8-epi-prostaglandin-f2alpha and Body-Weight

It has been previously reported that pasta containing wholegrain sorghum flour exhibits high content of polyphenols and antioxidant capacity and hence might enhance antioxidant status and reduce markers of oxidative stress in vivo; however no clinical studies have yet been reported. Therefore, the present study assessed the effect of pasta containing red or white wholegrain sorghum flour on plasma total polyphenols, antioxidant capacity and oxidative stress markers in humans. The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN: 12612000324819).. In a randomised crossover design, healthy subjects (n = 20) consumed three test meals of control pasta (CP), 30% red sorghum pasta (RSP) or 30% white sorghum pasta (WSP), 1-2 wk apart. The test meals were consumed as breakfast after an overnight fast. Blood samples were obtained at fasting and 2 h after consumption and analysed for total polyphenols, antioxidant capacity, superoxide dismutase (SOD) activity, protein carbonyl and 8-isoprostanes.. Compared to baseline, the 2 h post-prandial levels following the RSP meal of plasma polyphenols, antioxidant capacity and SOD activity were significantly (P < 0.001) higher while the protein carbonyl level was significantly lower (P = 0.035). Furthermore, net changes in polyphenols, antioxidant capacity and SOD activity were significantly (P < 0.001) higher while protein carbonyl were significantly (P = 0.035) lower following consumption of the RSP meal than the CP meal.. The results demonstrated that pasta containing red wholegrain sorghum flour enhanced antioxidant status and improved markers of oxidative stress in healthy subjects.

Topics: Adult; Antioxidants; Biomarkers; Body Mass Index; Body Weight; Cross-Over Studies; Dinoprost; Female; Flour; Healthy Volunteers; Humans; Male; Oxidative Stress; Polyphenols; Protein Carbonylation; Sorghum; Superoxide Dismutase; Surveys and Questionnaires; Waist Circumference; Young Adult

This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea.. Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 μg b.d. × 4 weeks followed by 10 μg b.d. × 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2α (PGF2α), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) were investigated.. Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2α was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-CRP and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2α was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all).. Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Chemokine CCL2; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin Resistance; Male; Middle Aged; Oxidative Stress; Peptides; Pilot Projects; Venoms

Glycemic excursion is significantly associated with oxidative stress, which plays a role in the development of chronic complications in type 2 diabetes mellitus (T2DM). Acarbose has been reported to reduce cardiovascular risk in patients with impaired glucose tolerance and T2DM. We hypothesize that treatment with acarbose could attenuate glycemic excursions and reduce oxidative stress in patients with T2DM.. This study aimed to evaluate the effects of acarbose versus glibenclamide on mean amplitude of glycemic excursions (MAGE) and oxidative stress in patients with T2DM who are insufficiently controlled by metformin.. T2DM outpatients aged 30 to 70 years who were taking single or dual oral antidiabetic drugs for ≥3 months and had a glycosylated hemoglobin (HbA(1c)) value between 7.0% and 11.0% were eligible. Patients were treated with metformin monotherapy (1500 mg daily) for 8 weeks, followed by randomization to either acarbose or glibenclamide add-on for 16 weeks. The dosage of acarbose and glibenclamide was 50 mg TID and 2.5 mg TID, respectively, for the first 4 weeks. In the following 12 weeks, the dosage was doubled in both groups. Continuous glucose monitoring (CGM) for 72 hours and a meal tolerance test (MTT) after a 10-hour overnight fast were conducted before randomization and at the end of study. MAGE was calculated from CGM data. β-cell response to postprandial glucose increments was assessed by the ratio between incremental AUC of insulin and glucose during MTT. Oxidative stress was estimated by plasma oxidized LDL (ox-LDL) and urinary excretion rates of 8-iso prostaglandin F(2α) (8-iso PGF(2α)). The primary outcomes included changes in MAGE, plasma ox-LDL, and urinary excretion of 8-iso PGF(2α). Adverse events, including hypoglycemia, were recorded.. A total of 55 patients were randomized (mean age, 54 years; males, 47%; mean body mass index, 25.9 kg/m(2); mean duration of diabetes, 6.9 years; mean HbA(1c), 8.3%) and 51 patients completed this study (acarbose, n = 28; glibenclamide, n = 23). HbA(1c) decreased significantly in both treatment groups (acarbose: 8.2 [0.8]% to 7.5 [0.8]% [P < 0.001]; glibenclamide: 8.6 [1.6]% to 7.4 [1.2]% [P < 0.001]). MAGE did not change significantly in glibenclamide-treated patients (6.2 [2.8] mmol/L to 6.3 [2.3] mmol/L; P = 0.82), whereas ox-LDL (242.4 [180.9] ng/mL to 470.7 [247.3] ng/mL; P = 0.004) and urinary excretion of 8-iso PGF(2α) (121.6 [39.6] pmol/mmol creatinine to 152.5 [41.8] pmol/mmol creatinine; P = 0.03) increased significantly. Acarbose decreased MAGE (5.6 [1.5] mmol/L to 4.0 [1.4] mmol/L; P < 0.001) without significant change in ox-LDL levels (254.4 [269.1] ng/mL to 298.5 [249.8) ng/mL; P = 0.62) or 8-iso PGF(2α) excretion rates (117.9 [58.1] pmol/mmol creatinine to 137.8 [64.4] pmol/mmol creatinine; P = 0.12). Body weight and serum triglycerides (fasting and 2-hour postprandial) decreased (all, P < 0.01) and serum adiponectin increased (P < 0.05) after treatment with acarbose, whereas HDL-C decreased (P < 0.01) after treatment with glibenclamide. β-cell response to postprandial glucose increments was negatively correlated with MAGE (r = 0.570, P < 0.001) and improved significantly with acarbose (35.6 [32.2] pmol/mmol to 56.4 [43.7] pmol/mmol; P = 0.001) but not with glibenclamide (27.9 [17.6] pmol/mmol to 36.5 [24.2] pmol/mmol; P = 0.12).. In this select population of adult Taiwanese patients with T2DM who were inadequately controlled by metformin, add-on acarbose or glibenclamide significantly reduced HbA(1c). However, treatment with acarbose decreased MAGE, body weight, and serum triglyceride and increased serum adiponectin without significant effect on oxidative stress. Treatment with glibenclamide had no statistically significant effect on MAGE but increased oxidative stress and decreased HDL-C. ClinicalTrials.gov identifier: NCT00417729.

Topics: Acarbose; Adult; Aged; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dinoprost; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins, LDL; Male; Medication Adherence; Metformin; Middle Aged; Outpatients; Oxidative Stress; Regression Analysis; Taiwan; Time Factors; Treatment Outcome

Dietary patterns that involve both a decrease in fat and an increase in fruit and vegetable (FV) intake may decrease cancer risks. In this study, a total of 122 premenopausal women with a family history of breast cancer were randomized into one of four diets for 12 mo: nonintervention, low-fat (15% of energy from fat), high-FV(9 servings/d), and combination low-fat/high-FV Fasting blood samples were obtained at baseline and after 3, 6, and 12 mo. Levels of 8-isoprostane-F2a in plasma were deter-mined by immunoassay kits. Statistical analyses indicated that levels of 8-isoprostane-F2a decreased significantly with time in the low-fat arm, which is the only intervention that resulted in weight loss; there were no significant changes in the other three diet arms. It is unlikely that this is due to changes in levels of blood lipids because there was little change overtime in plasma total cholesterol, high-density lipoprotein,low-density lipoprotein (LDL), or triglyceride levels in any diet arm, although mean LDL did decrease slightly in women who reduced fat intake after adjustment for change in body mass index (BMI). Levels of baseline 8-isoprostane-F2a were significantly higher in obese women than in overweight or normal weight women, and change in BMI was significantly correlated with change in 8-isoprostane-F2a levels. These results indicate that low-fat diets or high-FV diets are unlikely to affect plasma levels of 8-isoprostane-F2a in healthy,premenopausal women who do not lose weight during dietary change.

