Plasma 8-isoprostane Levels Research Articles

Effect of Time-Restricted Eating on Circulating Levels of IGF1 and Its Binding Proteins in Obesity: An Exploratory Analysis of a Randomized Controlled Trial

Obesity is associated with alterations in circulating IGF1, IGF1-binding proteins (IGFBPs), insulin, inflammatory markers, and hormones implicated in cardiovascular disease, diabetes, cancer, and aging. However, the effects of 4 and 6 h time-restricted eating (TRE) on circulating IGF1 and IGFBPs is uncertain. Objective: This study aimed to investigate the effects of TRE on plasma IGF1, IGFBP1, IGFBP2, and IGFBP3, and whether these effects were mediated by weight loss or body composition changes. Insulin sensitivity, glucose control, adipokines, and inflammatory markers were also examined. Design: An exploratory analysis of an 8-week randomized controlled trial implementing a daily TRE intervention was carried out. Participants/Setting: This study was conducted at the University of Illinois at Chicago in 2019. Participants with obesity were randomized to 4 or 6 h TRE (n = 35) or a control (n = 14) group. Plasma biomarkers were measured by ELISA at baseline and week 8. In a sub-analysis, participants were stratified into higher- (>3.5%) and lower- (≤3.5%) weight-loss groups. Intervention: Participants fasted daily from 7 p.m. to 3 p.m. in the 4 h TRE group (20 h) and from 7 p.m. to 1 p.m. in the 6 h TRE group (18 h), followed by ad libitum eating for the remainder of the day. Controls received no dietary recommendations. Main outcome measures: IGF1, IGFBPs, hsCRP, and adipokines were the main outcome measures of this analysis. Statistical Analysis: Repeated measures ANOVA and mediation analysis were conducted. Results: Body weight significantly decreased with TRE (−3.6 ± 0.3%), contrasting with controls (+0.2 ± 0.5%, p < 0.001). Significant effects of TRE over time were observed on plasma IGFBP2, insulin, HOMA-IR, and 8-isoprostane levels, without affecting other biomarkers. In the sub-analysis, IGFBP2 increased while leptin and 8-isoprostane decreased significantly only in the “higher weight loss” subgroup. Changes in insulin and HOMA-IR were related to TRE adherence. Conclusions: Eight-week daily 4 to 6 h TRE did not affect IGF1, IGFBP1, or IGFBP3 levels but improved insulin, HOMA-IR, and 8-isoprostane. IGFBP2 increased and leptin decreased when weight loss exceeded 3.5% of baseline.

Topical Application of Aprepitant Inhibits Erlotinib-induced Facial Dermatitis/Hair Loss

Erlotinib, an EGFR-TKI, has been used as an effective anti-tumorigenesis agent against several cancers including lung, colon, head and neck. However, it has been reported to cause significant and severe cutaneous side effects. Our previous studies implicated substance P, a neuropeptide, as a significant mediator of skin toxicity. Our present study was designed to determine if the topical application of aprepitant, a specific substance P receptor blocker, would be protective against these skin side effects. Erlotinib in the diet was administered to the rats for 12 weeks. Facial rash and hair loss began to occur after 6 weeks and were most severe at 12 weeks when animals were sacrificed. Topical treatment of aprepitant to the facial area 3 times a week showed dose-dependent and progressive inhibition up to 70% of the induced dermatitis/hair loss. These results were comparable to the effects produced by oral doses in our prior study. At sacrifice, we also found significant elevations of neutrophil superoxide, that were inhibited by topical aprepitant, along with elevated plasma 8-isoprostane levels, that were also suppressed. Facial skin samples revealed increased leukocyte (CD11b positive) infiltration in the erlotinib-treated rats, which were substantially reduced by the topical aprepitant. In conclusion, the indicators of reactive oxidative species (ROS) suggest that neurogenic inflammation played a critical role in causing EGFR-TKI-induced toxicity; it also confirmed that the systemic inhibition of ROS production due to blockade of substance P action was significantly protective against the dermatitis/hair loss pathology.

Room air versus 100% oxygen for delivery room resuscitation of preterm neonates in low resource settings: A randomised, blinded, controlled trial.

