Serum 8-isoprostane Research Articles

Contrast-Induced Nephropathy in Aged Critically Ill Patients

Background. Aging is associated with renal structural changes and functional decline. The attributable risk for renal dysfunction from radiocontrast agents in critically ill older patients has not been well established. Methods. In this prospective study, we assessed the incidence of contrast-induced nephropathy (CIN) in critically ill patients with stable renal function who underwent computed tomography with intravenous contrast media. Patients were categorized into two age groups: <65 (YG) or ≥65 years old (OG). CIN was defined as 25% or greater increase from baseline of serum creatinine or as an absolute increase by 0.5 mg/dL until the 5th day after the infusion of contrast agent. We also evaluated the alterations in oxidative stress by assessing serum 8-isoprostane. Results. CIN occurred in 5 of 13 OG patients (38.46%) whereas no YG patient presented CIN (P = 0.015). Serum creatinine kinetics in older patients demonstrated a rise over five days following contrast infusion time while a decline was observed in the YG (P = 0.005). Conclusions. Older critically ill patients are more prone to develop renal dysfunction after the intravenous infusion of contrast agent in relation to their younger counterparts.

Monitoring changes in serum 8-isoprostane concentration as a possible marker of oxidative stress in pregnancy

Introduction: Oxidative stress represents a pathophysiological mechanism lying behind occurrence of different acute and chronic diseases. Pregnancy, mainly due to placenta rich with mitochondria, is also being associated with the state of oxidative stress. Numerous markers have been proposed in order to test oxidative stress in pregnancy state, one of them being 8-isoprostane. The aim of this study was to analyse serum concentrations of 8-isoprostane as a possible oxidative stress marker in pregnancy.Methods: Serum concentrations of 8-isoprostane were measured in overall population of 84 woman, between 20 and 30 years of age. Tested population was divided in 2 groups: 42 pregnant woman were classifi ed as being either in the fi rst or second trimester of pregnancy. In the control group healthy nonpregnant women were included. Concentration of 8-isoprostane in serum was determined by commercial 8-isoprostane EIA test kit of Cayman Chemical Company, USA.Results: The 8-isoprostane levels were signifi cantly increased in pregnant women in relation to healthy non pregnant women (p&lt;0.05). The 8-isoprostane levels were signifi cantly increased in second and third trimester of pregnancy (p&lt;0.05).Conclusions: According to the obtained results, 8-isoprostane might be used as a possible marker of oxidative stress in pregnancy state, but not as a biomarker for the risk of complications development in pregnancy in analysed population.

The antioxidant tempol decreases acute pulmonary thromboembolism-induced hemolysis and nitric oxide consumption

Acute pulmonary thromboembolism (APT) is a critical condition associated with acute pulmonary hypertension. Recent studies suggest that oxidative stress and hemolysis contribute to APT-induced pulmonary hypertension, possibly as a result of increased nitric oxide (NO) consumption. We hypothesized that the antioxidant tempol could attenuate APT-induced hemolysis, and therefore attenuate APT-induced increases in plasma NO consumption. APT was induced in anesthetized sheep with autologous blood clots. The hemodynamic effects of tempol infused at 1.0mg/kg/min 30 min after APT were determined. Hemodynamic measurements were carried out every 15 min. To assess oxidative stress, serum 8-isoprostanes levels were measured by ELISA. Plasma cell-free hemoglobin concentrations and NO consumption by plasma samples were determined. An in vitro oxidative AAPH-induced hemolysis assay was used to further validate the in vivo effects of tempol. APT caused pulmonary hypertension, and increased pulmonary vascular resistance in proportion with the increases in 8-isoprostanes, plasma cell-free hemoglobin concentrations, and NO consumption by plasma (all P<0.05). Tempol attenuated the hemodynamic alterations by approximately 15-20% and blunted APT-induced increases in 8-isoprostanes, in cell-free hemoglobin concentrations, and the increases in NO consumption by plasma (P<0.05). Tempol dose-dependently attenuated AAPH-induced in vitro hemolysis (P<0.05). Our findings are consistent with the idea that antioxidant properties of tempol decrease APT-induced hemolysis and nitric oxide consumption, thus attenuating APT-induced pulmonary hypertension.

