in the patients compared to the anemic subjects. But plasma Cu levels were significantly higher in the patients (p < 0.05) when compared with the levels of anemic subjects. This study was concluded that cellular antioxidant activity decreases in proteinuric patients with moderate glomerular function. This may increase lipid peroxidation reactions by causing oxidative stress in erythrocyte membranes.     

Night work is associated with glycemic levels and anthropometric alterations preceding diabetes: Baseline results from ELSA-Brasil

Night work has been suggested as a risk factor for diabetes. Individuals with high triglyceride levels, high LDL cholesterol, low HDL cholesterol and obesity, especially abdominal obesity, have a greater chance of developing diabetes. The aim of this study was to analyze glycemic levels, total cholesterol, HDL-C, LDL-C, triglycerides and the anthropometric alterations that precede diabetes, considering their possible association with nigh work among a non-diabetic population. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) comprises of 15,105 civil servants (35–74 years old) at baseline (2008–2010). The following parameters were analyzed: serum cholesterol (total cholesterol, HDL-C, LDL-C), triglycerides and glucose drawn from 12-hour fasting blood sample, glycated hemoglobin and 2-hour plasma glucose obtained after a 75 g oral glucose tolerance test, BMI, hip and waist measurements using standard equipment and techniques. Participants with diabetes, retired workers and day workers with previous experience of night work were excluded. Generalized linear models, a gamma regression model with an identity link function, were performed to test the association of night work with metabolic and anthropometric variables. The study sample consisted of 3918 men and 4935 women; 305 (7.8%) and 379 (7.7%) of the participants were men and women who worked at night, respectively. Among the men, the exposure to night work was associated with an increase in BMI (b-value = 0.542; p = 0.032) and waist circumference (b-value = 1.66; p = 0.014). For women, increased fasting plasma glucose (b-value = 2.278; p < 0.001), glycated hemoglobin (b-value = 0.099, p < 0.001) and 2 hour plasma glucose (b-value = 5.479, p = 0.001) were associated with night work after adjustments. No significant associations between night work and triglycerides, LDL-C, HDL-C, total cholesterol levels or waist–hip ratio were found. The influences of night work on metabolic and anthropometric factors suggest night work as a potential risk factor for type 2 diabetes. Further studies are needed to investigate the inconclusive data on gender differences in the associations.     

Elevated serum GGT concentrations predict reduced insulin sensitivity and increased intrahepatic lipids.

Elevated serum gamma-glutamyltransferase (GGT) concentrations have been related to features of the metabolic syndrome as well as increased risk of cardiovascular and liver disease. More recently, elevated GGT levels were shown to predict development of type 2 diabetes in a longitudinal study from Korea. The aim of the present study was to test the hypothesis that serum GGT is associated with glucose tolerance, insulin sensitivity and beta-cell function in a healthy, non-diabetic Caucasian population from the Tübingen family study. Insulin sensitivity was estimated by oGTT (n = 850) or measured by hyperinsulinemic euglycemic clamp (n = 245), respectively. A subgroup (n = 70) underwent additional determination of intrahepatic lipid content using 1H magnetic resonance spectroscopy. Serum GGT was positively correlated with two-hour glucose during oGTT (r = 0.15, p < 0.0001) and negatively correlated with insulin sensitivity from oGTT (r = -0.31, p < 0.0001) and clamp (r = -0.27, p < 0.0001). The relationship between GGT and insulin sensitivity remained significant after adjusting for sex, age, BMI, and AST using multivariate regression analysis. Inclusion of serum triglyceride levels as a parameter of lipid metabolism kept the relationship significant in the oGTT group (p < 0.0001), but not in the smaller clamp group (p = 0.11). Additionally, serum GGT was positively correlated with hepatic lipid content (r = 0.49, p < 0.001) independent of sex, age, BMI, AST or serum triglycerides. There was no significant correlation between GGT and the index for beta-cell function after adjusting for age, sex, BMI and insulin sensitivity (p = 0.74). In conclusion, elevated serum GGT levels predict glucose intolerance probably via insulin resistance rather than beta-cell dysfunction. This may be primarily related to hepatic insulin resistance and increased intrahepatic lipids. The association observed between elevated hepatic lipids and reduced insulin sensitivity might explain the increased diabetes risk observed in subjects with elevated serum GGT concentrations. In the absence of overt liver disease, elevated serum GGT concentrations may point the clinician to incipient disturbances in the glucose metabolism.     