International Liaison Committee on Resuscitation (ILCOR-2020) report recommend starting delivery room resuscitation of all preterm neonates of <35 weeks' gestation with 21-30% oxygen. However, the correct initial oxygen concentration for resuscitation of preterm neonates in delivery room is inconclusive. In this blinded, randomised, controlled trial, we compared room air with 100% oxygen for oxidative stress and clinical outcomes in delivery room resuscitation of preterm neonates. Preterm neonates 28-33 weeks' gestation requiring positive pressure ventilation at birth were randomly allocated to room air or 100% oxygen. Investigators, outcome assessors and data analysts were blinded. Rescue 100% oxygen was used whenever trial gas failed (need for positive pressure ventilation >60 s or chest compression). Plasma 8-isoprostane levels at 4 h of age. mortality by discharge, bronchopulmonary dysplasia, retinopathy of prematurity and neurological status at 40 weeks post-menstrual age. All subjects were followed till discharge. Intention to treat analysis was carried out. A total of 124 neonates were randomised to room air (n = 59) or 100% oxygen (n = 65). Isoprostane level at 4 h was similar in both the groups (median (interquartile range): 280 (180-430) vs. 250 (173-360) pg/mL, P = 0.47). No difference was observed in mortality and other clinical outcomes. Room air group had higher treatment failures (27 (46%) vs. 16 (25%); relative risk (RR) 1.9 (1.1-3.1)) and took longer time to establish regular respiration (230 ± 231 vs. 182 ± 261, mean difference = 48 (40, 136) seconds). In preterm neonates 28-33 weeks' gestation requiring resuscitation in the delivery room, room air (21%) is not the correct concentration to initiate resuscitation. Larger controlled trials involving multiple centres in low- and middle-income countries are immediately required for a conclusive answer.

A multistrain probiotic improves handgrip strength and functional capacity in patients with COPD: A randomized controlled trial

PurposeThe age-related muscle loss, termed sarcopenia and functional dependency, are common findings in patients with chronic obstructive pulmonary disease (COPD). However, an effective bedside treatment remains elusive. ObjectiveTo assess the effects of probiotics on sarcopenia and physical capacity in COPD patients. MethodsRandomized, double-blind, computer-controlled, multicenter trial in two tertiary-care hospitals for 16 weeks. A central computer system randomly allocated male, 63—73 years old COPD patients into placebo (n=53) and probiotic (n=51) groups. The intervention was Vivomix 112 billion*, one capsule a day for 16 weeks. The main outcomes measured were sarcopenia phenotype, short physical performance battery (SPPB), plasma markers of intestinal permeability (zonulin and claudin-3) and neuromuscular junction degradation (CAF22), body composition, and handgrip strength (HGS) before and following the probiotics treatment. Findings4 patients discontinued intervention due to poor compliance and 100 patients, including placebo (n=53) and probiotic (n=47) groups were analyzed. Probiotics reduced plasma zonulin, claudin-3, and CAF22, along with an improvement in HGS, gait speed, and SPPB scores (all p<0.05). Probiotic treatment also reduced the plasma c-reactive proteins and 8-isoprostane levels, the markers of systemic inflammation and oxidative stress (p<0.05). Correlation analysis revealed varying degrees of association of plasma biomarkers with sarcopenia indexes. Despite a statistical trend, we did not find a reduction in sarcopenia prevalence in the probiotic group. ConclusionTaken together, the multistrain probiotic improves muscle strength and functional performance in COPD patients by reducing intestinal permeability and stabilizing neuromuscular junction. Trial registrationGMC clinical trial unit, GMC-CREC-00263