8-Isoprostane levels in serum and bronchoalveolar lavage in idiopathic pulmonary fibrosis and sarcoidosis

Sarcoidosis and idiopathic pulmonary fibrosis (IPF) are both associated with deregulated inflammatory mechanisms partially triggered by aggravated oxidative stress. 8-Isoprostane has been proposed as a reliable marker of oxidative stress, linked to several pulmonary diseases. We aimed to explore differences in 8-isoprostane levels in IPF and sarcoidosis patients, and controls. We included 16 IPF and 55 sarcoidosis patients, as well as 17 controls in the study. 8-Isoprostane levels were measured in serum and in bronchoalveolar lavage (BAL). Serum 8-isoprostane levels were increased in all patient groups vs controls (p<0.001). The systemic 8-isoprostane concentrations were higher in sarcoidosis patients as compared to IPF subjects and controls (p=0.017 and p<0.001, respectively). IPF patients exhibited increased serum 8-isoprostane levels when compared to controls (p<0.001). Sarcoidosis patients presented significantly increased 8-isoprostane BAL levels when compared to IPF patients (p=0.002). Our data indicate that the level of oxidative stress, as reflected by 8-isoprostane concentrations, is enhanced in patients with sarcoidosis, and to a lesser extent, in IPF patients when compared to controls, suggesting a potential implication of redox imbalance in both diseases.

Paraoxonase-1 status in patients with hereditary hemochromatosis

Hereditary hemochromatosis (HH) is characterized by accumulation of iron, oxidative stress, inflammation, and fibrogenesis in liver tissue. In this setting, research on the protection afforded by intracellular antioxidants is of clinical relevance. Paraoxonase-1 (PON1) is an enzyme that degrades lipid peroxides. This study investigates the alterations in serum PON1 status, PON1 gene polymorphisms, and PON1 hepatic expression in patients with HH. We performed a case-control study in 77 patients with HH (80.5% men, 22-70 years of age) and 408 healthy individuals (43.1% men, 26-74 years of age). Serum PON1 activities against different substrates and PON1192 and PON155 polymorphisms were analyzed. PON1 protein expression was investigated in 20 liver biopsies. HH patients had significantly lower serum PON1 activity, which was inversely correlated with ferritin (marker of iron stores) and serum 8-isoprostane concentrations (index of oxidative stress). PON1 protein expression in liver tissue was higher in patients and showed stronger staining in hepatocytes surrounding the areas of inflammation. Our study provides preliminary evidence that PON1 may play a role in protecting against iron-induced oxidative stress in hereditary hemochromatosis.

Cinacalcet Improves Endothelial Dysfunction and Cardiac Hypertrophy in Patients on Hemodialysis with Secondary Hyperparathyroidism

Background: Secondary hyperparathyroidism (SHPT) in patients on hemodialysis is strongly associated with cardio-vascular morbidity and mortality. Treatment of SHPT with cinacalcet decreases circulating parathyroid hormone (PTH) concentrations and lowers serum calcium and phosphorus concentrations. Therefore, we investigated the cardiovascular effects of cinacalcet in hemodialysis patients with SHPT. Methods: We studied 12 hemodialysis patients with SPHT [serum intact PTH (iPTH) >300 pg/ml]. The study consisted of three phases: an initial run-in period of 16 weeks, including a wash-out period of 4 weeks (pretreatment), a cinacalcet treatment period of 20 weeks (treatment), and 20-week follow-up after suspension of cinacalcet treatment (posttreatment). In this study, vitamin D sterols were not prescribed to all the study subjects for at least 1 year during the pretreatment period. Results: Cinacalcet significantly decreased serum iPTH (pretreatment vs. treatment; 628.2 ± 250.8 vs. 251.7 ± 237.4 pg/ml, p < 0.01), calcium, phosphorus, and calcium × phosphorus product (p < 0.01), all of which returned to baseline levels after treatment. There was no change in C-reactive protein during the study period. There was significantly improvement in brachial flow-mediated dilatation (p < 0.01) and enhanced cardio-ankle vascular index (p < 0.01) with cinacalcet treatment. Moreover, cinacalcet significantly improved diastolic function (E/e' ratio, p < 0.05) and the left ventricular mass index (p < 0.05). Cinacalcet also increased serum NO x (p < 0.05) and decreased serum isoprostane (p < 0.05) and soluble intercellular adhesion molecule-1 concentrations (p < 0.05). All of these biochemical parameters returned to their pretreatment concentrations after withdrawal of cinacalcet. Conclusions: Cinacalcet hydrochloride without vitamin D might ameliorate endothelial dysfunction, diastolic dysfunction, and cardiac hypertrophy by decreasing oxidative stress and increasing the serum nitric oxide production in hemodialysis patients with SHPT.