Topics: Adult; Body Mass Index; Body Weight; Breast Neoplasms; Dietary Fats; Dinoprost; Energy Intake; Female; Fruit; Humans; Lipids; Middle Aged; Oxidative Stress; Vegetables

The objective of the present study was to determine the influence of dietary supplementation with pomegranate seed oil (PSO) and/or an aqueous extract of dried bitter melon fruits (BME) on breast cancer risk and fatty acid profile in serum of female rats with chemical carcinogen-inflicted mammary tumours. Sprague-Dawley rats (n = 96) were fed control diet or experimental diets supplemented with 0.15 ml PSO/day, BME or jointly PSO and BME. After 21 weeks mammary tumours were subjected to histopathological examination and in serum fatty acids, 8-isoprostaglandin F

Topics: Animals; Body Weight; Carcinogenesis; Dietary Supplements; Dinoprost; Dose-Response Relationship, Drug; Fatty Acids; Female; Mammary Neoplasms, Experimental; Momordica charantia; Organ Size; Plant Oils; Pomegranate; Rats; Rats, Sprague-Dawley; Risk; Seeds

Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high-fat/high-sucrose diet. We found that adipocyte-specific deletion of MR did not affect the body weight, fat weight, glucose tolerance or insulin sensitivity. While liver weight was slightly reduced in AdipoMR-KO, there were no significant differences in the mRNA expression levels of genes associated with lipogenesis, lipolysis, adipocytokines and oxidative stress in adipose tissues between the control and AdipoMR-KO mice. The results indicated that MR in mature adipocytes plays a minor role in the regulation of insulin resistance and inflammation in high-fat/high-sucrose diet-induced obese mice.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Dinoprost; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice, Knockout; Obesity; Primary Cell Culture; Receptors, Mineralocorticoid; RNA, Messenger; Sucrose; Triglycerides

Caffeine or ketorolac decrease the risk of retinopathy of prematurity and may act synergistically to improve beneficial effect. Combination of caffeine (Caff) and ketorolac (Keto) to prevent oxygen-induced retinopathy was studied.. Newborn rats exposed to room air (RA) or intermittent hypoxia (IH) consisting of 12% O2 during hyperoxia (50% O2) from birth (P0) had single daily IP injections of Caff from P0-P13 or saline; and/or ocular Keto (Acuvail, 0.45% ophthalmic solution) administered subcutaneously over the eyes from P5-P7. Pups were studied at P14 or placed in RA for recovery from IH (IHR) until P21. Eyes were examined for neovascularization, histopathology, growth factors, and VEGF-signaling genes.. Severe retinal damage noted during IHR in the untreated groups evidenced by hemorrhage, neovascularization, and oxygen-induced retinopathy (OIR) pathologies were prevented with Keto/Caff treatment. Keto and/or Caff treatment in IH also promoted retinal neural development evidenced by eye opening (92%, P < 0.001 vs. 31% in the placebo-treated IH group). No corneal pathologies were noted with Keto.. Caff or Keto given individually reduced retinal neovascularization, but the two drugs given together prevented severe OIR.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Apyrase; Arteries; Body Weight; Caffeine; Central Nervous System Stimulants; Choroid; Citrates; Dinoprost; Drug Synergism; Female; Hemorrhage; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Ketorolac; Neovascularization, Pathologic; Oxygen; Rats; Rats, Sprague-Dawley; Retina; Retinopathy of Prematurity; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.

Topics: Actins; Adenosine; Adenosine A3 Receptor Antagonists; Albuminuria; Animals; Body Weight; Creatinine; Dinoprost; Disease Models, Animal; Doxorubicin; Immunohistochemistry; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-kappa B; Oxidative Stress; Plasminogen Activator Inhibitor 1; Proteinuria; Transforming Growth Factor beta1

Preeclampsia is responsible for more than one-third of all maternal deaths in Brazil. The objectives of the present study were to evaluate magnesium status and its association with oxidative stress and inflammation in preeclamptic women, and to identify the predictor variables of the disorder.. The study population consisted of 36 women divided into preeclamptic (n = 18) and control groups (n = 18). The preeclamptic group included women (≥20 weeks of pregnancy) with arterial pressure ≥ 140/90 mmHg and proteinuria >0.3 g/24 h, while the control group comprised pregnant women with no clinical/obstetric complications. Magnesium intake was assessed via a food frequency questionnaire validated for pregnant women in Brazil. Plasma, erythrocyte and urinary magnesium levels were determined by flame atomic absorption spectroscopy, while oxidative stress and inflammatory markers were assessed using standard protocols. Logistic regression analysis was used to identify the predictors of preeclampsia.. Preeclamptic and control groups were similar with respect to magnesium intake and urinary excretion, while plasma and erythrocyte magnesium concentrations were higher in the former group. Plasma magnesium was positively correlated with catalase and glutathione peroxidase activities and with concentrations of interleukin-6 and tumor necrosis factor alpha. Regression analysis showed that plasma magnesium and urinary 8-isoprostane were associated with preeclampsia.. Magnesium status appears to result from homeostatic imbalance and physiological alterations typical of preeclampsia. Increased plasma magnesium and decreased urinary 8-isoprostane were considered predictors of preeclampsia.

Topics: Adolescent; Adult; Biomarkers; Body Mass Index; Body Weight; Brazil; Case-Control Studies; Catalase; Dinoprost; Female; Glutathione Peroxidase; Humans; Inflammation; Interleukin-6; Logistic Models; Magnesium; Oxidative Stress; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha; Young Adult

Oxidative stress has been implicated in the pathogenesis of many conditions, including insulin resistance and obesity. However, in vivo data concerning these relationships are scarce and conflicting. Therefore, the aim of this study was to investigate the association of oxidative stress with abdominal adiposity and insulin resistance in individuals at high cardiometabolic risk.. A total of 116 overweight/obese individuals participating in the HealthGrain and Etherpaths European Projects, having waist circumference (WC) and any other component of the metabolic syndrome, were included in this cross-sectional evaluation. 8-Isoprostane concentrations in 24-hr urine were measured as marker of oxidative stress in vivo. Baseline anthropometric and metabolic parameters were analyzed according to quartiles of 8-isoprostanes. Linear regression (LR) analysis was used to assess clinical correlates of oxidative stress.. Urinary 8-isoprostane levels were 52% higher in men than in women (P<0.001). Across the isoprostanes quartiles, there was a significant increase in WC and body weight [P for trend<0.001; analysis of variance (ANOVA) P<0.001] and fasting triglycerides (P for trend<0.05; ANOVA P<0.05), and a significant decrease in high-density lipoprotein cholesterol (P for trend<0.001; ANOVA P=0.001). No significant association between urinary isoprostane concentrations and insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] was found. WC circumference and body weight remained significant after adjustment for age and gender (P=0.023 and P=0.014, respectively) and independently associated with isoprostanes at LR (P<0.005 for both).. Central obesity was independently associated with oxidative stress even in a population homogeneous for adiposity and cardiometabolic risk, whereas no relationship was observed between oxidative stress and insulin resistance.

Topics: Abdominal Fat; Adiposity; Adult; Age Factors; Aged; Body Weight; Cholesterol, HDL; Cross-Sectional Studies; Dinoprost; Female; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Oxidative Stress; Risk Assessment; Sex Characteristics; Triglycerides; Waist Circumference

To investigate the relationship between oxidative stress and biochemical parameters and the expression of TXNIP, IL-6, IL-1β and TNF-α in peripheral mononuclear cells (PMCs) from type-2 diabetic patients.. We studied 60 males: 20 normal-weight type- 2 diabetic patients (NW), 20 obese diabetic patients (OB) and 20 controls (C). Biochemical and oxidative stress parameters were evaluated. PMCs were isolated and total RNA was extracted in order to determine the expression of TXNIP, IL-6, IL-1β and TNF-α by qRT-PCR.. OB had higher weight, BMI and abdominal circumference (One way ANOVA, p<0.0001). NW had higher fasting glycemia (One way ANOVA, p=0.0034) however OB had higher HbA1c (One way ANOVA, p<0.0001). OB also had higher hsCRP (One way ANOVA, p=0.0158). TBARS and AGES were elevated in both NW and OB (One way ANOVA, p<0.0001 and p=0.0008, respectively). Compared to OB and C participants, the expression of TXNIP was significantly higher in NW (Kruskal Wallis, p=0.0074); IL-1β, IL-6 and TNF-α transcripts were higher in NW and OB (Kruskal Wallis, p<0.0001, for all). In NW patients, the expression of TXNIP was positively correlated with fasting glycemia and AGES and negatively correlated with HOMA-β (r=0.72; r=0.59; r=-0.44, respectively, for all p<0.05), in OB there was correlation only with 8-Isoprostanes (r=0.42, p=0.046).. Our results suggest that fasting glycemic control, independent of adiposity and nutritional status, represents a risk factor for β-cell dysfunction, increases oxidative stress markers and it is related with an elevation of TXNIP expression.. Objetivo: Investigar la relación existente entre parámetros bioquímicos y de estrés oxidativo y la expresión de TXNIP, IL-6, IL-1y TNF-en células mononucleares periféricas (CMPs) de sujetos diabéticos. Material y métodos: Se estudió 60 sujetos hombres: 20 con peso normal y diabetes tipo 2 (NW), 20 sujetos obesos con diabetes (OB) y 20 sujetos controles (C). Se evaluaron parámetros bioquímicos y de estrés oxidativo. Además se aislaron CMPs para la extracción de RNA total y se determinó la expresión de los genes TXNIP, IL-6, IL- 1y TNF-mediante PCR de tiempo real cuantitativo. Resultados: Los OB presentaron mayor IMC y circunferencia abdominal que los NW y los C (ANOVA de una vía, p.