Nitric Oxide Therapy Attenuates Heart Failure with Preserved Ejection Fraction

IntroductionNitric oxide (NO) based therapeutics have proven to exert cardioprotective actions in the setting of heart failure with reduced ejection fraction (HFrEF). However, NO therapy has failed to exert beneficial effects in clinical studies of heart failure with preserved ejection fraction (HFpEF).We investigated (1) the effects of the NO donor, sodium nitrite, as a monotherapy, (2) hydralazine monotherapy, a known vasodilator and antioxidant, and (3) combination therapy with both drugs in a murine model of HFpEF. We assessed left ventricular (LV) function, oxidative/nitrosative stress, exercise tolerance, and cardiac fibrosis.Materials and MethodsMale, C57/BL6N (n=15 per group) were placed on a Western high fat diet (60% kCal from fat) and treated with L‐NG‐Nitro arginine methyl ester (L‐NAME, 0.5 g/L/day) in the drinking water beginning at 10 weeks of age. At 15 weeks of age, mice were randomly assigned to four separate groups for five additional weeks: HFpEF control, sodium nitrite in drinking water (75 mg/L), hydralazine (2 mg/kg/day, i.p., b.i.d.), or the combination of sodium nitrite and hydralazine.Plasma was collected to measure circulating 8‐isoprostane and 3‐nitrotyrosine levels, biomarkers of oxidative and nitrosative stress respectively. In addition, cardiac tissue was harvested at 20 weeks for Masson’s Trichrome staining and to measure cardiac nitrite levels. Echocardiography and exercise tolerance testing was performed at 10, 15, and 20 weeks of age.ResultsThere was a significant increase in circulating nitrite levels (p &lt; 0.05) in the sodium nitrite + hydralazine group compared to the control and either monotherapy groups. There was no significant difference in the cardiac tissue nitrite levels between the combination therapy and the control group. Plasma 8‐isoprostane and 3‐nitrotyrosine levels were significantly (p &lt; 0.05) reduced in the sodium nitrite + hydralazine group compared to the HFpEF control group, indicating a reduction in oxidative and nitrosative stress. Although there was no significant difference in the extent of interstitial cardiac fibrosis between groups, there was a significant decrease (p &lt; 0.05) in myocardial perivascular fibrosis in the sodium nitrite + hydralazine group compared to control. Left ventricular end‐diastolic pressure (LVEDP) was significantly reduced in all treatment groups, and LVEDP was reduced to the greatest extent in the nitrite + hydralazine group vs. HFpEF control. Furthermore, we observed a significant (p &lt; 0.01) improvement in LV diastolic function (i.e., E/e’) in the sodium nitrite and hydralazine group that was superior to either of the treatments alone. There was no significant difference in the exercise distance or duration among the various groups.ConclusionThese data demonstrate that the combination of a powerful antioxidant with NO donor therapy significantly enhances the beneficial effects NO therapy in the setting of severe HFpEF.

The effects of orally administered lactoferrin in the prevention and management of viral infections: A systematic review.

SummaryIt has been demonstrated that lactoferrin (LF) plays a role in host defence, but evidence on its potential antiviral property from clinical studies is fragmented. Our systematic review aimed at identifying the effects of orally administered LF against virus infections. The systematic search was conducted on PubMed, Scopus, Web of Science, BioRxiv.org and ClinicalTrials.gov from database inception to 7th January 2021. Eligible articles investigated any virus family and provided data on the effects of orally administered LF of any origin in the prevention and/or management of confirmed viral infections in people of any age. A narrative synthesis of the results was performed. Quality was assessed with the Cochrane Risk‐Of‐Bias and ROBINS‐1 tools. A total of 27 records were included, nine of which were registered protocols. We found data on Flaviviridae (n = 10), Retroviridae (n = 3), Coronaviridae (n = 2), Reoviridae (n = 2) and Caliciviridae (n = 1). Most published trials were at high risk of bias. The findings were heterogeneous across and within viral families regarding virological, immunological and biological response, with no clear conclusion. Some weak but positive results were reported about decrease of symptom severity and duration, or reduction in viral loads. Despite high tolerability, the effects of LF as oral supplement are still inconsistent, both in preventing and managing viral infections. Small sample sizes, variety in recruitment and treatment protocols, and low study quality may have contributed to such heterogeneity. Better‐designed studies are needed to further investigate its potential benefits against viral infections, including SARS‐CoV‐2.

The Effects of Combined Physical Exercise on Serum Redox Biomarkers and Leukocyte DNA Damage of Obese Women.