Relationship between iron metabolism, oxidative stress, and insulin resistance in patients with systemic lupus erythematosus

Objective: The aim of the present study was to assess oxidative stress and iron metabolism in systemic lupus erythematosus (SLE) patients with and without insulin resistance (IR).Method: This study included 236 subjects (125 controls and 111 SLE patients). Patients with SLE were divided in two groups: with (n = 72) or without (n = 39) IR.Results: SLE patients with IR showed higher advanced oxidation protein product (AOPP) levels (p = 0.030) and gamma-glutamyltransferase (GGT) levels (p = 0.001) and lower sulfhydryl groups of proteins (p = 0.0002) and total radical-trapping antioxidant parameter (TRAP) corrected by uric acid (UA) levels (p = 0.04) when compared to SLE patients without IR. However, SLE patients with IR presented lower serum 8-isoprostane (p = 0.05) and carbonyl protein levels (p = 0.04) when compared to SLE patients without IR. Serum ferritin levels were significantly higher in SLE patients (p = 0.0006) than in controls, and SLE patients with IR presented higher serum ferritin levels (p = 0.01) than SLE patients without IR. Patients with SLE showed that IR was inversely correlated to TRAP/UA (r = −0.2724, p = 0.0008) and serum ferritin was positively correlated to AOPP (r = 0.2870, p = 0.004).Conclusions: This study found that oxidative stress was higher in the group of SLE patients with IR, and increased ferritin, whether caused by the inflammatory process per se or hyperinsulinaemia, can favour the redox process. In addition, the preset data reinforce the need to measure oxidative stress with several methodologies with different assumptions.

Oxidative stress markers in laparoscopic versus open colectomy for cancer: a double-blind randomized study

Colorectal cancer as well as colorectal surgery is associated with increased oxidative stress through different mechanisms. In this study the levels of different oxidative stress markers were comparatively assessed in patients who underwent laparoscopic or conventional resection for colorectal cancer. Sixty patients with colorectal cancer were randomly assigned to undergo laparoscopic (LS) or open surgery (OS). Lipid, protein, RNA, and nitrogen damage was investigated by measuring serum 8-isoprostanes (8-epiPGF2α), protein carbonyls (PC), 8-hydroxyguanosine (8-OHG), and 3-nitrotyrosine (3-NT), respectively. The primary end point of the study was to analyze and compare serum levels of the oxidative stress markers between the groups. Postoperative serum levels of 8-epiPGF2α, 3-NT, and 8-OHG were significantly lower in the LS group at 24 h after surgery (p < 0.05). At 6 h postoperatively, the levels of 8-epiPGF2α and 3-NT were significantly lower in the LS group (p < 0.05). No difference in the levels of PC was found between the two groups at any time point. In the OS group, postoperative levels of 8-epiPGF2α were significantly lower than the preoperative values (p < 0.01). In the LS group, the postoperative values of 8-epiPGF2α, 3-NT, and 8-OHG were significantly lower than the preoperative values (p < 0.05). Laparoscopic surgery for colorectal cancer is associated with lower oxidative stress compared to open surgery. 8-epiPGF2α was the most suitable marker for readily defining the oxidative status in patients who underwent surgery for colorectal cancer.

Mulberry Leaf Reduces Oxidation and C-Reactive Protein Level in Patients with Mild Dyslipidemia

C-reactive protein (CRP) is the inflammatory marker that could represent the inflammation in blood vessels resulted from dyslipidemia. The objective of this study was to evaluate the antioxidative activity of mulberry leaf powder using DPPH assay and the effect of mulberry leaf powder on lipid profile, CRP level, and antioxidative parameters in mild dyslipidemia patients. A within-subjects design was conducted and patients received three tablets of 280 mg mulberry leaf powder three times a day before meals for 12 weeks. Total of 25 patients were enrolled but one subject was excluded. After three months of mulberry leaf consumption, serum triglyceride and low-density lipoprotein (LDL) level were significantly reduced and more than half of all patients' CRP levels decreased every month as well as the mean CRP level but no statistically significant difference was found. The average erythrocyte glutathione peroxidase activity of patients was increased but not at significant level; however, the mean serum 8-isoprostane level was significantly lower after mulberry treatment for 12 weeks. It can be concluded that mulberry leaf powder exhibited antioxidant activity and mulberry leaf powder has potential to decrease serum triglyceride, LDL, and CRP levels in mild dyslipidemia patients without causing severe adverse reactions.