Intracellular glutathione deficiency is associated with enhanced nuclear factor-kappaB activation in older non-insulin dependent diabetic patients.

Diabetes mellitus may be associated with intracellular glutathione (GSH) deficiency. Since in vivo studies have shown that plasma intracellular GSH plays a key role in regulating the activation of nuclear factor kappaB (NF-kappaB), we have investigated the relationship between intracellular thiols (GSH, homocysteine, cysteine and cysteinyglycine) and NF-kappaB activity in the peripheral blood mononuclear cells (PBMC) of 63 elderly non-insulin dependent diabetes mellitus (NIDDM) patients (28 microalbuminurics and 35 normoalbuminurics) and 30 healthy age- and sex-matched subjects. In addition, we have measured plasma concentrations of these thiol compounds, serum concentrations of interleukin-6 (IL-6) and vascular cell adhesion molecule-1 (sVCAM-1), that are partly dependent on the NF-kappaB activation, as well as the serum levels of thiobarbituric acid reacting substances (TBARS), as index of lipid peroxidation. Diabetic patients with microalbuminuria (MAB) and normoalbuminuria had NF-kappaB activity 2.1- and 1.5-fold greater, respectively, than the control group. As compared to normoalbuminuric patients, patients with MAB had significantly higher levels of glycemia, plasma homocysteine, and serum concentrations of TBARS, IL-6 and sVCAM-1 (in all cases, p < 0.01), and significantly lower GSH content in the PBMC (p < 0.05). The intracellular GSH in PBMC correlated with NF-kappaB activation (r = -0.82; p < 0.0001), serum TBARS (r = -0.60; p < 0.001), and with fasting glycemia (r = -0.56; p < 0.001) in patients with MAB, whereas a weaker association between GSH levels in PBMC and NF-kappaB activation (r = -0.504, p < 0.001) was seen in patients without MAB. These results suggest that the decrease of intracellular GSH content in elderly NIDDM patients with MAB is strongly associated with enhanced NF-kappaB activation, which could contribute to the development of increased glomerular capillary permeability and its rapid progression.     

Changes in the intracellular homocysteine and glutathione content associated with aging

Since moderate hyperhomocysteinemia is an independent risk factor for vascular disease by mean of its oxidant effect and glutathione plays a main role as intracellular redox-regulating agent, we have studied for the first time the total intracellular content of homocysteine in aging. Plasma homocysteine concentration, total intracellular and plasma glutathione, and other related thiol compounds such as cysteine and the glutathione catabolite cysteinglycine were also studied. Forty three healthy elderly subjects and twenty seven healthy young ones were studied. The total intracellular peripheral blood mononuclear cell content was higher for homocysteine, cysteine and cysteinglycine, whereas that of the total glutathione was greatly decreased in elderly people with respect to young ones. Elderly subjects showed significantly higher levels than young ones of total plasma homocysteine and cysteinglycine, but not cysteine, whereas total plasma glutathione levels were increased. In addition, elderly subjects showed significantly decreased plasma vitamin E levels and increased concentrations of serum lipid peroxides measured as TBARS (reaction product of malondialdehyde with thiobarbituric acid). The intracellular glutathione content presented significantly negative correlation with serum TBARS, and intracellular and plasma homocysteine levels. These findings show an increase of homocysteine synthesis associated with aging, which in turn can produce an augmented oxidant effect on endothelium, and an impaired intracellular antioxidant capacity leading to an enhanced lipid peroxidation and decreased total intracellular glutathione content.     

Serum level of advanced glycation end-products (AGEs) is an independent determinant of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic general population.