Obesity is usually linked to oxidative stress, which can lead to damage to biomolecules. The combination of aerobic and strength exercises seems to induce health benefits in obese individuals, but little is known about the effects of combined physical exercise on redox homeostasis and DNA damage in this population. Thus, the aim of the current study was to determine the effects of 16 weeks of combined physical exercise on biomarkers of oxidative stress and DNA damage in obese women. 17 obese women underwent 16 weeks of a combined physical training program, 3 times per week. Anthropometric and biochemical parameters, serum superoxide dismutase (SOD) and glutathione peroxidase activity, plasma 8-isoprostane levels, and DNA and chromosomal damage were evaluated before and after physical training. Combined physical exercise training decreased body weight (83.2 ± 9.6 vs. 80.2 ± 9.6 kg), body mass index (33.8 ± 3.6 vs. 32.6 ± 3.7 kg·m−2), body fat (40.2 ± 2.6 vs. 39.0 ± 3.2%), and waist circumference (99.3 ± 9.4 vs. 94.1 ± 8.8 cm), while the fat-free mass was augmented (59.9 ± 2.9 vs. 60.7 ± 3.1 kg). Moreover, blood glucose reduced (113.5 ± 29.6 vs. 107.3 ± 28.9 mg/dL) along with high-density lipoprotein (54.6 ± 18.1 vs. 59.0 ± 18.8 mg/dL), TSH (2.1 ± 1.1 vs. 2.6 ± 1.2 mIU/mL), and free T4 (0.9 ± 0.1 vs. 1.12 ± 0.2 ng/dL) increase after physical exercise training. Plasma 8-isoprostane levels (17.24 ± 7.9 vs. 29.11 ± 17.44 pg/mL) and DNA damage (34.16 ± 7.1 vs. 45.96 ± 5.8% DNA in tail) were also higher after physical training. No changes were observed in chromosomal damage levels. These results suggest that 16 weeks of combined exercise training 3 times per week is effective in reducing body fat but also increases oxidative stress and DNA damage in obese women.

Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats.

We determined if HIV-1 expression in transgenic (HIV-1-Tg) rats enhanced hepatic genomic changes related to oxidative/nitrosative stress and lipogenesis during cART-treatment, and assessed effects of Mg-supplementation. A clinically used cART (atazanavir-ritonavir+Truvada) was given orally to control and HIV-1-Tg rats (18 weeks) with normal or 6-fold dietary-Mg. Oxidative/nitrosative and lipogenic genes were determined by real-time RT-PCR. cART induced a 4-fold upregulation of sterol regulatory element-binding protein-1 (SREBP-1) in HIV-1-Tg-rats, but not in controls; Tg rats displayed a 2.5-fold higher expression. Both were completely prevented by Mg-supplementation. Nrf2 (Nuclear erythroid-derived factor 2), a master transcription factor controlling redox homeostasis, was down-regulated 50% in HIV-Tg rats, and reduced further to 25% in Tg+cART-rats. Two downstream antioxidant genes, heme oxygenase-1(HmOX1) and Glutathione-S-transferase(GST), were elevated in HIV-Tg alone but were suppressed by cART treatment. Decreased Nrf2 in Tg±cART were normalized by Mg-supplementation along with the reversal of altered HmOX1 and GST expression. Concomitantly, iNOS (inducible nitric oxide synthase) was upregulated 2-fold in Tg+cART rats, which was reversed by Mg-supplementation. In parallel, cART-treatment led to substantial increases in plasma 8-isoprostane, nitrotyrosine, and RBC-GSSG (oxidized glutathione) levels in HIV-1-Tg rats; all indices of oxidative/nitrosative stress were suppressed by Mg-supplementation. Both plasma triglyceride and cholesterol levels were elevated in Tg+cART rats, but were lowered by Mg-supplementation. Thus, the synergistic effects of cART and HIV-1 expression on lipogenic and oxidative/nitrosative effects were revealed at the genomic and biochemical levels. Down-regulation of Nrf2 in the Tg+cART rats suggested their antioxidant response was severely compromised; these abnormal metabolic and oxidative stress effects were effectively attenuated by Mg-supplementation at the genomic level.

Naringin Activates AMPK Resulting in Altered Expression of SREBPs, PCSK9, and LDLR To Reduce Body Weight in Obese C57BL/6J Mice.