Increased dietary fruit intake was associated with lower burden of carotid atherosclerosis in Chinese patients with Type 2 diabetes mellitus

Previous studies demonstrated that high fruit consumption was associated with a lower risk of cardiovascular events in patients with Type 2 diabetes mellitus. However, the relationship between fruit intake and carotid atherosclerosis in these patients is unknown. We studied the relationship between dietary fruit intake and carotid intima-media thickness in patients with Type 2 diabetes. A total of 255 Chinese patients with Type 2 diabetes were recruited. Dietary fruit intake was assessed by a validated food-frequency questionnaire, and carotid intima-media thickness was measured by high-resolution ultrasonography. Among patients with three different tertiles of fruit intake (14.5 ± 8.6 vs. 41.5 ± 7.1 vs. 92.6 ± 39.7 g/day), there was no difference in their clinical characteristics (all P > 0.05). Patients with the highest tertile of fruit intake had a significantly higher BMI and diastolic blood pressure than those with the lowest tertile intake. Furthermore, serum high-sensitivity C-reactive protein, 8-isoprostane and superoxide dismutase were similar among the three tertiles of patients (all P > 0.05). However, patients with the highest tertile of fruit intake had lower carotid intima-media thickness (0.97 ± 0.02 vs. 1.08 ± 0.03 mm, P = 0.046) and prevalence of carotid plaque (11.76 vs. 1.18%, P = 0.022) than those with the lowest tertile of fruit intake. Multivariate regression analysis revealed the highest tertile of fruit intake (β = -0.086, P = 0.049) was independently associated with carotid intima-media thickness. Our results demonstrated that, in Chinese patients with Type 2 diabetes, higher dietary fruit intake was associated with a lower burden of carotid atherosclerosis as reflected by lower carotid intima-media thickness and prevalence of carotid plaque.

Effects of a whole rice diet on metabolic parameters and inflammatory markers in prediabetes

Summary Background and aims Epidemiological studies have shown an association between consumption of white rice and prevalence of insulin resistance. We wanted to test the effect of substituting brown rice for white rice on insulin resistance. Methods A group of Chinese American (n = 100) with screening pre-diabetes in the area of Flushing, New York City, were randomized to either continue their usual white rice intake (n = 51) or change to brown rice (n = 49) for 3 months. Fasting blood was obtained at baseline and end of study in both groups for measurement of circulating and cellular (peripheral mononuclear cells) metabolic and inflammatory markers. Results Only 58 subjects (white rice = 28 and brown rice = 30) finished the study. Their analysis shows significant weight loss and fall of systolic and diastolic blood pressure only in those ingesting brown rice. Insulin and HOMA, serum AGEs and 8-isoprostane decreased, while SIRT1 mRNA increased in the brown rice group as compared to the white rice group. Conclusions Substituting brown rice for white rice in a pre-diabetes population with high daily consumption of rice has a very beneficial effect in improving their metabolic risk factors. Further studies are needed to confirm these findings.

THE EFFECTS OF ATORVASTATIN WITH DIFFERENT DOSES ON SLOX-1 AND H2S IN ACUTE CORONARY SYNDROME

ObjectivesTo investigate the effects of atorvastatin with different doses on soluble lectin-like oxidised low-density lipoprotein receptor-1 (sLOX-1), 8-isoprostane, hydrogen sulphide (H2S) and nitric oxide (NO) in patients with Acute Coronary...

Late Intervention with a Myeloperoxidase Inhibitor Stops Progression of Experimental Chronic Obstructive Pulmonary Disease

Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation. To determine the role of MPO in COPD. We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure. At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding. We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

Association of oxidative stress with mortality: the Beaver Dam Eye Study.