Glucose can react nonenzymatically with amino groups of proteins to form senescent macroprotein derivatives termed advanced glycation end-products (AGEs). Recently, AGEs have been shown to play an important role in atherosclerosis even in nondiabetic subjects. However, the molecular mechanism underlying this is not fully understood. We have now investigated whether serum AGE level was an independent determinant of plasminogen activator inhibitor-1 (PAI-1), a major physiological inhibitor of fibrinolysis, in nondiabetic general population. One-hundred and eighty-six nondiabetic Japanese subjects underwent a complete history and physical examination, determination of blood chemistries, PAI-1, and AGEs. Uni- and multivariate analyses were applied for the determinants of PAI-1 levels. The average PAI-1 levels were 29.7+/-23.8 ng/ml in males and 21.8+/-17.1 ng/ml in females, respectively. Univariate regression analysis showed that PAI-1 levels were associated with age (inversely, p=0.003), male (p=0.003), body mass index (BMI) (p<0.001), HDL-cholesterol (inversely, p<0.001), triglycerides (p<0.001), fasting plasma glucose (p<0.001), insulin (p<0.001), uric acids (p<0.001), AGEs (p=0.037), and alcohol intake (p<0.001). By the use of multiple regression analyses, BMI (p<0.001), male (p=0.003), fasting plasma glucose (p=0.005), age (inversely, p=0.017), and AGEs (p=0.034) remained significant. The present study is the first demonstration that serum AGE level was one of the independent determinants of PAI-1 in nondiabetic general population. The AGE-associated thrombogenic abnormality may be involved in atherogenesis in nondiabetic subjects.     

Parameters related to oxygen free radicals in erythrocytes,plasma and epidermis of the hairless rat

The following parameters related to oxygen free radicals (OFR) were determined in erythrocytes and the epidermis of hairless rats: catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced (GSH) and oxidized (GSSG) glutathione, glutathione S-transferase (GST), superoxide dismutase (SOD) and thiobarbituric acid reactive substances (TBARS). GSH, GSSG and TBARS were also analyzed in plasma. In erythrocytes, the Pearson correlation coefficients (r) were significant (p < 0.001) between glutathione and other parameters as follows: GSH correlated negatively with GSSG (r = -0.665) and TBARS (r = -0.669); GSSG correlated positively with SOD (r = 0.709) and TBARS (r = 0.752). Plasma GSSG correlated negatively with erythrocytic thermostable GST activity (r = -0.608; p=0.001) and with erythrocytic total GST activity (r = -0.677; p < 0.001). In epidermis (p < 0.001 in all cases), GSH content correlated with GSSG (r = 0.682) and with GPx (r = 0.663); GSSG correlated with GPx (r = 0.731) and with GR (r = 0.794). By multiple linear regression analysis some predictor variables (R(2)) were found: in erythrocytes, thermostable GST was predicted by total GST activity and GSSG, GSSG content was predicted by GSH and by the GSH/GSSG ratio and GPx activity was predicted by GST, CAT and SOD activities; in epidermis, GSSG was predicted by GR and SOD activities and GR was predicted by GSSG, TBARS and GPx. It is concluded that the hairless rat is a good model for studying OFR-related parameters simultaneously in blood and skin, and that it may provide valuable information about other animals under oxidative stress.     

High Levels of Cadmium and Lead in Seminal Fluid and Blood of Smoking Men are Associated with High Oxidative Stress and Damage in Infertile Subjects

We measured the levels of malondialdehyde (MDA), protein carbonyls, glutathione S-transferase (GST) and reducte glutathione (GSH) in seminal plasma and spermatozoa from 95 subjects including 50 infertile patients to evaluate the association between oxidative stress and damage and the components of the anti-oxidant defenses in seminal plasma and spermatozoa of infertile subjects and concentrations of cadmium (Cd) and lead (Pb) in the blood and seminal plasma because of tobacco smoke exposure. The reactive oxygen species (ROS) in spermatozoa were also evaluated by luminol (5-amino-2,3-dihydro-1,4-phthalazinedione)-enhanced chemiluminescence assay. The sperm count, motility, and morphology in the smokers infertile group were found to be lower than those in the fertile male group and nonsmokers infertile group (p < 0.001). Concentrations of Cd, Pb, MDA, protein carbonyls, and ROS levels in the smokers infertile group were significantly higher than those in the fertile male and nonsmokers infertile male groups (p < 0.001). However, GSH levels and GST activities were decreased in the smokers infertile male group than those in the fertile male and nonsmokers infertile male groups (p < 0.001). The results indicate that smoking could affect semen quality and oxidative lipid and protein damage in human spermatozoa. From Pearson correlation analysis, positive correlations were demonstrated between the seminal plasma Cd and seminal plasma protein carbonyls and between seminal plasma Pb and spermatozoa ROS levels in smokers of the subfertile group, while there was a significant positive correlation between blood Cd and ROS levels in smokers of the fertile group. There was also a significant negative correlation of the Cd level of the blood and GSH levels of the sperm and seminal plasma. These findings suggest that cigarette smoking enhances the levels of Cd and Pb in seminal plasma and blood and the extent of oxidative damage associated with a decrease in components of the anti-oxidant defenses in the sperm of infertile males.     

Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis

In recent years, a great number of studies have investigated the possible role of reactive oxygen species in the aetiology and pathogenesis of rheumatoid arthritis (RA). The aim of this study was to investigate plasma concentrations of vitamin E, beta-carotene, activities of glutathione peroxidase (GSH-Px) and catalase, levels of lipid peroxidation (MDA) and reduced glutathione (GSH) in 36 patients with rheumatoid arthritis (RA) and 22 healthy age-matched controls. The plasma activity of GSH-Px and catalase (p < 0.001), levels of GSH (p < 0.01), concentration of beta-carotene (p < 0.05) and vitamin E (p < 0.001), haemoglobin and hematocrit (p < 0.05) were significantly lower in patients with RA than in controls. The MDA levels (p < 0.01), C reactive protein, rheumatoid factor, anti-streptolysin-o values (p < 0.001), platelet count (p < 0.05) and erythrocyte sedimentation rate (p < 0.001) were higher in the patient group than in the control group. These results provide some evidence for a potential role of increased lipid peroxidation and decreased enzymic and non-enzymic antioxidants in RA by its inflammatory character. These results suggested that oxidant stress plays a very important role in the pathogenesis of RA.     

Hepatic glutathione content in patients with alcoholic and non alcoholic liver diseases

Reduced and oxidized hepatic glutathione was evaluated during alcoholic and non alcoholic liver injury. We studied 35 chronic alcoholics, 20 patients with non alcoholic liver diseases, 15 control subjects. Hepatic glutathione was measured in liver biopsies and correlated with histology and laboratory tests. Alcoholic and non alcoholic patients exhibited a significant decrease of hepatic glutathione compared to control subjects (controls: 4.14 +/- 0.1 mumol/g liver; alcoholics: 2.55 +/- 0.1, p less than 0.001; non alcoholics 2.77 +/- 0.1, p less than 0.001). Oxidized glutathione was significantly higher in the two groups of patients compared to controls (controls: 4.4 +/- 0.2% of total; alcoholics 8.2 +/- 0.3, p less than 0.001; non alcoholics: 8.5 +/- 0.8, p less than 0.001). The decreased hepatic glutathione levels in patients with alcoholic and non alcoholic liver diseases may represent a contributing factor of liver injury and may enhance the risk of toxicity in these patients.     

Age- and gender-related oxidative status determined in healthy subjects by means of OXY-SCORE,a potential new comprehensive index

Oxidative stress has been related to various diseases, gender and ageing, and has been measured by various markers. The authors developed a procedure to compute a global oxidative stress index (OXY-SCORE), reflecting both oxidative and antioxidant markers in healthy subjects. Its performance was tested in relation to age and gender and in coronary artery disease (CAD) patients. Eighty-two healthy subjects and 20 CAD patients were enrolled. Plasma free and total malondialdehyde (F- and T-MDA), glutathione disulphide/reduced form ratio (GSSG/GSH) and urine isoprostanes (iPF_2α-III) levels were combined as oxidative damage markers (damage score). GSH, α- and γ-tocopherol (TH) levels, and individual antioxidant capacity were combined as antioxidant defence indexes (protection score). The OXY-SCORE was computed by subtracting the protection score from the damage score. Among single parameters, T-MDA and iPF_2α-III significantly correlated with age; only GSH and both tocopherols correlated with male gender in healthy subjects. The OXY-SCORE was positively associated with age (p=0.004) and male gender (p=0.03). As expected, the OXY-SCORE was higher in CAD with a very significant p-value (<0.0001), after adjusting for age, gender and smoking. Combining different markers can potentially provide a powerful index in the evaluation of oxidative stress related to age, gender and CAD status.     