Topics: Adult; Anthropometry; Blood Glucose; Body Mass Index; Body Weight; Carrier Proteins; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Inflammation; Insulin; Interleukin-1beta; Interleukin-6; Lipids; Male; Middle Aged; Overweight; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Salt-induced hypertension in the Dahl rat is associated with increases in angiotensin II, aldosterone, free radical generation and endothelial dysfunction. However, little is known about the specific mechanism(s) associated with the end-organ damage effects of aldosterone. We hypothesised that eplerenone reduces kidney damage by blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.. Dahl salt-sensitive rats fed either a low-salt (LS) or high-salt (HS) diet were treated with aldosterone in the presence of eplerenone or apocynin. Indirect blood pressure was measured prior to start of diet and weekly thereafter. Levels of plasma nitric oxide (NO) and urinary 8-isoprostane were measured following treatment. Protein levels of selected subunits of NADPH were assessed by western blot.. Eplerenone and apocynin inhibited the rise in blood pressure induced by HS and/or aldosterone. This observation was accompanied with a parallel change in kidney protein levels of NADPH oxidase 4 (NOX-4) and p22phox. Aldosterone and high salt were associated with lower NO levels and greater renal oxidative stress.. NADPH oxidase is associated with the vascular and renal remodelling observed in high dietary salt intake. Aldosterone-induced expression of NOX-4 plays a pivotal role in the end-organ damage effect of aldosterone, as eplerenone tended to reduce kidney damage and inhibit NOX expression.

Topics: Acetophenones; Aldosterone; Animals; Blood Pressure; Blotting, Western; Body Weight; Dinoprost; Eplerenone; Male; NADPH Oxidase 4; NADPH Oxidases; Nitric Oxide; Protein Subunits; Proteinuria; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary; Spironolactone; Systole; Urinalysis

The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress play in the progression of diabetes vascular complications are well recognized; however, the relative contribution and importance of these individual factors remain uncertain. At 6, 10, or 14 weeks old, blood samples and thoracic aortae were collected from db/db mice and their non-diabetic controls. Plasma samples were analyzed for glucose, 8-isoprostane, CRP, triglycerides, LDL, and HDL as markers of glycemic status, oxidative stress, inflammation, and dyslipidemia, respectively. The responses of the aortic rings to high KCl, phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside were examined. Statistical methods were used to estimate the strength of the association between plasma variables and vascular functions. Systemic inflammation occurred in db/db mice at an earlier age than did hyperglycemia or oxidative stress. Aortae of db/db showed augmented contractions to PE which were positively correlated with weight, plasma glucose, 8-isoprostane, and CRP. Also, db/db mice showed impaired endothelium-dependent ACh vasorelaxation which was negatively correlated with weight, plasma glucose, and 8-isoprostane. Multivariate analysis and stepwise modeling show that CRP is the major determinant of the contractile responses, while weight and HDL are the major determinants of ACh-induced relaxation. Among the traditional risk factors of obesity, hyperglycemia, oxidative stress, inflammation, and dyslipidemia, our study reveals that weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Our findings partially resolve the complexity of diabetes vasculopathies and suggest targeting weight loss and inflammation for effective therapeutic approaches.

Topics: Animals; Aorta; Biomarkers; Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Experimental; Dinoprost; Dyslipidemias; Inflammation; Lipids; Male; Mice; Mice, Inbred Strains; Multivariate Analysis; Oxidative Stress; Vasodilation

This study investigated the cardioprotective effect of N-acetylcysteine (NAC) on isoproterenol (ISO)-induced cardiotoxicity in rats. Male Sprague-Dawley rats were divided into control, NAC alone (100 mg/kg BW orally for 14 days), ISO-control (85 mg/kg BW), and ISO with NAC (for 14 days). Serum creatine kinase-MB and Lactate dehydrogenase were measured. From the heart homogenate lipid hydroperoxides (LPO), superoxide dismutase (SOD), total glutathione (GSH), and 8-isoprostane (IP) were measured. Histopathological examination of the heart was also carried out. There was a significant increase (P < 0.05) in LPO and IP levels in ISO-control group and NAC treatment reduced these changes. Antioxidant enzyme, SOD and GSH, level decreased significantly (P < 0.05) in ISO-control group, and treatment with NAC was able to reverse these changes significantly (P < 0.05). Histopathologically, ISO-control group showed morphological changes suggestive of cardiotoxicity with large areas of coagulative necrosis, with diffused interstitial edema. NAC treatment successfully reduced these histopathological changes. In conclusion, the study proves that NAC has a strong cardioprotective effect against isoproterenol-induced cardiac changes. NAC decreases isoproterenol-induced LPO and IP levels in the heart tissue and prevented free radicals-induced damage to the myocardium.

Topics: Acetylcysteine; Animals; Body Weight; Cardiotonic Agents; Creatine Kinase, MB Form; Dinoprost; Drug Therapy, Combination; Edema; Free Radical Scavengers; Glutathione; Heart; Isoproterenol; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Myocardium; Necrosis; Organ Size; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

The aim of the present study was to look into the possible protective effects of glycyrrhizic acid (GA) against isoproterenol-induced acute myocardial infarction in Sprague-Dawley rats. The effect of three doses of glycyrrhizic acid in response to isoproterenol (ISO)-induced changes in 8-isoprostane, lipid hydroperoxides, super oxide dismutase and total glutathione were evaluated. Male Sprague-Dawley rats were divided into control, ISO-control, glycyrrhizic acid alone (in three doses-5, 10 and 20 mg/kg BW) and ISO with glycyrrhizic acid (in three doses) groups. ISO was administered at 85 mg/kg BW at two consecutive days and glycyrrhizic acid was administered intraperitoneally for 14 days. There was a significant increase in 8-isoprostane (IP) and lipid hydroperoxide (LPO) level in ISO-control group. A significant decrease in total superoxide dismutase (SOD) and total glutathione (GSH) was seen with ISO-induced acute myocardial infarction. Treatment with GA significantly increased SOD and GSH levels and decreased myocardial LPO and IP levels. Histopathologically, severe myocardial necrosis and nuclear pyknosis and hypertrophy were seen in ISO-control group, which was significantly reduced with GA treatment. Gycyrrhizic acid treatment proved to be effective against isoproterenol-induced acute myocardial infarction in rats and GA acts as a powerful antioxidant and reduces the myocardial lipid hydroperoxide and 8-isoprostane level.

Topics: Animals; Body Weight; Cardiotonic Agents; Dinoprost; Glutathione; Glycyrrhizic Acid; Isoproterenol; Lipid Peroxidation; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

The aim was to examine the role of cyclooxygenase (COX)-2-mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high-fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co-treated with vehicle (HFa), or a selective COX-2 inhibitor celecoxib (HFa-Cel) or mesulid (HFa-Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12-week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa-Cel, and HFa-Mes. Time-dependent increases in plasma insulin, glucose, 8-isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The enhanced COX-2 and tumor necrosis factor-alpha (TNF-alpha) but attenuated PPAR-gamma and C/EBP-alpha mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa-Cel and HFa-Mes. Our findings suggest that COX-2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Blood Glucose; Body Weight; Celecoxib; Cell Size; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprost; Disease Models, Animal; Fatty Liver; Insulin; Insulin Resistance; Leptin; Liver; Macrophages; Male; Membrane Proteins; Obesity; Panniculitis; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

In the present study, we described ultrastructural changes occurring in the neurons of the hypothalamic arcuate nucleus after food deprivation. Young male Wistar rats (5 months old, n = 12) were divided into three groups. The animals in Group I were used as control (normally fed), and the rats in Groups II and III were fasted for 48 hours and 96 hours, respectively. In both treated groups, fasting caused rearrangement of the rough endoplasmic reticulum forming lamellar bodies and membranous whorls. The lamellar bodies were rather short in the controls, whereas in the fasting animals they became longer and were sometimes participating in the formation of membranous whorls composed of the concentric layers of the smooth endoplasmic reticulum. The whorls were often placed in the vicinity of a very well developed Golgi complex. Some Golgi complexes displayed an early stage of whorl formation. Moreover, an increased serum level of 8-isoprostanes, being a reliable marker of total oxidative stress in the body, was observed in both fasting groups of rats as compared to the control.

Topics: Age Factors; Aging; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Biomarkers; Body Weight; Dinoprost; Endoplasmic Reticulum, Rough; Endoplasmic Reticulum, Smooth; Energy Metabolism; Fasting; Food Deprivation; Golgi Apparatus; Intracellular Membranes; Male; Neurons; Oxidative Stress; Rats; Rats, Wistar

This study was designed to examine the role of cyclooxygenase (COX) 2-mediated low-grade inflammation in the development of fructose-induced whole body and muscular insulin resistance in rats. The rats were on regular or fructose-enriched diets for 8 weeks. Fructose-fed rats were further divided into 3 groups (n = 8 per group). There were fructose-fed rats, fructose-fed rats with nimesulide (a selective COX2 inhibitor, 30 mg/kg/day, gavage) and fructose-fed rats with celecoxib (a selective COX2 inhibitor, 30 mg/kg/day, gavage). The present result showed that fructose-induced time-dependent increases in systolic blood pressure and fasting plasma insulin and triglyceride levels were significantly suppressed in rats treated with nimesulide or cerecoxib. The ratio of area under glucose curve divided by area under insulin curve obtained during the oral glucose tolerance test was significantly decreased in fructose-fed rats, which were markedly reversed in those co-treated with nimesulide or celecoxib. Accordingly, fructose-induced decrease in insulin-stimulated glucose uptake in soleus muscle was significantly reversed in those combined with nimesulide or celecoxib. Fructose-induced time-dependent increases in plasma 8-isoprostane and PGE metabolites were concomitantly suppressed by nimesulide or celecoxib co-treatment. The present study demonstrates that the COX2-mediated low-grade inflammation, especially mediated by increase in oxidative stress was important in the development of insulin resistance in fructose-fed rats.