Previous investigations have shown molecular cross-talk among activated adenosine monophosphate-activated protein kinase (AMPK), proprotein convertase subtilisin/kexin type 9 (PCSK9), sterol regulatory element-binding proteins (SREBPs), and low-density lipoprotein receptor (LDLR) and that it may be an innovative pharmacologic objective for treating obesity. We scrutinized the beneficial effect of naringin, a flavanone-7- O-glycoside, on obesity and the mechanisms in the present study. We arbitrarily divided 50 mice into five groups ( n = 10): 25 or 50 or 100 mg/kg/day naringin-treated obese mice (gavage for 8 weeks), untreated obese mice, and C57BL/6J control. After 8 weeks, body weight was 51.8 ± 4.4 in the untreated obese mice group, while the weights were 41.4 ± 4.1, 34.6 ± 2.2, and 28.0 ± 2.3 in 25, 50,100 mg/kg naringin groups, respectively. Moreover, naringin treatment significantly decreased plasma 8-isoprostane (an indicator of the oxidative stress) level, fat weight, liver weight, hepatic total cholesterol concentration, hepatic triglyceride concentration, plasma leptin level, plasma insulin content, plasma low-density lipoprotein cholesterol level, and plasma PCSK9 production concomitantly with down-regulated expression of SREBP-2, PCSK9, and SREBP-1, and up-regulated expression of p-AMPKα and LDLR. The present results suggest that naringin activates AMPK resulting in altered expression of SREBPs, PCSK9, and LDLR to reduce the body weight of obese C57BL/6J mice.

APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury

Recent studies have suggested that renal Nox is important in the progression of diabetic nephropathy. Therefore, we investigated the effect of a novel pan-NOX-inhibitor, APX-115, on diabetic nephropathy in type 2 diabetic mice. Eight- week-old db/m and db/db mice were treated with APX-115 for 12 weeks. APX-115 was administered by oral gavage at a dose of 60 mg/kg per day. To compare the effects of APX-115 with a dual Nox1/Nox4 inhibitor, db/db mice were treated with GKT137831 according to the same protocol. APX-115 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion, but GKT137831 did not. In addition, F4/80 infiltration in the adipose tissue and kidney decreased with APX-115 treatment. We also found that TGF-β stimulated ROS generation in primary mouse mesangial cells (pMMCs) from wild-type, Nox1 KO, and Duox1 KO mice, but did not induce Nox activity in pMMCs from Nox2 knockout (KO), Nox4 KO, or Duox2 KO mice. These results indicate that activating Nox2, Nox4, or Duox2 in pMMCs is essential for TGF-β-mediated ROS generation. Our findings suggest that APX-115 may be as effective or may provide better protection than the dual Nox1/Nox4 inhibitor, and pan-Nox inhibition with APX-115 might be a promising therapy for diabetic nephropathy.

Anti-aging and redox state regulation effects of A-type proanthocyanidins-rich cranberry concentrate and its comparison with grape seed extract in mice

We investigated the anti-aging and redox state regulation effects by A-type proanthocyanidins (PACs)-rich cranberry concentrate (CBC) and its comparison with B-type PACs-rich grape seed extract (GSE). Using the Q-Extractive mass spectrometry, PACs dimer A and B were identified as predominant phenolic compounds of CBC and GSE, respectively, while epicatechin was present in both extracts. Using the d-galactose-induced aging mice model, effects were investigated via an 8-week oral gavage considering water-soluble vitamin E as the positive control. Both CBC and GSE reduced hepatic and brain thiobarbituric acid reactive substances, and plasma 8-isoprostane levels by 30–57%, 24–30% and 11–62%, respectively, and decreased brain and plasma monoamine oxidase activities by 27–59% and 65–71%, respectively. CBC could improve hepatic glutathione peroxidase activity by 42%, while GSE increased hepatic superoxide dismutase activity by 13%. Therefore, both extracts exerted anti-aging effects probably via regulating in vivo redox state. However, neither generated any effect on catalase activities.

Antioxidant potential of dietary chia seed and oil (Salvia hispanica L.) in diet-induced obese rats

This study aimed to investigate the effects of dietary chia seed and oil on plasma and liver oxidative status in diet-induced obese rats. Thirty-six Wistar rats were divided in six groups (6 animals each): control group was fed the American Institute of Nutrition (AIN)-93M diet; HFF group was fed a high-fat and high-fructose (HFF) diet; chia seed short (6-weeks) and long (12-weeks) treatments received an HFF diet with chia seed; chia oil short (6-weeks) and long (12-weeks) treatments received an HFF diet with chia oil. Plasma and hepatic biomarkers of lipid peroxidation, endogenous enzymatic and non-enzymatic antioxidant systems and antioxidant capacity were determined. HFF diet induced weight gain, oxidative stress and lipid peroxidation in plasma and liver of animals. Compared to HFF group chia seed and chia oil (12 and 6weeks) intake increased plasma reduced thiol (GSH) levels, plasma catalase (CAT) and glutathione peroxidase (GPx) activities. In the liver glutathione reductase (GRd) activity was enhanced, while CAT and GPx activities did not change. There were no differences in plasma and liver superoxide dismutase activity among chia diets and HFF group. Chia (seed and oil) intake did not modify liver lipid peroxidation, but was able to reduce plasma thiobarbituric acid reactive substances (TBARS) and 8-isoprostane levels increased by HFF group. Plasma and hepatic antioxidant capacity values were increased in chia seed and oil groups about 35% and 47%, respectively, compared to HFF group. Chia groups presented similar antioxidant potential, regardless of treatment time. Dietary chia seed and oil reduced oxidative stress in vivo, since it improved antioxidant status and reduced lipid peroxidation in diet-induced obese rats.

Efficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: Results of a double blind, placebo-controlled trial

BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased airway and systemic inflammation. There is evidence that erdosteine accelerates recovery from AECOPD by reducing airway inflammation. AimTo investigate the dose-dependent antioxidant/anti-inflammatory activity of erdosteine in COPD patients. MethodsIn this single-centre, double blind, double dummy study, patients with mild-to-moderate COPD (GOLD stage II–III), were randomised to receive either placebo or two dosages of oral erdosteine (300 mg tid or 300 mg bid + 1 capsule of indistinguishable placebo) for 28 days in addition to their standard treatment. Primary variables were plasma reactive oxygen species (ROS) and 8-isoprostane levels, while secondary variable was lung function (FEV1; FEV1/FVC; FEV1 short-term reversibility), all assessed in baseline; every two weeks during the study, and one week after the end of the study. ResultsBaseline demographic characteristics, plasma ROS and 8-isoprostane levels and lung function were not significantly different in the 24 eligible patients (14 males, aged 38–75 years). At 2 weeks, there was a dose-dependent decrease in ROS in the erdosteine groups. By week 4 there were significant differences in ROS levels compared to baseline between patients receiving 900 mg/day (p < 0.003) and those receiving 600 mg/day (p < 0.04). This effect continued in the follow-up week (p < 0.021). Erdosteine also lowered 8-isoprostane plasma levels after 4 weeks (p < 0.01), and this effect lasted over the post-treatment week. Moreover, % FEV1 reversibility after salbutamol 400 mcg obtained after a 4 -week treatment of erdosteine 900 mg/day was significantly higher than that obtained after 600 mg/day (p < 0.01). Erdosteine was well tolerated and no treatment-related adverse event was reported. ConclusionsResults confirm the antioxidant dose- and time-dependent activity of erdosteine, and support the utility of including erdosteine it in the therapeutic strategy for the prevention and treatment of oxidative stress-induced inflammation, which frequently leads to AECOPD occurrence.

Consistent antioxidant and antihypertensive effects of oral sodium nitrite in DOCA-salt hypertension

Hypertension is a common disease that includes oxidative stress as a major feature, and oxidative stress impairs physiological nitric oxide (NO) activity promoting cardiovascular pathophysiological mechanisms. While inorganic nitrite and nitrate are now recognized as relevant sources of NO after their bioactivation by enzymatic and non-enzymatic pathways, thus lowering blood pressure, mounting evidence suggests that sodium nitrite also exerts antioxidant effects. Here we show for the first time that sodium nitrite exerts consistent systemic and vascular antioxidant and antihypertensive effects in the deoxycorticosterone-salt (DOCA-salt) hypertension model. This is particularly important because increased oxidative stress plays a major role in the DOCA-salt hypertension model, which is less dependent on activation of the renin-angiotensin system than other hypertension models. Indeed, antihypertensive effects of oral nitrite were associated with increased plasma nitrite and nitrate concentrations, and completely blunted hypertension-induced increases in plasma 8-isoprostane and lipid peroxide levels, in vascular reactive oxygen species, in vascular NADPH oxidase activity, and in vascular xanthine oxidoreductase activity. Together, these findings provide evidence that the oral administration of sodium nitrite consistently decreases the blood pressure in association with major antioxidant effects in experimental hypertension.