Plasma BDNF and PDGF-AA levels are associated with high TCD velocity and stroke in children with sickle cell anemia

Sickle cell anemia (SCA) associated cerebrovascular disease includes vascular remodeling, abnormal cerebral blood flow (CBF) and infarction. We studied the relationships between plasma brain derived neurotropic factor (BDNF), platelet derived growth factors (PDGF-AA and -AB/BB) and high trans-cranial Doppler (TCD) velocity, an indication of CBF velocity. Baseline plasma samples from 39 children (19 SCA with abnormal/high TCD [SATCD], 13 SCA with normal TCD [SNTCD] and 7 healthy non-SCA), were assayed for BDNF, PDGF-AA and -AB/BB plus 11 other cytokines. The sensitivity, specificity and usefulness of these biomarkers for stroke prediction was investigated. All subject groups were of similar age and gender distribution. Mean BDNF was significantly higher among SATCD than SNTCD (p=0.004) as was mean PDGF-AA (p=0.001). Similarly, mean PDGF-AA was higher among SCA subjects who developed stroke than those who did not (p=0.012). Elevated BDNF and PDGF-AA were good predictors of the presence of abnormally high CBF velocity and were both associated with severity of anemia. Elevated PDGF-AA predicted risk for stroke development. Stroke incidence and high TCD velocity were associated with elevated BDNF and PDGF-AA. These findings suggest a role for BDNF and PDGF-AA in the patho-physiological mechanism of cerebrovascular disease in SCA.     

Altered redox status in the blood of psoriatic patients: involvement of NADPH oxidase and role of anti-TNF-α therapy

Abstract

Background

Psoriasis is a chronic hyperproliferative inflammatory skin disease, characterized by a generalized redox imbalance. Anti-tumor necrosis factor (TNF)-α therapy is widely used for the treatment of this disease, but its effect on blood redox status hasn't been explored.

Objective

To investigate the effects of anti-TNF-α therapy on blood redox status in psoriatic patients.

Methods

Twenty-nine psoriatic patients (PSO) were divided into two groups: one remained untreated (NRT) and to another the anti-TNF-α therapy was prescribed (TR). The levels of main oxidative stress markers and total antioxidant capacity (TAC) in plasma, levels of total reactive oxygen species (ROS) production, lipoperoxidation, TAC, glutathione content, and activity of NADPH oxidase in white blood cells (WBC) were evaluated in PSO, in NTR and TR after 6 months of the study.

Results

Plasma levels of malondialdehyde (MDA) and protein carbonyl content (PCO), ROS production, lipoperoxidation, and glutathione content in WBC were increased, while TAC in both plasma and WBC was decreased in PSO with respect to controls. In the plasma of TR, levels of MDA and PCO were significantly lower with respect to PSO and NTR. The activity of NADPH oxidase was significantly increased in WBC of PSO and NTR but not in TR versus controls.

Discussion

Our results represent novel data about the redox status of WBC in psoriatic patients. A significant redox-balancing effect of anti-TNF-α therapy, probably associated with the normalization of NADPH oxidase activity in WBC, was demonstrated.     

The optimization of the diagnostic work-up in patients with suspected obstructive lung disease

Background

Liver dysfunction reflects the status of heart failure, with congestion and low perfusion of the liver serving as causative mechanisms. Previous studies demonstrated relationship between the results of liver function test and the prognosis in patients with heart failure. However, few studies have examined this relationship in patients with pulmonary arterial hypertension (PAH).

Methods

The subjects were 37 patients with PAH (8 men and 29 women; 18 with idiopathic PAH and 19 with connective tissue disease-associated PAH). A blood test was performed after a 3-month period free from hospitalization and without changes in functional class, treatment, heart sounds, body weight, or heart rate.

Results

In a mean follow-up period of 635 ± 510 days, 12 patients died due to heart failure, 2 died due to pulmonary hemorrhage, and 23 patients survived. Cox proportional hazard analyses identified functional class (p < 0.001), plasma concentration of brain natriuretic peptide (BNP) (p = 0.001), and hyperbilirubinemia (serum total bilirubin > 1.2 mg/dL; p < 0.001; hazard ratio = 13.31) as predictors of mortality. Patients with hyperbilirubinemia had a worse functional class (P = 0.003), a higher right atrial pressure (p < 0.001), a higher plasma concentration of BNP (p = 0.004), and a larger Doppler right ventricular index of the right ventricle (p = 0.041).

Conclusion

Elevated serum bilirubin is a risk factor for death in patients with PAH.