Topics: Animals; Blood Pressure; Body Weight; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Fructose; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Muscle, Skeletal; Prostaglandins E; Rats; Rats, Sprague-Dawley; Sweetening Agents

Regulation of coronary function in diabetic hearts is an important component in preventing ischemic cardiac events but remains poorly studied. Exercise is recommended in the management of diabetes, but its effects on diabetic coronary function are relatively unknown. We investigated coronary artery myogenic tone and endothelial function, essential elements in maintaining vascular fluid dynamics in the myocardium. We hypothesized that exercise reduces pressure-induced myogenic constriction of coronary arteries while improving endothelial function in db/db mice, a model of type 2 diabetes. We used pressurized mouse coronary arteries isolated from hearts of control and db/db mice that were sedentary or exercised for 1 h/day on a motorized exercise-wheel system (set at 5.2 m/day, 5 days/wk). Exercise caused a approximately 10% weight loss in db/db mice and decreased whole body oxidative stress, as measured by plasma 8-isoprostane levels, but failed to improve hyperglycemia or plasma insulin levels. Exercise did not alter myogenic regulation of arterial diameter stimulated by increased transmural pressure, nor did it alter smooth muscle responses to U-46619 (a thromboxane agonist) or sodium nitroprusside (an endothelium-independent dilator). Moderate levels of exercise restored ACh-simulated, endothelium-dependent coronary artery vasodilation in db/db mice and increased expression of Mn SOD and decreased nitrotyrosine levels in hearts of db/db mice. We conclude that the vascular benefits of moderate levels of exercise were independent of changes in myogenic tone or hyperglycemic status and primarily involved increased nitric oxide bioavailability in the coronary microcirculation.

Topics: Animals; Blood Glucose; Body Weight; Coronary Circulation; Coronary Vessels; Diabetes Mellitus, Type 2; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Exercise Therapy; Hyperglycemia; Insulin; Mice; Microcirculation; Nitric Oxide; Oxidative Stress; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Angiotensin II type 1 receptor may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. In the present study, we investigated the long-term effect of angiotensin II type 1a receptor (AT1a) deficiency on hypercholesterolemia-induced atherosclerosis by the use of AT1a-knockout (AT1a-KO) mice and apolipoprotein E-knockout (apoE-KO) mice. AT1a-KO were crossed with apoE-KO, generating double-knockout (D-KO) mice. Mice were fed a standard diet and analyzed at 25- or 60-weeks-old. The quantification of atherosclerotic volume in the aortic root revealed that the atherosclerotic lesions of D-KO mice were significantly smaller than those of apoE-KO mice at 25-week-old (0.81+/-0.16 mm2 vs. 1.05+/-0.21 mm2, p<0.001) and at 60-week-old (0.89+/-0.11 mm2 vs. 2.44+/-0.28 mm2, p<0.001). Surprisingly, there was no significant difference in atherosclerotic lesion size of D-KO mice at 25- and 60-week-old, suggesting that AT1a deficiency completely protected against the age-related progression of atherosclerosis. The amounts of collagen and elastin, the expression of p22phox, serum amyloid P (SAP), matrix metalloproteinase (MMP)-2, and MMP-9, and the number of apoptotic cells of D-KO mice were lower than those of apoE-KO mice. Furthermore, we confirmed that the expression of procollagen alpha1(I), procollagen alpha1(III), tropoelastin, p22phox, SAP, MMP-2, and MMP-9 decreased in cultured vascular smooth muscle cells from D-KO mice compared with those of apoE-KO mice. In conclusion, AT1a deficiency reduces atherosclerotic lesion size of apoE-KO mice and protects against the age-related progression of atherosclerosis. Reduction of oxidative stress, apoptosis, and MMP expression in atherosclerotic lesions by AT1a deficiency may contribute to plaque size.

Topics: Animals; Aorta; Apolipoproteins E; Apoptosis; Atherosclerosis; Blood Pressure; Body Weight; Cells, Cultured; Cholesterol; Dinoprost; Extracellular Matrix; Heart Rate; Hypercholesterolemia; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Oxidative Stress; Receptor, Angiotensin, Type 1

Squalene is an intermediate of cholesterol biosynthesis which can be obtained from the diet where it is abundant, for example, in olive oil. The effect of this isoprenoid on the development of atherosclerosis was investigated on apoE-knockout mice.. Two groups of animals, separated according to sex, were fed on standard chow diet: the control group receiving only vehicle and the second group an aqueous solution of squalene to provide a dose of 1g/kg/day in male and female mice. This treatment was maintained for 10 weeks. At the end of this period, plasma lipid parameters, oxidative stress markers and hepatic fat were measured as well as cross-sectional lesion area of aortic root in both groups. Data showed that in males squalene feeding reduced atherosclerotic lesion area independently of plasma lipids and activation of circulating monocytes. In contrast, squalene intake did not decrease lesion area in females, despite reducing plasma cholesterol and triglycerides, isoprostane and percentage of Mac-1 expressing white cells. In males, atherosclerotic lesion area was positively and significantly associated with hepatic fat content and the plasma triglycerides were also strongly associated with liver weight.. These results indicate that administration of squalene modulates lesion development in a gender specific manner, and that accumulation of hepatic fat by liver is highly correlated with lesion progression in males. Hence, squalene administration could be used as a safe alternative to correct hepatic steatosis and atherosclerosis particularly in males.

Topics: Animals; Apolipoprotein A-I; Apolipoprotein A-V; Apolipoproteins; Apolipoproteins E; Aryldialkylphosphatase; Atherosclerosis; Body Weight; CD11b Antigen; Cholesterol; Dinoprost; DNA-Binding Proteins; Fatty Liver; Female; Liver; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; RNA, Messenger; Scavenger Receptors, Class B; Sex Characteristics; Squalene; Triglycerides

ANG II promotes inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of cytokines and reactive oxygen species (ROS). The aim of the present study was to examine the effect of tetradecylthioacetic acid (TTA), a modified fatty acid, on NF-kappaB, proinflammatory markers, ROS, and nitric oxide (NO) production in two-kidney, one-clip (2K1C) hypertension. The 2K1C TTA-treated group had lower blood pressure (128 +/- 3 mmHg) compared with 2K1C nontreated (178 +/- 5 mmHg, P < 0.001). The p50 and p65 subunits of NF-kappaB were higher in the clipped kidney (0.44 +/- 0.01 and 0.22 +/- 0.01, respectively) compared with controls (0.25 +/- 0.03 and 0.12 +/- 0.02, respectively, P < 0.001). In the 2K1C TTA-treated group, these values were similar to control levels. The same pattern of response was seen in the nonclipped kidney. In 2K1C hypertension, cytokines plasma were higher than in control: TNF-alpha was 13.5 +/- 2 pg/ml (P < 0.03), IL-1beta was 58.8 +/- 10 pg/ml (P = 0.003), IL-6 was 210 +/- 33 pg/ml (P < 0.001), and monocyte chemoattractant protein-1 was 429 +/- 21 pg/ml (P = 0.04). In the 2K1C TTA-treated group, these values were similar to controls, and the same pattern was seen in the clipped kidney. Clipping increased 8-iso-PGF-2alpha (P < 0.01) and decreased NO production (P < 0.01 vs. control) in the urine. TTA treatment normalized these values. NO production was also lower in clipped and nonclipped kidney (P < 0.001). After TTA treatment, these values were similar to controls. The results indicate that TTA has a potent anti-inflammatory effect in 2K1C by inhibition of p50/p65 NF-kappaB subunit activation, reduction of cytokines production and ROS, and enhanced NO production.