Grape powder treatment prevents anxiety-like behavior in a rat model of aging

Earlier, we have reported that grape powder (GP) treatment prevented pharmacologic and psychological stress-induced anxiety-like behavior and memory impairment in rats. Protective effects of GP were attributed to its antioxidant effects. In this study, we tested the hypothesis that age-associated behavioral and cognitive deficits such as anxiety and memory impairment will be ameliorated with GP treatment. Using a National Institute of Aging recommended rodent model of aging, we examined a potentially protective role of antioxidant-rich GP in age-associated anxiety-like behavior and memory impairment. Male Fischer 344 rats were randomly assigned into 4 groups: young rats (3 months old) provided with tap water or with 15 g/L GP dissolved in tap water for 3 weeks, aged rats (21 months old) provided with tap water or with GP-treated tap water for 3 weeks (AG-GP). Anxiety-like behavior was significantly greater in aged rats compared with young rats, GP-treated young rats, or aged control rats (P < .05). Also, GP treatment prevented age-induced anxiety-like behavior in AG-GP rats (P < .05). Neither short-term nor long-term age-associated memory deficits improved with GP treatment in AG-GP rats. Furthermore, aged rats showed increased level of physiological stress (corticosterone) and increased oxidative stress in the plasma (8-isoprostane) as well as in selected brain areas (protein carbonylation). Grape powder treatment prevented age-induced increase in corticosterone levels and plasma 8-isoprostane levels in aged rats (P < .05), whereas protein carbonylation was recovered in the amygdala region only (P < .05). Grape powder by regulating oxidative stress ameliorates age-induced anxiety-like behavior in rats, whereas age-associated memory deficits seem unaffected with GP treatment.

Fermented sea tangle attenuates oxidative stress in individuals with a high level of γ-glutamyltransferase: A randomized, double-blind, and placebo-controlled clinical study

A randomized, double-blind, placebo-controlled study of fermented sea tangle (FST) was conducted using 48 healthy volunteers with high levels of γ-glutamyltransferase (GGT). Participants (n=48) were divided into a placebo group and a FST group, which consumed FST (1.5 g/day) for 4 weeks. Serum GGT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were determined. Plasma 8-isoprostane, 8-hydroxydeoxyguanosine (8-OHdG), and protein carbonyl contents, which indicate lipid peroxidation, DNA damage, and oxidation of protein, were determined. Decreased serum GGT was found in FST consumption group, compared to the placebo group [mean values (IU/L): 78.71±19.14 and 116.75±38.55, respectively, p<0.001]. Administration of FST significantly (p<0.05) decreased levels of serum AST [mean values (IU/L): 31.08±7.25 and 26.79±6.53 respectively, p<0.001] and ALT [mean values (IU/L): 42.63±18.99 and 31.83±14.21, respectively, p=0.001], compared to the placebo group, and significantly (p<0.05) decreased concentrations of plasma 8-isoprostane, 8-OHdG, and protein carbonyl levels.

Plasma 8-isoprostane levels are associated with endothelial dysfunction in resistant hypertension

BackgroundImpaired endothelial function and arterial stiffness are associated with hypertension and are important risk factors for cardiovascular events. Reactive oxygen species reduce nitric oxide bioavailability and have a pivotal role in endothelial function. Resistant hypertension (RHTN) is characterized by blood pressure (BP) above goal (140/90mmHg) in spite of the concurrent use of ≥3 antihypertensive drugs of different classes. This study evaluated the association between 8-isoprostane levels, an oxidative stress marker, endothelial function and arterial stiffness, in RHTN. MethodsNinety-four RHTN and 55 well-controlled hypertensive (HT) patients were included. Plasma 8-isoprostane levels were determined by ELISA. Also, flow-mediated dilation (FMD) and pulse wave velocity (PWV) were evaluated to determine endothelial function and arterial stiffness, respectively. ResultsLevels of 8-isoprostane were markedly higher in RHTN compared to HT patients (22.5±11.2 vs. 17.3±9.8pg/ml, p<0.05, respectively). A significant inverse correlation was observed between FMD and 8-isoprostane (r=−0.35, p=0.001) in RHTN. Finally, multiple logistic regression revealed that 8-isoprostane was a significant predictor of endothelial dysfunction (FMD≤median) in RHTN group. ConclusionRHTN showed markedly higher oxidative stress measured by 8-isoprostane, compared to HT patients. Taken together, our findings suggest the involvement of oxidative stress in endothelial function in RHTN.

PPARγ and NAD(P)H oxidase system interaction in glycerol-induced acute renal failure: role of gp91phox subunit of NAD(P)H oxidase

Increased NAD(P)H oxidase-dependent free radical generation has been proposed to be a mechanism in glycerol-induced acute renal failure (ARF). Previously, we showed a PPARγ-mediated regulation of free radical generation in ARF. In this study, we examined NAD(P)H oxidase-dependent pathology in ARF and its connection with PPARγ using both Sprague–Dawley rats and gp91phox (+/−) mice. Male gp91phox (+/−) or wild type (+/+) mice were distributed into vehicle and ARF group (50% glycerol; 8 mL/kg bw; i.m.). Animals were placed in metabolic cages for 24 hr and were sacrificed under pentobarbital anesthesia. Urine, plasma and kidneys were processed for biochemical and molecular analysis. Glycerol doubled proteinuria in (+/+) mice (68 ± 4 mg/24 hr) but not in (+/−) mice (43 ± 9 mg/24 hr). This was associated with a markedly reduced creatinine excretion in (+/+) mice (Con: 0.6 ± 0.03 & ARF: 0.37 ± 0.02). Basal plasma and urinary NO was higher in (+/−) mice than the (+/+) type while plasma 8-isoprostane level was lower in (+/−) mice (WT: 165 ± 20; KO: 100 ± 15 pg/mL). Glycerol reduced UNOXV in both (+/+) and (+/−) mice although plasma NO was unchanged. Glycerol also doubled 8-isoprostane in (+/+) (363 ± 22 pg/mL) but not in (+/−) mice (152 ± 20 pg/mL) and this was associated with an increased NAD(P)H oxidase activity in the (+/+) mice. In ARF, PPARγ expression was reduced in (+/+) mice but increased in (+/−) mice. PPARγ activity was also reduced in (+/+) mice but was unchanged in (+/−) mice. We conclude that gp91phox contributes to NAD(P)H oxidase-mediated increased free radical generation in ARF and this may be via reduced PPARγ.

T₃-induced liver AMP-activated protein kinase signaling: redox dependency and upregulation of downstream targets.

To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver. Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T3. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA). T3 upregulates AMPK signaling, including the upstream kinases Ca(2+)-calmodulin-dependent protein kinase kinase-β and transforming growth factor-β-activated kinase-1, with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1α (CPT-1α) activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO. T3 administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T3 preconditioning against ischemia-reperfusion injury.

Comparison of the effect of simvastatin versus simvastatin/ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia

ObjectivesStatins may exhibit anti-inflammatory and antioxidant effects. Whether different statins at equivalent doses or the combination of low-dose statin with ezetimibe have comparable anti-inflammatory and antioxidant effects is unknown. The aim of this study was to compare the effects of simvastatin, simvastatin/ezetimibe or rosuvastatin at equivalent low-density lipoprotein cholesterol lowering doses on inflammation and oxidative stress indices in subjects with hypercholesterolemia. MethodsThis was a pre-specified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study. We enrolled one hundred and fifty three (n = 153) hypercholesterolemic subjects who were randomized to receive simvastatin 40 mg or simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg daily. Plasma 8-Epi prostaglandin F2 alpha (8-epiPGF2a), oxidized LDL (oxLDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass were measured at baseline and following 12 weeks of treatment. ResultsA significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [by 10%, 8% and 6% (p < 0.05 compared with baseline) and 41%, 40% and 39% (p < 0.001 compared with baseline) in simvastatin, simvastatin/ezetimibe and rosuvastatin groups, respectively]. In all treatment groups a significant reduction in total plasma Lp-PLA2 activity and mass was observed (by 36%, 31% and 38% and 36%, 32% and 32% for simvastatin, simvastatin/ezetimibe and rosuvastatin, respectively, p < 0.001 compared with baseline). No intergroup differences were observed. ConclusionsSimvastatin 40 mg, simvastatin/ezetimibe 10/10 mg and rosuvastatin 10 mg significantly reduced 8-epiPGF2a, oxLDL and Lp-PLA2 activity and mass to a similar extent.