Epidemiological studies have shown that oxidative stress is associated with cardiovascular disease (CVD) and diabetes. However, the association of oxidative stress marker with non-CVD and CVD mortality has not been extensively evaluated. The association of baseline serum 8-isoprostane (8-ISO) with all-cause, non-CVD, and CVD mortality was examined in a random subset (n = 1,753) of a population-based study of 4,926 adults (99% non-Hispanic whites; 56% women) aged 43-86 years from the Beaver Dam Eye Study. Cause of death was ascertained by death certificate between 1987 and 2002. 8-ISO was measured by immunoassay. Cox proportional hazards regression analysis was used to estimate mortality hazard ratios (HRs) and 95% confidence intervals (CIs) by one 8-ISO standard deviation. During a median follow-up of 13.1 years, 590 (33.7%) participants died (290 CVD deaths). After adjusting for socio-demographics and CVD risk factors, 8-ISO was significantly associated with all-cause (HR = 1.1, 95% CI 1.01-1.2) and non-CVD (HR = 1.14, 95% CI 1.01-1.28) mortality but not with CVD mortality (HR = 1.06, 95% CI 0.93-1.2). When limited to participants with BMI < 25 kg/m2, individuals in the highest 8-ISO quartile had approximately 34 to 36% increased risk of all-cause, non-CVD, and CVD death compared to those at the lowest quartile. In contrast, 8-ISO was not significantly associated with mortality among those with BMI ≥ 25 kg/m2. These findings suggest that baseline serum 8-ISO, a marker of oxidative stress, is an independent risk factor of all-cause, non-CVD, and CVD mortality among a cohort of middle-aged adults with normal BMI.

Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91phox and p22phox) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1β and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca2+]i) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca2+]i response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91phox expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions.

Flavonoid-Rich Cocoa Consumption Affects Multiple Cardiovascular Risk Factors in a Meta-Analysis of Short-Term Studies

A growing body of evidence suggests that the consumption of foods rich in polyphenolic compounds, particularly cocoa, may have cardioprotective effects. No review, however, has yet examined the effect of flavonoid-rich cocoa (FRC) on all major cardiovascular risk factors or has examined potential dose-response relationships for these effects. A systematic review and meta-analysis of randomized, controlled trials was performed to evaluate the effect of FRC on cardiovascular risk factors and to assess a dose-response relationship. Inclusion and exclusion criteria as well as dependent and independent variables were determined a priori. Data were collected for: blood pressure, pulse, total cholesterol, HDL cholesterol, LDL cholesterol, TG, BMI, C-reactive protein, flow-mediated vascular dilation (FMD), fasting glucose, fasting insulin, serum isoprostane, and insulin sensitivity/resistance indices. Twenty-four papers, with 1106 participants, met the criteria for final analysis. In response to FRC consumption, systolic blood pressure decreased by 1.63 mm Hg (P= 0.033), LDL cholesterol decreased by 0.077 mmol/L (P= 0.038), and HDL cholesterol increased by 0.046 mmol/L (P= 0.037), whereas total cholesterol, TG, and C-reactive protein remained the same. Moreover, insulin resistance decreased (HOMA-IR: –0.94 points; P< 0.001), whereas FMD increased (1.53%;P< 0.001). A nonlinear dose-response relationship was found between FRC and FMD (P= 0.004), with maximum effect observed at a flavonoid dose of 500 mg/d; a similar relationship may exist with HDL cholesterol levels (P= 0.06). FRC consumption significantly improves blood pressure, insulin resistance, lipid profiles, and FMD. These short-term benefits warrant larger long-term investigations into the cardioprotective role of FRC.

Simvastatin Displays an Antioxidative Effect by Inhibiting an Increase in the Serum 8-Isoprostane Level in Patients With Acute Ischemic Stroke

Oxidative stress plays an important role in ischemic stroke pathophysiology. Some drugs are known to have a substantial influence on oxidative stress. In this study, we examined the antioxidant effect of simvastatin through its influence on patients' serum 8-isoprostane levels. We measured serum 8-isoprostane levels in 67 patients with acute ischemic stroke treated and not treated with simvastatin within 5 days after stroke onset, in comparison with 20 normal controls. Stroke patients from both groups had significantly higher initial serum 8-isoprostane levels than the controls. The median value of serum 8-isoprostane level was significantly lower in the simvastatin-treated group after 5 days of treatment. The results confirm the contribution of oxidative stress to brain ischemia and suggest antioxidative properties of statins in the acute phase of ischemic stroke patients.

AGE formation blockade with aminoguanidine does not ameliorate chronic allograft nephropathy