Topics: Animals; Body Weight; Chemokine CCL2; Dinoprost; Disease Models, Animal; Eating; Free Radical Scavengers; Hypertension, Renal; Interleukin-1beta; Interleukin-6; Kidney Cortex; Male; Nephritis; NF-kappa B p50 Subunit; Nitrates; Nitric Oxide; Nitrites; Rats; Rats, Wistar; Reactive Oxygen Species; Sodium, Dietary; Sulfides; Surgical Instruments; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Polysomnography is the standard method for evaluating results of treatments for obstructive sleep apnea syndrome (OSAS), but it is time-consuming and often unavailable.. This study aimed to analyze the correlations between sleepiness, anthropometric parameters, exhaled breath condensate (EBC) and serum cytokine levels with changes in the apnea-hypopnea index (AHI), in order to identify potential measurements that could be an alternative to polysomnography.. Based on AHI results, 22 non-OSAS and 68 OSAS cases were followed up. Among the 68 patients, 5 underwent surgery, 2 were treated with oral appliances, 33 were treated using continuous positive airway pressure and 28 were untreated. AHI, anthropometric parameters, serum and EBC levels of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and 8-isoprostane were measured at baseline and after a 2-month follow-up. Correlations between the AHI and the other parameters were examined. Akaike's information criterion (AIC) was used to evaluate the fit of logistic regression models, predicting improvements in the severity of the condition from the parameters.. IL-6 and TNF-alpha in EBC and serum gave the highest correlation coefficients (r = 0.62 and r = 0.71 in EBC; r = 0.58 and r = 0.66 in serum, respectively) as well as the lowest AIC values (63.87, 68.97; 62.65, 70.64, respectively). Reductions in waist circumference and weight also correlated with changes in AHI (r = 0.69, AIC = 80.26 and 88.76, respectively).. IL-6 and TNF-alpha measurements may be used in OSAS treatment follow-ups, when polysomnography is not available. Waist circumference and weight could also be used when cytokine laboratory facilities are unavailable.

Topics: Adult; Biomarkers; Body Weight; Case-Control Studies; Cytokines; Dinoprost; Female; Humans; Male; Predictive Value of Tests; Prospective Studies; Severity of Illness Index; Sleep Apnea, Obstructive; Waist Circumference

There is evidence that plasma homocysteine augments angiopathy in patients with diabetes mellitus. Although lowering homocysteine with folic acid improves endothelial function, the precise mechanisms underlying this effect are unknown. To study this area further, the effect of administration of folic acid to diabetic rabbits on intraaortic oxidative stress was studied by assessing the formation of superoxide (O(2)(-)), 8-isoprostane F(2alpha) (8-IPF(2alpha)), and prostacyclin (as 6-keto-PGF(1alpha)) as well as acetylcholine-stimulated relaxation and gp47(phox) content. Nonketotic diabetes mellitus was induced in New Zealand rabbits with alloxan, and low- and high-dose folic acid was administered daily for 1 month. Rabbits were killed, aortae were excised, and rings were prepared. Rings were mounted in an organ bath, and relaxation was elicited with acetylcholine. The O(2)(-) release was measured spectrophotometrically; the gp47(phox) expression, by Western blotting; and the 8-IPF(2alpha) and 6-keto-PGF(1alpha) formation, by enzyme-linked immunosorbent assay. Blood was collected for measurement of homocysteine, red blood cell folate, and glucose. In aortae from the diabetic rabbits, acetylcholine-induced relaxation was significantly impaired compared with that in untreated controls. The O(2)(-) release, p47(phox) expression, and 8-IPF(2alpha) formation were all enhanced and 6-keto-PGF(1alpha) formation was reduced compared with controls. All these effects were reversed by both low- and high-dose folic acid. Plasma total homocysteine was reduced by high-dose, but not low-dose, folic acid. Red blood cell folate was elevated in both groups. The improvement of endothelial function in patients receiving folic acid may be due to inhibition of nicotinamide adenine nucleotide phosphate oxidase (NADPH) oxidase expression and therefore conservation of nitric oxide and prostacyclin bioavailability, 2 vasculoprotective factors.

Topics: Alloxan; Animals; Aorta; Body Weight; Diabetes Mellitus, Experimental; Dinoprost; Epoprostenol; Folic Acid; Homocysteine; Male; NADPH Oxidases; Oxidative Stress; Rabbits; Superoxides

Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low(AGE) diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66(shc) levels compared with mice pair-fed the regular (Reg(AGE)) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low(AGE) mice, compared with Reg(AGE) mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.

Topics: Adaptor Proteins, Signal Transducing; Aging; Animals; Body Weight; Collagen Type IV; Diet; Dinoprost; Eating; Glucose; Glutathione; Glycation End Products, Advanced; Insulin; Kidney; Life Expectancy; Male; Mice; Mice, Inbred C57BL; Oxidants; Oxidative Stress; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1; Transforming Growth Factor beta1

Recent studies have uncovered various pleiotrophic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibiting drugs (statins). Several studies have identified a beneficial effect of statins on diabetic nephropathy; however, the molecular mechanisms are unclear. In this study, we show that statin ameliorates nephropathy in db/db mice, a rodent model of type 2 diabetes, via downregulation of NAD(P)H oxidase NOX4, which is a major source of oxidative stress in the kidney. Pitavastatin treatment for 2 weeks starting at 12 weeks of age significantly reduced albuminuria in the db/db mice concomitant with a reduction of urinary 8-hydroxy-2'-deoxyguanosine and 8-epi-prostaglandin F(2alpha). Immunohistochemical analysis found increased amounts of 8-hydroxy-2'-deoxyguanosine and NOX4 protein in the kidney of db/db mice. Quantitative reverse transcription-polymerase chain reaction also showed increased levels of NOX4 mRNA. Pitavastatin normalized all of these changes in the kidneys of diabetic animals. Additionally, 12-week treatment with the statin completely normalized the levels of transforming growth factor-beta1 and fibronectin mRNA as well as the mesangial expansion characteristic of diabetic nephropathy. Our study demonstrates that pitavastatin ameliorates diabetic nephropathy in db/db mice by minimizing oxidative stress by downregulating NOX4 expression. These findings may provide insight into the mechanisms of statin therapy in early stages of diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Blood Glucose; Body Weight; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Models, Animal; Down-Regulation; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Mesangial Cells; Mice; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Quinolines; RNA, Messenger; Time Factors; Transforming Growth Factor beta1

Intrauterine infection may be causally related to inflammation and injury of the fetal brain, however the mechanisms by which this occurs are unclear. We have investigated whether nuclear factor (NF)-kappaB, a transcription factor for proinflammatory cytokines, is activated in the fetal brain after acute LPS-exposure. At 95 days of gestation (term = approximately 147 days), 5 fetuses received a single intravenous bolus dose of LPS (1 microg/kg); 6 fetuses served as controls. Fetal blood samples were taken hourly for 6 hr post LPS-exposure to assess physiological status. Ewes and fetuses were then euthanased, placental and brain tissue examined histologically, and NF-kappaB activation assessed in several regions of the fetal brain using an electromobility shift assay (EMSA). Oxidative stress was measured using lipid peroxidation and 8-isoprostane biochemical assays and brain cytokine concentrations analysed by enzyme linked immunosorbent assay (ELISA). LPS-exposed fetuses (relative to controls) were hypoxemic and the haematocrit and lactate levels had increased. In the brains of LPS-exposed fetuses compared to controls, NF-kappaB binding activity was elevated in the hippocampus and the thalamus/basal ganglia; 8-isoprostane levels were elevated overall (P < 0.05) in the parietal/occipital/temporal lobes and thalamus/basal ganglia. TNF-alpha and IL-6 concentrations were not elevated, however, there was a tendency for an elevation of IFN-gamma concentrations in the thalamus/basal ganglia. IFN-gamma concentration was elevated (P < 0.05) in the plasma 4 hr after LPS-exposure. In the placenta, NF-kappaB binding activity was increased (P < 0.05). We conclude that acute systemic administration of LPS leads to increased binding activity of NF-kappaB subunits in specific regions of the fetal brain and in the placenta, but that there is no clear-cut relationship between this elevation and vulnerability to endotoxic damage.

Topics: Animals; Body Weight; Brain; Brain Chemistry; Cytokines; Dinoprost; Electrophoretic Mobility Shift Assay; Female; Interferon-gamma; Interleukin-6; Lipid Peroxidation; Lipopolysaccharides; NF-kappa B; Organ Size; Oxidative Stress; Placenta; Pregnancy; Sheep; Tumor Necrosis Factor-alpha

Oxidative stress has been proposed as important in the pathogenesis of hypertension. Measurement of 8-iso prostaglandin F2alpha (8-ISO) is introduced for evaluating oxidative stress in vivo. 8-ISO is the major urinary metabolite of F2-isoprostanes and is formed nonenzymatically from the attack of superoxide radicals on arachidonic acid. We examined the oxidative stress level in the Dahl salt-sensitive (Dahl-S) rats and the Dahl salt-resistant (Dahl-R) rats. Dahl-S and Dahl-R rats were fed either a high salt diet (8% NaCl; HS) or low salt diet (0.3% NaCl; LS) for 3 weeks, and systolic blood pressure (SBP) and 24-hr urinary excretion of 8-ISO (U-8-ISO) were measured. In Dahl-S rats, the high salt diet induced hypertension (139 +/- 3 mmHg in LS versus 186 +/- 2 mmHg in HS, p < .05) and significantly increased the U-8-ISO (24.9 +/- 3.6 ng/24 hr in LS versus 63.2 +/- 14.6 ng/24 hr in HS, p < .05). No significant difference in blood pressure or U-8-ISO was observed between high-salt and low-salt treated Dahl-R rats. U-8-ISO concentration was correlated with SBP in all four experimental groups (r = 0.866). Moreover, urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), which is one of the most commonly used markers for evaluation of oxidative stress, was higher in Dahl-S-8% rats than in Dahl-S-0.3% rats (136.1 +/- 48.4 ng/24 hr in LS versus 322.8 +/- 46.7 ng/24 hr in HS, p < .05), and U-8-OHdG was correlated with SBP (r = 0.681) in Dahl-S rats. These results suggest oxygen radicals are involved in the pathogenesis of hypertension.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Blood Pressure; Body Weight; Deoxyguanosine; Dinoprost; Heart Rate; Hypertension; Male; Oxidative Stress; Rats; Rats, Inbred Dahl

Aging is characterized by renal functional and structural abnormalities resembling those observed in diabetes. These changes have been related to the progressive accumulation of advanced glycation end-products (AGEs) and cumulative oxidative stress occurring in both conditions. We previously reported that galectin-3 ablation is associated with increased susceptibility to diabetes- and AGE-induced glomerulopathy, thus indicating a protective role of galectin-3 as an AGE receptor. To investigate the role of the AGE/AGE receptor pathway in the pathogenesis of age-related renal disease, we evaluated the development of glomerular lesions in aging galectin-3 knockout (KO) vs. wild-type (WT) mice and their relation to the increased AGE levels and oxidative stress characterizing the aging process. KO mice showed significantly more pronounced age-dependent increases in proteinuria, albuminuria, glomerular sclerosis, and glomerular and mesangial areas, starting at 18 mo, as well as renal extracellular matrix mRNA and protein expression, starting at 12 mo vs. age-matched WT mice. Circulating and renal AGEs, plasma isoprostane 8-epi-PGF2alpha levels, glomerular content of the glycoxidation and lipoxidation products N(epsilon)-carboxymethyllysine and 4-hydroxy-2-nonenal, and renal nuclear factor-kappaB activity also increased more markedly with age in KO than WT mice. AGE levels correlated significantly with renal functional and structural parameters. These data indicate that aging galectin-3 KO mice develop more pronounced changes in renal function and structure than coeval WT mice, in parallel with a more marked degree of AGE accumulation, oxidative stress, and associated low-grade inflammation, thus supporting the concept that the AGE/AGE receptor pathway is implicated in age-related renal disease.

Topics: Age Factors; Aging; Aldehydes; Animals; Body Weight; Dinoprost; Extracellular Matrix; Galectin 3; Glomerulonephritis; Glycation End Products, Advanced; Kidney Glomerulus; Lysine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Receptor for Advanced Glycation End Products; Receptors, Immunologic; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db(++) mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db(++) mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two- and fourfold) and more AGE-modified fat (by two- and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dietary Fats; Dinoprost; Fasting; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glycation End Products, Advanced; Hyperplasia; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Lipids; Mice; Mice, Inbred C57BL

Topics: Blood Glucose; Body Mass Index; Body Weight; Dinoprost; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin Resistance; Japan; Male; Obesity; Oxidative Stress; Reference Values; Triglycerides

To probe into therapeutic effect and its mechanism of "Huo Xue Bu Qi Fang" (HXBQF) on fetal rats with intrauterine growth retardation (IUGR).. The model of pregnant rat with IUGR was established by passive smoking method. Forty pregnant rats with IUGR were randomly divided into intervention group (with high-, middle- and low-dose Chinese traditional medicine) and non-intervention group. In addition, 10 normal pregnant rats were taken into control group. Intervention group was adminstered with 16.2, 5.4 and 1.62 g/kg HXBQF respectively. Non-intervention group and control group were administered with 10 ml/kg saline. Fetal rats were taken out, and blood and urine samples were collected from pregnant rats on day 21 of the pregnancy. The weight, nose-hip-length and poundera index of these fetal rats were measured. Serum NO, plasma ET-1 and urine 8-epi-PGF2 alpha level from pregnant rats were determined by nitro-reductase method, radioimmunoassay (RIA) and enzyme immunoassay (EIA) respectively.. Compared with fetal rats from non-intervention group, fetal weight, distance between nose-hip, poundera index serum NO level and NO/ET-1 were increased, plasma ET-1 level and urine 8-epi-PGF2 alpha level were decreased in those from intervention group (P < 0.01).. There is an enhancement of lipid peroxidation and NO/ET-1 ratio imbalance in pregnant rats with IUGR. HXBQF has good therapeutic effect on IUGR since it can inhibit lipid oxidation and regulate NO/ET-1 balance.

Topics: Animals; Antioxidants; Body Weight; Dinoprost; Drugs, Chinese Herbal; Endothelin-1; Female; Fetal Growth Retardation; Nitric Oxide; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley

Adrenomedullin (AM) is expressed in cardiac tissue, and plasma AM levels increase in patients with acute myocardial infarction (MI). This study was performed to determine whether AM administration immediately after acute MI inhibits progression of heart failure in rats.. Rats were infused with 1.0 microg/h IP AM or saline over 7 days immediately after MI inducted by left coronary ligation and were examined 9 weeks after MI. Compared with the saline infusion, AM infusion significantly improved survival (59% versus 81%; P<0.05) and body weight gain (32%; P<0.01) and reduced heart weight (-28%; P<0.01), lung weight (-26%; P<0.01), left ventricular (LV) end-diastolic pressure (11.4+/-2.0 versus 4.0+/-0.6 mm Hg, mean+/- SEM; P<0.01), collagen volume fraction of noninfarcted LV (-39%; P<0.05), and plasma levels of endogenous rat AM (-38%; P<0.05) without affecting infarct size. To investigate the mechanism of AM actions, another series of MI rats infused with AM were killed on day 7. AM infusion had no effect on organ weights and hemodynamic parameters on day 7 of MI but significantly reduced urinary excretion of isoprostane (-61%; P<0.01) and noninfarcted LV mRNA levels of ACE (-31%; P<0.05) and p22-phox (-30%; P<0.05).. AM administration during the early period of MI improved the survival and ameliorated progression of LV remodeling and heart failure. This beneficial effect was accompanied by reductions in oxidative stress and ACE mRNA expression in noninfarcted LV in the AM infusion period.

Topics: Adrenomedullin; Aldosterone; Animals; Body Weight; Dinoprost; Disease Progression; Drug Evaluation, Preclinical; Heart Failure; Hemodynamics; Ligation; Lung; Male; Membrane Transport Proteins; Models, Animal; Myocardial Infarction; Myocardium; NADPH Dehydrogenase; NADPH Oxidases; Organ Size; Peptides; Peptidyl-Dipeptidase A; Phosphoproteins; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Ventricular Remodeling

We hypothesised that maternal uterine artery vascular dysfunction could contribute to cardiovascular dysfunction in offspring of rats fed a diet rich in fat. Sprague-Dawley rats were fed for 10 days prior to pregnancy and throughout gestation either: (a) a control breeding diet, or (b) the same diet supplemented with 20 % w/w lard, vitamins, essential micronutrients and protein to control values. At 20 days gestation vascular function was assessed in uterine arteries and third-order mesenteric arteries. Vascular reactivity in response to application of potassium, noradrenaline, the thromboxane analogue U46619, acetylcholine and nitric oxide was assessed. Maternal plasma concentrations of factors likely to contribute to endothelial dysfunction were measured. Maximum acetylcholine-induced relaxation was impaired in the mesenteric arteries of the lard-fed dams (max % relaxation: lard-fed, 69.7 +/- 6.48; control, 85.37 +/- 2.69, P = 0.03). Uterine artery vascular function was similar in the two groups (max % acetylcholine-induced relaxation: lard-fed, 73.7 +/- 4.01; control, 77.5 +/- 4.72, P = 0.98). Concentrations of plasma lipids, 8-epi-PGF(2alpha) and leptin were normal, whereas insulin and corticosterone concentrations were raised in the lard-fed group (insulin (ng ml(-1)): lard-fed, 8.04 +/- 0.47; control, 1.35 +/- 0.37, P < 0.0001; corticosterone (ng ml(-1)): lard-fed, 1164.0 +/- 170.9; control, 541.9 +/- 96.3, P = 0.005). Fetal and placental weights were reduced in lard-fed dams (fetus (g): lard-fed, 4.27 +/- 0.38; control, 2.96 +/- 0.40, P = 0.025; placenta (g): lard-fed, 0.72 +/- 0.06; control, 0.57 +/- 0.04, P = 0.05). Cardiovascular dysfunction in offspring is not associated with reduced uterine artery endothelial function but is associated with activation of the hypothalamic-pituitary-adrenal axis, hyperinsulinaemia and fetoplacental growth retardation.

Topics: Animal Feed; Animals; Arteries; Body Weight; Cholesterol; Corticosterone; Diet; Dietary Fats; Dinoprost; Eating; Endothelium, Vascular; Energy Metabolism; F2-Isoprostanes; Female; Insulin; Leptin; Lipid Peroxidation; Litter Size; Mesenteric Arteries; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Uterus; Vasoconstriction; Vasodilation

Diet and exercise can affect blood pressure and atherosclerotic risk.. The present study was designed to examine the effects of a short-term, rigorous diet and exercise intervention on blood pressure, hyperinsulinemia, and nitric oxide (NO) availability. Men (n=11) were placed on a low-fat, high-fiber diet combined with daily exercise for 45 to 60 minutes for 3 weeks. Pre- and post fasting blood was drawn for serum lipid, insulin, 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), and glucose measurements. Anthropometric parameters, blood pressure (BP), and 24-hour urinary NO metabolite excretion (NO(X)), a marker of NO bioavailability, were measured. Systolic (P<0.01) and diastolic BP (P<0.01) and 8-iso-PGF(2alpha) decreased (P<0.05), whereas urinary NO(X) increased (P<0.05). There was a significant reduction in fasting insulin (P<0.01) and a significant correlation between the decrease in serum insulin and the increase in urinary NO(X) (r2=0.68, P<0.05). All fasting lipids decreased significantly, and the total cholesterol to high-density lipoprotein cholesterol ratio improved. Although body weight and body mass index (P<0.01) decreased, obesity was still present and there were no correlations between the change in body mass index and the change in insulin, BP, or urinary NO(X).. This intervention resulted in dramatic improvements in BP, oxidative stress, NO availability, and the metabolic profile within 3 weeks, mitigating the risk for atherosclerosis progression and its clinical sequelae.

Topics: Adult; Aged; Arteriosclerosis; Blood Pressure; Body Mass Index; Body Weight; Combined Modality Therapy; Dinoprost; Exercise; F2-Isoprostanes; Humans; Hypertension; Insulin; Male; Middle Aged; Nitric Oxide; Oxidative Stress

Evidence exists to support the beneficial effects of superoxide dismutase on endothelial dysfunction induced by hyperglycemia in vitro. In vivo, however, studies of the effects of native superoxide dismutase preparations on the vascular complications accompanying diabetes are limited, and their therapeutic application potential has so far been disappointing. The objective of this study was to evaluate, for the first time in vivo, the effects of long-term administration of tempol, a stable superoxide dismutase-mimic compound, on diabetes-induced endothelial dysfunction in rats. Diabetes was induced by streptozotocin and rats were monitored for 8 weeks with or without treatment with tempol (100 mg/kg, s.c., b.i.d). Diabetic rats showed increased vascular levels of superoxide, which was accompanied by increased levels of the oxidative stress markers malondialdehyde and 8-epi-prostaglandin F(2alpha). In addition, the vasorelaxant as well as the cGMP-producing effects of acetylcholine and glyceryl trinitrate were reduced in diabetic rats. Treatment with tempol abolished not only the differences in the vascular content of superoxide, malondialdehyde and 8-epi-prostaglandin F(2alpha), but also the differences in the relaxation and cGMP responses of aortic rings to both acetylcholine and glyceryl trinitrate between control and diabetic rats. These results support the involvement of reactive oxygen species in mediation of hyperglycemia-induced endothelial dysfunction in vivo, and provide the rationale for potential utilization of stable superoxide dismutase-mimic nitroxides for the prevention of the vascular complications accompanying diabetes.

Topics: Acetylcholine; Animals; Antioxidants; Aorta; Blood Glucose; Body Weight; Cyclic GMP; Cyclic N-Oxides; Diabetes Mellitus, Experimental; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; In Vitro Techniques; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Spin Labels; Superoxides; Vasodilation; Vasodilator Agents

The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity. When Sprague-Dawley rats (n=60) are fed a moderately high fat diet (32 kcal% fat) for 10 to 16 weeks, approximately half of them develop obesity (obesity-prone [OP] group) and mild hypertension (158+/-3.4 mm Hg systolic pressure), whereas the other half (obesity-resistant [OR] group) maintains a body weight equivalent to that of a low fat control group and is normotensive (135.8+/-3.8 mm Hg). We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid-reactive substances showed a significant increase in the LDL fraction of OP rats (2.8+/-0.32 nmol malondialdehyde/mg protein) compared with OR and control rats (0.9+/-0.3 nmol malondialdehyde/mg protein). Also, aortic and kidney thiobarbituric acid-reactive substances showed a significant (3- and 5- fold) increase in OP rats after 16 weeks of diet. In addition, superoxide generation by aortic rings, measured by lucigenin luminescence, showed a 2-fold increase in the OP group compared with both the OR and control groups. In addition, free isoprostane excretion and nitrotyrosine in the kidney showed an increase in OP rats only. The urine and plasma nitrate/nitrite measured by the LDH method showed a 1.8-fold decrease in OP rats compared with OR rats. However, endothelial NO synthase expression in the kidney cortex and medulla assessed by reverse transcriptase-polymerase chain reaction showed a strong increase in the OP rats versus OR and control rats (endothelial NO synthase/beta-actin ratio 1.3+/-0.04 in OP rats versus 0.44+/-0.02 in OR rats), suggesting a possible shift toward superoxide production by the enzyme. Collectively, the data show a decreased NO bioavailability in OP animals that is due in part to the increased oxidative stress.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Dietary Fats; Dinoprost; Disease Models, Animal; F2-Isoprostanes; Hyperlipidemias; Hypertension; Kidney Cortex; Kidney Medulla; Lipid Peroxides; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renin; Thiobarbituric Acid Reactive Substances

This article describes a procedure for the quantitation of the isoprostane 15-F2t-IsoP (9a,11a,15S-trihydroxy-(8b)-prosta-5Z,13E-dien-1-oic acid [CAS#27415-26-5] formerly known as 8-epi-PGF2a or 8-iso-PGF2a, and also as iPF2a-III). We have combined features from several earlier methods for 15-F2t-IsoP and prostaglandins, and identified and modified those steps that may lead to poor recoveries. The resulting protocol is precise and reliable, and was validated by a blind time-course study of plasma levels in rats treated with 120 and 1200 mg CCl4/kg body weight. Plasma levels of 15-F2t-IsoP, as measured according to the procedure described above, are good indicators of acute oxidative stress as induced by CCl4. The precision of the measurements allows detection of elevated plasma 15-F2t-IsoP levels as long as 16 h after an acute exposure of 120 mg CCl4/kg body weight, and 2 h after an exposure of 1 mg CCl4/kg body weight. The results of this low-dose, pilot study suggest that this method has sufficient analytical precision to allow the detection of the small changes in plasma isoprostane levels, which result from chronic and/or lower-level exposures to agents causing oxidative stress.

Topics: Animals; Body Weight; Carbon Tetrachloride; Dinoprost; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Gas Chromatography-Mass Spectrometry; Hydrolysis; Male; Oxidative Stress; Pilot Projects; Rapeseed Oil; Rats; Rats, Inbred F344; Reproducibility of Results; Sensitivity and Specificity; Time Factors

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has recently been reported to have the antioxidative activity in vitro. However, it is still unclear whether chronic treatment with this drug actually leads to amelioration of the redox status in the body. In this study, we investigated the antioxidative effect of fluvastatin in vivo, using a vitamin E-deficient hamster model, an in vivo model of enhanced oxidative stress. After pre-treatment with a vitamin E-deficient diet for 2 months, fluvastatin, pravastatin or probucol was added to the diet for 1 month. Vitamin E deficiency caused a significant increase in the levels of plasma oxidative stress markers such as 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) and hydroperoxides. Furthermore, there was a significant increase in the oxidizability of plasma lipids in the vitamin E-deficient animals, indicating that the oxidative stress was increased in the circulation. Fluvastatin markedly depressed the above oxidative stress markers in plasma, and significantly decreased the oxidizability of plasma lipids without affecting their levels. Probucol, a reference antioxidant, also showed a similar effect while pravastatin, another HMG-CoA reductase inhibitor, showed only a weak improvement. We suggest that the treatment with fluvastatin leads to a reduction of oxidative stress in vivo, which is mainly derived from its antioxidative property rather than its lipid-lowering activity.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Cricetinae; Dinoprost; Eating; F2-Isoprostanes; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Lipid Peroxidation; Lipid Peroxides; Liver; Myocardium; Oxidation-Reduction; Oxidative Stress; Time Factors; Vitamin E; Vitamin E Deficiency

Lipid peroxidation is thought to be an important factor in the pathophysiology of a number of diseases and in the process of aging. We investigated the effects of supplementation with vitamin E on lipid peroxidation in rats. Both free radical-induced nonenzymatic- and cyclooxygenase-catalyzed enzymatic lipid peroxidation were investigated by measuring the levels of F(2)-isoprostanes (8-iso-PGF(2alpha)) and PGF(2alpha)-metabolite (15-K-DH-PGF(2alpha)), respectively, in blood, urine and liver. Samples were collected from control rats (n = 6) and from rats supplemented with vitamin E in the diet for 3 wk (n = 8, 20 g/kg diet of DL-alpha-tocopherol hydrogen succinate). Plasma alpha-tocopherol concentration and antioxidative capacity were greater in the vitamin E-supplemented rats than in the control rats (17.9 +/- 1.7 vs. 50.4 +/- 10.4 micromol/L, P < 0.001 and 181 +/- 6 vs. 275 +/- 27 micromol/L trolox equivalents, P < 0.001). Urine 8-iso-PGF(2alpha) tended to be lower in the vitamin E-supplemented rats (0.72 +/- 0.40 vs. 0.34 +/- 0.19 nmol/mmol creatinine, P = 0.056). Urine 15-K-DH-PGF(2alpha) was lower due to vitamin E supplementation (0.97 +/- 0.38 vs. 0.56 +/- 0. 21 nmol/mmol creatinine, P < 0.05), as was liver-free 8-iso-PGF(2alpha) concentration (0.47 +/- 0.11 vs. 0.18 +/- 0.04 nmol/g, P < 0.001). Supplementation with vitamin E did not affect plasma 8-iso-PGF(2alpha) or 15-K-DH-PGF(2alpha) concentrations, liver total 8-iso-PGF(2alpha) or plasma malondialdehyde levels. Thus, vitamin E supplementation reduced urine basal levels of biomarkers of both nonenzymatic and enzymatic lipid peroxidation. In liver, vitamin E reduced the basal level of free 8-iso-PGF(2alpha) but not total 8-iso-PGF(2alpha).

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Diet; Dinoprost; F2-Isoprostanes; Lipid Peroxidation; Liver; Male; Malondialdehyde; Oxytocics; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vitamin E

Recent work indicates that free radical-mediated lipid peroxidation takes place within the diaphragm on strenuous contraction. This phenomenon has only been demonstrated using fairly artificial experimental models and has not been studied during the type of sustained respiratory loading typically seen in patients with lung disease. The purpose of the present study was to measure the levels of several biochemical markers of protein oxidation (protein carbonyl levels) and lipid peroxidation (8-isoprostane, reduced glutathione, and oxidized glutathione levels) in diaphragms of rats subjected to chronic respiratory loading. Respiratory loading was accomplished by tracheal banding; groups of animals were loaded for 4, 8, or 12 days, and a group of sham-operated unloaded animals was used as controls. After loading, animals were killed, diaphragm contractility was assessed in vitro by using a portion of the excised diaphragm, and the remaining diaphragm and the soleus muscles were used for biochemical analysis. We found diminished force generation in diaphragms from all groups of banded animals compared with muscles from controls. For example, twitch force averaged 7.8 +/- 0.8 (SE) N/cm2 in unloaded animals and 4.0 +/- 0.4, 3.0 +/- 0.4, and 3.4 +/- 0.4 N/cm2 in animals loaded for 4, 8, and 12 days, respectively (P < 0.0001). Loading also elicited increases in diaphragmatic protein carbonyl concentrations (P < 0.001), and the time course of alterations in carbonyl levels paralleled loading-induced alterations in the diaphragm force-frequency relationship. Although loading was also associated with increases in diaphragmatic 8-isoprostane levels (P < 0.003) and reductions in diaphragm reduced glutathione levels (P < 0.003), the time course of changes in these latter parameters did not correspond to alterations in force. Soleus glutathione and carbonyl levels were not altered by banding. We speculate that respiratory loading-induced alterations in diaphragmatic force generation may be related to free radical-mediated protein oxidation, but not to free radical-induced lipid peroxidation.

Topics: Animals; Body Weight; Diaphragm; Dinoprost; F2-Isoprostanes; Glutathione; Glutathione Disulfide; Lipid Metabolism; Lipid Peroxidation; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Organ Size; Oxidative Stress; Rats; Time Factors

We have concurrently investigated oxidant stress, glucose tolerance and glucose-stimulated insulin responses in the obese Zucker rat, a widely used model of insulin resistance. The plasma level of the lipid peroxidation product 8-epi-prostaglandin F2alpha, a sensitive in vivo marker of oxidant stress, was elevated approximately 5-fold in 13-week old obese relative to age-matched, insulin-sensitive lean Zucker rats. Supplementation of the diet with vitamin E (as (+)-alpha-tocopherol acetate, 0.5% w/w) for 4 weeks, reduced plasma 8-epi-prostaglandin F2alpha and concomitantly reversed glucose-stimulated hyperinsulinaemia in the obese Zucker rat without worsening glucose tolerance. We therefore provide evidence of oxidant stress, measured as elevated plasma 8-epi-prostaglandin F2alpha, for the first time in the obese Zucker rat which now provides a rationale for the beneficial effects of antioxidants on insulin action previously reported in this model of insulin resistance.

Topics: Animals; Blood Glucose; Body Weight; Dietary Supplements; Dinoprost; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Male; Obesity; Oxidative Stress; Rats; Rats, Zucker; Vitamin E

Oxidative DNA damage is emerging as an biomarker of effect in studies assessing the health risks of occupational chemicals. Trichloroethylene (TCE) and perchloroethylene (PERC) are used in the dry cleaning industry and their metabolism can produce reactive oxygen compounds. The present study examined the potential for TCE and PERC to induce oxidative DNA damage in rats that was detectable as increased urinary excretion of 8-hydroxydeoxyguanosine (8OHdG). Thiobarbaturic acid reactive substances (TBARS) and 8-epiprostaglandin F2alpha (8epiPGF) were also measured as biomarkers of increased oxidative stress. Male Fischer rats were administered a single i.p. injection of 0, 100, 500, or 1000 mg/kg of PERC or TCE. Control rats received only vehicle (1:4 v/v of Alkamuls/water). A positive control group received 100 mg/kg 2-nitropropane (2NP). Rats were sacrificed 24 h after dosing. In rats receiving 2NP or TCE but not PERC, TBARS and the 8OHdG/dG ratios were significantly elevated in liver. Lymphocyte 8OHdG/dG was not affected significantly by 2NP, TCE or PERC. In rats receiving 2NP, urinary excretion of 8OHdG and 8epiPGF2 were significantly increased. In rats receiving TCE or PERC, significant increases in 8epiPGF2 or 8OHdG were not evident. Results indicate that a single high dose of TCE, but not PERC, can induce an increase in oxidative DNA damage in rat liver. However, the usefulness of 8OHdG as a biomarker of TCE-induced oxidative DNA damage is questionable.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Body Weight; Chromatography, High Pressure Liquid; Creatinine; Deoxyguanosine; Dinoprost; DNA Damage; Electrochemistry; Enzyme-Linked Immunosorbent Assay; Injections, Intraperitoneal; Kidney; Liver; Lymphocytes; Male; Organ Size; Oxidative Stress; Rats; Rats, Inbred F344; Tetrachloroethylene; Trichloroethylene; Urine

Oxidative stress and dyslipidaemia are key features of diabetes mellitus and may be involved in mediating the vascular endothelial dysfunction associated with this disease. The aim of this study was to examine the effect of dietary lipid-lowering and antioxidant agents on vascular endothelial function and oxidative stress. Diabetic male Sprague-Dawley rats (i.v. streptozotocin, 45 mg/kg) were fed for 4 weeks on a standard diet or on a diet supplemented with either the lipid-lowering antioxidant probucol (1% w/w in diet) or the 3-hydroxy 3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor simvastatin (0.01% w/w in diet). Responses to noradrenaline, acetylcholine, and sodium nitroprusside were assessed in small mesenteric arteries (mean internal diameter 300+/-5 microm, n = 80) mounted on a small vessel myograph. Plasma concentrations of total cholesterol and triglycerides were significantly raised in standard-fed diabetic rats and significantly reduced in probucol and simvastatin-fed diabetic rats 8-epi-prostaglandin (PG)F2alpha, an indicator of oxidative stress, was raised in liver and aorta from diabetic rats compared to controls. Probucol supplementation reduced 8-epi-PGF2alpha in aorta and liver of diabetic rats but increased 8-epi-PGF2alpha content in plasma and aorta from control animals. The abnormal relaxation to acetylcholine in arteries from the diabetic rats (pEC550 diabetic 6.763+/-0.172 vs control 7.541+/-0.175; p < 0.05) was not improved by probucol or simvastatin. These data, therefore, do not support a role for oxidative stress or dyslipidaemia in mediating the impaired ACh-induced endothelium-dependent relaxation of small mesenteric arteries from the streptozotocin-diabetic rat.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diet; Dinoprost; Eating; Endothelium, Vascular; F2-Isoprostanes; Hypolipidemic Agents; Lipid Peroxidation; Lipids; Male; Mesenteric Arteries; Muscle Relaxation; Oxidative Stress; Probucol; Rats; Rats, Sprague-Dawley; Simvastatin; Tissue Distribution