AimsAdvanced glycation end products (AGEs) are produced by glycoxidation and lipid peroxidation. AGEs induce oxidative stress and inflammation, and accumulate in tubular cells after kidney transplantation. We hypothesize that the AGE formation blocker aminoguanidine (AG) reduces AGE formation and improves renal transplant function. Main methodsFisher 344 kidneys were orthotopically transplanted into Lewis recipients. Recipients were treated with AG (100mg/kg/day), candesartan (CAND; 5mg/kg/day), or vehicle (VEH) for 24weeks. The major non-cross linking AGE Nε-carboxymethyllysine (CML) was measured post-transplantation with gas chromatography-tandem mass spectrometry or immunohistochemistry. As a marker of systemic lipid peroxidation 8-isoprostane was measured by ELISA. We determined intra-arterial blood pressure, heart weight/body weight ratio, size of cardiomyocytes and cardiac hypertrophy as assessed by echocardiography. For biochemical evaluation of cardiac and renal fibrosis we measured hydroxyproline content. Key findingsAG significantly reduced serum CML and 8-isoprostane, but did not reduce signs of chronic allograft nephropathy (CAN) or blood pressure. AG did not alter tubular AGE accumulation. AG reduced heart weight/body weight ratio (AG: 2.7±0.1g/kg; CAND: 2.2±0.1, VEH: 3.0±0.4g/kg), size of cardiomyocytes (P<0.05) and showed a tendency to reduce cardiac hypertrophy (wall volume average radial AG 7.072±0.83cm3 vs. CAND 6.841±0.66cm3 vs. VEH 7.839±0.74cm3). SignificanceDespite effective reduction of serum CML and 8-isoprostane, AG did not ameliorate CAN or reduce renal AGE accumulation. On the other hand AG reduced cardiac size suggesting a supportive cardio-protective action which is blood pressure independent.

Thyroid Hormone Administration Induces Rat Liver Nrf2 Activation: Suppression byN-Acetylcysteine Pretreatment

Oxidative stress associated with 3,3',5-triiodo-l-thyronine (T(3))-induced calorigenesis upregulates the hepatic expression of mediators of cytoprotective mechanisms. The aim of this study was to evaluate the hypothesis that in vivo T(3) administration triggers a redox-mediated translocation of the cytoprotective nuclear transcription factor erythroid 2-related factor 2 (Nrf2) from the cytosol to the nucleus in rat liver. Such translocation of transcription factors is considered to be an activating step. The effect of T(3) administration in the presence and absence of N-acetylcysteine (NAC) on cytosol-to-nuclear translocation of Nrf2 was evaluated, with inhibition of this process by NAC taken as evidence that the process was redox mediated. Male Sprague-Dawley rats weighing 180-200 g were given a single intraperitoneal dose of 0.1 mg T(3)/kg. Another group of rats were given the same dose of T(3) and were also pretreated with NAC (0.5 g/kg) at 0.5 hour before T(3) administration. Two other groups of rats received vehicle treatment and NAC, respectively. Following these treatments, rectal temperature of the animals, liver O(2) consumption, serum and hepatic levels of 8-isoprostanes, and liver protein levels of Nrf2, Akt, p38, and thioredoxin (Western blot) were determined at different times up to 48 hours. T(3) administration induced a significant increase in the hepatic nuclear levels of Nrf2 at 1 and 2 hours after treatment and a concomitant decrease in cytosolic Nrf2. It also increased hepatic thioredoxin, a protein whose gene transcription is induced by nuclear Nrf2. Levels of nuclear Nrf2 were at a plateau from 4 to 6 hours after T(3). Rectal temperature of the animals rose from 36.6°C to 37.5°C as did liver O(2) consumption. Serum and liver 8-isoprostanes levels increased (p < 0.05) from 38.4 ± 4.0 pg/mL (n = 4) to 69.2 ± 2.0 pg/mL (n = 3) and from 0.75 ± 0.09 ng/g liver (n = 3) to 1.53 ± 0.10 ng/g liver (n = 5), respectively. In the group of rats pretreated with NAC, the increase in cytosol-to-nuclear translocation of Nrf2 was only 28% that induced by T(3). In addition, T(3) induced liver Akt and p38 activation during the period of 1-4 hours after T(3) administration. p38 activation at 2 hours after T(3) administration was abolished in NAC-pretreated animals. In vivo T(3) administration leads to a rapid and transient cytosol-to-nuclear translocation of liver Nrf2. This appears to be promoted by a redox-dependent mechanism as it is blocked by NAC. It may also be contributed by concomitant p38 activation, which in turn promoted Nrf2 phosphorylation. Nrf2 cytosol-to-nuclear translocation may represent a novel cytoprotective mechanism of T(3) to limit free radical or electrophile toxicity, as this would likely entail promoting thioredoxin production.

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: A randomized controlled trial

AimsCoronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). Methods and resultsWe performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300mg/day, n=28) vs. placebo (controls, n=28) for 8weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20μg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect −2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=−0.29, P=0.047). ConclusionIn patients with ischaemic LVSD, 8weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD.