8-isoprostane Levels Research Articles

High urinary oxidative DNA damage in wild chimpanzees ranging in proximity of agricultural fields in Sebitoli area, Uganda.

Agriculture expansion is a major cause of habitat loss and exposure to phytochemical pollution for non-human primates. In addition to endocrine disruption, exposure to pesticides may have other sublethal physiological consequences for animals, such as generation of oxidative damage to macromolecules. In this study, we analyzed the pesticides contained in the river water across the home range of wild chimpanzees (Pan troglodytes) in Sebitoli area located on the Northern part of Kibale National Park (Uganda). We tested whether levels of three urinary markers of oxidative damage vary among individuals in relation to their ranging patterns, as a proxy for pesticide exposure intensity. To better characterize the foraging habitat use, the trophic level, and the energetic status of study individuals, we also quantified urinary levels of carbon and nitrogen stable isotope signatures and of C-peptide. Among the 511 pesticides screened, 18 compounds including herbicides, insecticides, and fungicides were found in the water sampled in the Western part of the home range of chimpanzees. In this area, chimpanzees used to feed on maize crops. By contrast, in the Eastern part where crop feeding was never observed, we found only seven pesticides. According to their ranging patterns and thus crop feeding frequency, the 139 urine samples collected from 43 Sebitoli chimpanzees were categorized as belonging to low, medium, and high exposure level. Chimpanzees from the high exposure zone had higher oxidative DNA damage (8-OHdG) than chimpanzees from both the low and medium exposure groups, who had similar levels of oxidative DNA damage. In addition, individuals with higher C-peptide tended to have significantly higher oxidative DNA damage and lipid peroxides. The three exposure groups had similar levels of urinary 8-isoprostanes and of urinary lipid peroxides. These results were robust for any potential confounding effect of other variables because neither age category nor sex or isotope levels were significantly associated with markers of oxidative damage. Our study points to genotoxic effects as one potential sublethal consequence of ranging in proximity of agricultural fields owing to exposure to pesticides or other unidentified sources of stress. Given our phylogenetic proximity, this information is relevant for the conservation of this species which is endangered and also sentinel for human health.

6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Alleviates Oxidative Stress and NF-κB-Mediated Inflammation in Rats with Experimental Parkinson's Disease.

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) factor, and the inflammatory response in rats during the development of rotenone-induced Parkinsonism. The findings indicate that HTHQ, with its antioxidant attributes, reduced the levels of 8-isoprostane, lipid oxidation products, and protein oxidation products. The decrease in oxidative stress due to HTHQ led to a reduction in the mRNA content of proinflammatory cytokines and myeloperoxidase activity, accompanying the drop in the expression of the factor NF-κB. These alterations promoted an improvement in motor coordination scores and increased tyrosine hydroxylase levels, whereas histopathological changes in the brain tissue of the experimental animals were attenuated. HTHQ exhibited greater effectiveness than the comparative drug rasagiline based on the majority of variables.

Metabolic syndrome, adiposity, diet, and emotional eating are associated with oxidative stress in adolescents.

Metabolic syndrome (MS), a condition related to adiposity and oxidative stress, can develop in adolescence, a critical stage in life that impacts health in adulthood. However, there is scarce scientific research about the relationship between lifestyle factors, emotion management, and oxidative stress in this phase of life. To analyze whether nutritional parameters, lifestyle factors, emotion management, and MS in adolescents are associated with oxidative stress measured by the biomarker 8-isoprostane. A cross-sectional study was carried out in 132 adolescents (48.5% girls, aged 12 ± 0.48 years) and data were collected on nutritional parameters (anthropometric measurements, biochemical analyzes, and blood pressure), lifestyle factors (physical activity, sleep, and diet), and emotion management (self-esteem, emotional eating, and mood). 8-isoprostane was analyzed in spot urine samples. The study population was categorized in three groups (healthy, at-risk, and with MS) using the International Diabetes Federation definition of MS in adolescents. To capture more complex interactions, a multiple linear regression was used to analyze the association between 8-isoprostane and the aforementioned variables. Urinary 8-isoprostane levels were significantly higher in the MS group compared to the healthy group (1,280 ± 543 pg./mg vs. 950 ± 416 pg./mg respectively). In addition, univariable analysis revealed positive significant associations between 8-isoprostane and body mass index, waist circumference, waist-to-height ratio, body fat percentage, blood lipid profile and glucose, emotional eating, and refined cereal intake. Conversely, a negative significant association was found between 8-isoprostane and sleep duration and fish intake. The multiple linear regression analysis revealed associations between 8-isoprostane and LDL-c (β = 0.173 value of p = 0.049), emotional eating (low β = 0.443, value of p = 0.036; high β = 0.152, value of p = 0.470), refined cereal intake (β =0.191, value of p = 0.024), and fish intake (β = -0.187, value of p = 0.050). The MS group, LDL-c, emotional eating, and high refined cereals and low fish intakes were associated with higher levels of oxidative stress in an adolescent population.

Oxidative stress in rat brain during experimental status epilepticus: effect of antioxidants.

Antioxidants have been proposed as a treatment for diseases of the central nervous system. However, few studies actually studied their effects in the brain. To test central actions of antioxidants, we used the lithium-pilocarpine (Li-Pilo) model of status epilepticus (SE) in the rat in which seizures are accompanied by significant oxidative stress. We used in vivo microdialysis to determine isoprostane levels during SE in real time and brain homogenates for other measures of oxidative stress. Six different antioxidants were tested in acute and preventive experiments (vitamin C, vitamin E, ebselen, resveratrol, n-tert-butyl-α-phenylnitrone and coenzyme Q10). None of the antioxidants had an effect when given acutely during SE. In contrast, when antioxidants were given for 3days prior to seizure induction, vitamins C and E reduced isoprostane formation by 58% and 65%, respectively. Pretreatment with the other antioxidants was ineffective. In brain homogenates prepared after 90min of seizures, SE decreased the ratio of reduced vs. oxidized glutathione (GSH/GSSG ratio) from 60.8 to 7.50 and caused a twofold increase of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and protein carbonyls. Pretreatment with vitamin C or vitamin E mitigated these effects and increased the GSH/GSSG ratio to 23.9 and 28.3, respectively. Again, the other antioxidants were not effective. We conclude that preventive treatment with vitamin C or vitamin E ameliorates seizure-induced oxidative damage in the brain. Several well-studied antioxidants were inactive, possibly due to limited brain permeability or a lack of chain-breaking antioxidant activity in hydrophilic compounds.

Advancing Perfusion Models: Dual-Vessel Ex Vivo Rat Liver Perfusion Based on a Clinical Setup.

Normothermic ex vivo liver machine perfusion (NEVLP) has been developed to address the increasing organ shortage in liver transplantation, through optimal preservation, assessment, and conditioning of grafts from extended criteria donors. There remains a need to establish simple and standardized animal models that simulate clinical NEVLP to test novel therapies. Liver grafts from 36 Sprague-Dawley rats were perfused for 6 h in a dual-vessel NEVLP system with a Dulbecco's modified Eagles medium-based perfusate supplemented with rat plasma and erythrocytes. Varying doses of the clinically used vasodilator epoprostenol, Kupffer cell inhibitor glycine, and a Steen™-based perfusate were assessed. Perfusion pressures and bile production were recorded, and perfusate was analyzed for transaminase secretion. Tissue samples were evaluated histologically, and levels of cytokines and 8-Isoprostane were measured. Increasing levels of epoprostenol and the addition of glycine resulted in a stepwise decrease of transaminase secretion and improved bile production. Steen further decreased transaminase release and interleukin 1 beta levels. Liver grafts perfused with the optimized Steen-based protocol exhibited lowest levels of oxidative stress and best-preserved liver integrity. In conclusion, epoprostenol seemed to ameliorate liver function and prevent cellular damage beyond its vasodilatory effect, with glycine acting synergistically. The anti-inflammatory and antioxidative properties of Steen further improved the outcome of perfusion. Our rodent NEVLP system may be used to rapidly test new agents for the pharmacologic conditioning of livers and help translate findings from bench-to-bedside.

Pan-Nox inhibitor treatment improves renal function in aging murine diabetic kidneys.

Aging is a risk factor for development of chronic kidney disease and diabetes mellitus with commonly shared features of chronic inflammation and increased oxidative stress. Here, we investigated the effect of pan-Nox-inhibitor, APX-115, on renal function in aging diabetic mice. Diabetes was induced by intraperitoneal injection of streptozotocin at 50 mg/kg/day for 5 days in 52-week-old C57BL/6J mice. APX-115 was administered by oral gavage at a dose of 60 mg/kg/day for 12 weeks in nondiabetic and diabetic aging mice. APX-115 significantly improved insulin resistance in diabetic aging mice. Urinary level of 8-isoprostane was significantly increased in diabetic aging mice than nondiabetic aging mice, and APX-115 treatment reduced 8-isoprostane level. Urinary albumin and nephrin excretion were significantly higher in diabetic aging mice than nondiabetic aging mice. Although APX-115 did not significantly decrease albuminuria, APX-115 markedly improved mesangial expansion, macrophage infiltration, and expression of fibrosis molecules such as transforming growth factor beta 1 and plasminogen activator inhibitor 1. Interestingly, the expression of all Nox isoforms including Nox1, Nox2, and Nox4 was significantly increased in diabetic aging kidneys, and APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. Furthermore, Klotho expression was significantly decreased in diabetic aging kidneys, and APX-115 restored Klotho level. Our results provide evidence that pan-Nox inhibition may improve systemic insulin resistance and decrease oxidative stress, inflammation, and fibrosis in aging diabetic status and may have potential protective effects on aging diabetic kidney.

Elevated leukotriene B4 and 8-isoprostane in exhaled breath condensate from preterm-born infants

BackgroundInflammation and oxidative stress play a key role in the development of bronchopulmonary dysplasia (BPD), possibly contributing to persistent respiratory morbidity after preterm birth. We aimed to assess if inflammatory markers were elevated in exhaled breath condensate (EBC) of infants born very prematurely (< 32 weeks gestation) at 12–16 corrected months of age, and if increased levels were associated with BPD diagnosis and respiratory morbidity.MethodsEBC samples and respiratory questionnaires were collected from 15 term-born infants and 33 preterm-born infants, 12 with a neonatal BPD diagnosis. EBC samples were analysed for leukotriene B4 (inflammation) and 8-isoprostane (oxidative stress) concentrations using enzyme-linked immune-assays. Differences between groups were analysed by Kruskal-Wallis Test with post-hoc comparisons, independent samples t-test or Mann-Whitney U test depending on normality of the data.ResultsLeukotriene B4 and 8-isoprostane levels were elevated in exhaled breath condensate of preterm-born infants compared to those born at term (mean difference [95% CI]; 1.52 [0.45, 2.59], p = 0.02; 0.77 [0.52, 1.02], p < 0.001, respectively). Leukotriene B4 and 8-isoprostane levels were independent of BPD diagnosis and respiratory morbidity over the first year of life.ConclusionsInfants born very prematurely exhibit elevated markers of airway neutrophilic inflammation and oxidative stress beyond the first year of life, regardless of a neonatal diagnosis of chronic lung disease or respiratory morbidity during infancy. These findings may have implications for future lung health.Trial RegistrationN/A.

Oxidative Stress Response Kinetics after 60 Minutes at Different (1.4 ATA and 2.5 ATA) Hyperbaric Hyperoxia Exposures.

Hyperbaric oxygen therapy (HBOT) is a therapeutical approach based on exposure to pure oxygen in an augmented atmospheric pressure. Although it has been used for years, the exact kinetics of the reactive oxygen species (ROS) between different pressures of hyperbaric oxygen exposure are still not clearly evidenced. In this study, the metabolic responses of hyperbaric hyperoxia exposures for 1 h at 1.4 and 2.5 ATA were investigated. Fourteen healthy non-smoking subjects (2 females and 12 males, age: 37.3 ± 12.7 years old (mean ± SD), height: 176.3 ± 9.9 cm, and weight: 75.8 ± 17.7 kg) volunteered for this study. Blood samples were taken before and at 30 min, 2 h, 24 h, and 48 h after a 1 h hyperbaric hyperoxic exposure. The level of oxidation was evaluated by the rate of ROS production, nitric oxide metabolites (NOx), and the levels of isoprostane. Antioxidant reactions were assessed through measuring superoxide dismutase (SOD), catalase (CAT), cysteinylglycine, and glutathione (GSH). The inflammatory response was measured using interleukine-6, neopterin, and creatinine. A short (60 min) period of mild (1.4 ATA) and high (2.5 ATA) hyperbaric hyperoxia leads to a similar significant increase in the production of ROS and antioxidant reactions. Immunomodulation and inflammatory responses, on the contrary, respond proportionally to the hyperbaric oxygen dose. Further research is warranted on the dose and the inter-dose recovery time to optimize the potential therapeutic benefits of this promising intervention.

The Relationship of Preconception and Early Pregnancy Isoprostanes with Fecundability and Pregnancy Loss.

Although redox stress likely plays an important role in reproductive health, the utility of peripheral biomarkers of oxidative stress, such as isoprostanes, during the periconception period remains underexplored. We evaluated the relationship between isoprostanes during preconception and gestational week 4 and women's reproductive health outcomes. The Effects of Aspirin in Gestation and Reproduction trial (2007-2011) enrolled 1228 women attempting pregnancy and followed them for up to 6 menstrual cycles and throughout pregnancy if they became pregnant. We measured creatinine-adjusted, log-transformed isoprostanes 8-iso-prostaglandin F 2α (8-iso-PGF2α), its metabolite 2,3-dinor-iPF2α-III, and stereoisomers 5-iso-PGF2α-VI and 8,12-iso-iPF2α-VI in urine during preconception and 4 weeks gestation. We evaluated pregnancy among participants in each menstrual cycle using human chorionic gonadotropin (hCG) and defined pregnancy loss as observed loss following positive hCG. We calculated fecundability odds ratios (FOR) and 95% confidence intervals (CI) using discrete-time Cox proportional hazards models and relative risk of pregnancy loss using adjusted log-binomial models. Higher preconception isoprostane levels were associated with lower fecundability [e.g., FOR = 0.89; 95% CI = 0.81, 0.97 per interquartile range (IQR) increase in 8-iso-PGF2α]. Among 797 pregnancies, isoprostane levels increased from preconception to 4 weeks gestation (e.g., mean difference = 0.12; 95% CI = 0.10, 0.14 ng/mL for 8-iso-PGF2α) and higher isoprostanes at 4 weeks gestation were associated with lower risk of pregnancy loss (e.g., RR = 0.79; 95% CI = 0.62, 1.00 per IQR increase in 8-iso-PGF2α). Preconception urinary isoprostanes may identify redox stress pathways associated with lower fecundability. However, the increase in isoprostanes into gestational week 4 and the associated lower risk of pregnancy loss may suggest confounding by latent factors in early pregnancy.

THE EVALUATION OF THE EFFECT OF THE TREATMENTS ON OXIDATIVE STRESS AND INFLAMMATION IN PATIENTS RECEIVING DIFFERENT DIALYSIS MODALITIES

ABSTRACT&#x0D; Aim: To evaluate the effects of different dialysis methods on oxidative stress and inflammation in patients with end-stage renal disease (ESRD) who are newly enrolled in a routine dialysis program.&#x0D; Material and Methods: In this prospective study, 138 ESRD patients and 30 healthy volunteers were evaluated. Fifty-four of 73 hemodialysis (HD) patients and 51 of 65 periton dialysis (PD) patients completed the study. Other patients were excluded from the study. The levels of superoxide dismutase (SOD) and total antioxidant capacity (TAC) were measured to determine the oxidative stress status, and IL-6, IL-10, and F2 isoprostane levels were measured to determine the inflammation status, just before the start of dialysis treatment and at 6 months.&#x0D; Results: At the beginning of the study, hs-CRP and IL-6 levels were significantly higher in the patient group compared to the control group (p

The Effect of Dietary Patterns and Nutrient Intake on Oxidative Stress Levels in Pregnant Women: A Systematic Review.

During pregnancy, reactive oxygen species (ROS) may physiologically increase due to changes and growth of mother and fetal tissues. Consequently, oxidative stress (OS) may occur and be involved in the onset of pregnancy and newborn complications. Among exogenous antioxidant sources, diet is a cost-effective prevention strategy supporting the health of mothers and newborns; however, there is still a lack of nutritional education during pregnancy interviews. This review aims to systematically summarize the knowledge on the association between OS and diet during pregnancy. Four electronic databases (PubMed Central, EMBASE, Web of Science, and Food Science and Technology Abstracts) were searched on 22 December 2022. Among 4162 records, 13 original articles were finally included. Overall, 80% of the studies considered dietary patterns as exposure and 60% of them assessed the association with malondialdehyde levels in blood and urine. Three studies analyzed the influence of daily intakes of fruit and vegetables on different OS biomarkers (malondialdehyde, nitric oxide and 8-hydroxy-2'-deoxyguanosine). Among studies exploring dietary fat intakes (39%), 80% focused on polyunsaturated fatty acids, finding a positive association with glutathione peroxidase, biopirryn and isoprostane levels, respectively. Four studies analyzed vitamin intakes and 50% of them in association with 8-hydroxy-2'-deoxyguanosine.

New potential biomarkers for early chronic kidney disease diagnosis in patients with different glucose tolerance status.

The purpose of the present study was to investigate the role of oxidative stress, platelet activation, and endocan levels in renal dysfunction in normal glucose tolerance (NGT) patients with 1-h plasma glucose values ≥155 mg/dl (NGT ≥ 155), compared to NGT < 155, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) newly diagnosed subjects. We enlisted 233 patients subjected to an oral glucose tolerance test (OGTT). The serum levels of platelet activation (glycoprotein VI and sP-selectin), oxidative stress biomarkers (8-isoprostane and Nox-2), and endocan were evaluated using an ELISA test. Among NGT < 155 patients and the T2DM group, there was a statistically significant increase in 8-isoprostane (p < 0.0001), Nox-2 (p < 0.0001), glycoprotein VI (p < 0.0001), and sP-selectin (p < 0.0001) serum levels. Higher serum endocan levels were found with the worsening of metabolic profile (p < 0.0001); specifically, NGT ≥ 155 patients presented higher serum endocan values when compared to NGT < 155 patients (p < 0.0001). From the multivariate linear regression analysis, 1-h glucose resulted in the major predictor of estimated glomerular filtration rate (e-GFR) justifying 23.6% of its variation (p < 0.0001); 8-isoprostane and Nox-2 added respectively another 6.0% (p < 0.0001) and 3.2% (p = 0.001). Our study confirmed the link between 1-h post-load glucose ≥155 mg/dl during OGTT and the possible increased risk for chronic kidney disease (CKD) in newly diagnosed patients. The novelty is that we demonstrated a progressive increase in oxidative stress, platelet activation, and serum endocan levels with the worsening of metabolic profile, which becomes evident early during the progression of CKD.

Correlations of Estimated Serum Small Dense Low-Density Lipoprotein and Isoprostane with Metabolic Syndrome Criteria between Metabolic Syndrome and Non-Metabolic Syndrome Subjects in Selangor

Introduction: Metabolic syndrome (MetS) is a global healthcare burden associated with increased risk of atherosclerosis (ATH). The relationship between atherogenic lipoprotein and oxidative stress biomarkers with clinical risk factors of MetS have not been fully explored. Therefore, the objective of this study is to determine the correlation between small dense low-density lipoprotein (sdLDL-c) and isoprostane (ISP) with MetS criteria and comparing these biomarkers between MetS and non-MetS. Materials and Methods: This was a cross sectional study involving 67 MetS and 43 non-MetS diagnosed by JIS criteria 2009. Demographic details and anthropometric measurements were recorded. Blood samples were collected to analyse serum plasma glucose, direct LDL, calculated sdLDL-c and ISP. Results: Mean serum sdLDL-c and ISP levels were significantly higher among those with MetS compared to non-MetS (1.14+0.44 mmol/L vs 0.87±0.38 mmol/L respectively, p=0.005). Similarly, mean serum ISP concentration was higher among MetS compared to non-MetS (884.40+602.69 ng/L vs 657.89±616.42 ng/L respectively, p= 0.054). sdLDL-c was positively correlated with TG in the MetS (Pearson correlation 0.501, p&lt;.001) whilst HDL-c was positively correlated with sdLDL-c among the non-MetS (Pearson Correlation 0.422, p&lt;.005). Conclusion: This study highlights the correlation between sdLDL-c and TG in among MetS, emphasizing the need to closely monitor and manage TG among this cohort to reduce the risk of ATH. It was also noted that HDL-c showed positive correlation with sdLDL-c among non-MetS. This discordant finding suggests that HDL-c itself may not be causally associated with cardiovascular benefits and that perhaps HDL-c subfractions may be a better approach to determine cardioprotective effects of HDL-c.

Increased oxidative stress responses in murine macrophages exposed at the air-liquid interface to third- and fourth-generation electronic nicotine delivery system (ENDS) aerosols

BackgroundNew fourth generation electronic nicotine delivery system (ENDS) devices contain high levels of nicotine salt (up to 60 mg/mL), whose cellular and molecular effects on immune cells are currently unknown. Here, we used a physiologically-relevant in vitro air-liquid interface (ALI) exposure model to assess the toxicity of distinct ENDS, a 3rd-generation electronic-cigarette (e-cig) and two 4th-generation ENDS devices (JUUL and Posh Plus). MethodsMurine macrophages (RAW 264.7) were exposed at the ALI to either air, Menthol or Crème Brûlée-flavored ENDS aerosols generated from those devices for 1-hour per day for 1 or 3 consecutive days. Cellular and molecular toxicity was evaluated 24 h post-exposure. Results1-day of Menthol-flavored JUUL aerosol exposure significantly decreased cell viability and significantly increased lactate dehydrogenase (LDH) levels compared to air controls. Further, JUUL Menthol elicited significantly increased reactive oxygen species (ROS) and nitric oxide (NO) production compared to air controls. Posh Crème Brûlée-flavored aerosols displayed significant cytotoxicity – decreased cell viability and increased LDH levels –after 1- and 3-day exposures, while the Crème Brûlée-flavored aerosol produced by the 3rd-generation e-cig device only displayed significant cytotoxicity after 3 days compared to air controls. Further, both Posh and third-generation e-cig Crème Brûlée flavored-aerosols elicited significantly increased ROS plus high levels of 8-isoprostane after 1 and 3 days compared to air controls, indicating increased oxidative stress. Posh and third-generation e-cig Crème Brûlée flavored-aerosols elicited reduction in NO levels after one day, but elicited increase in NO after 3 days. Genes in common dysregulated by both devices after 1 day included α7nAChR, Cyp1a1, Ahr, Mmp12, and iNos. ConclusionOur results suggest that ENDS Menthol and Crème Brûlée-flavored aerosol exposures from both 3rd- and 4th-generation ENDS devices are cytotoxic to macrophages and cause oxidative stress. This can translate into macrophage dysfunction. Although 4th-generation disposable ENDS devices have no adjustable operational settings and are considered low-powered ENDS devices, their aerosols can induce cellular toxicity compared to air-exposed control cells. This study provides scientific evidence for regulation of nicotine salt-based disposable ENDS products.

Can lipid mediators and free fatty acids guide acute coronary syndrome diagnosis and treatment?

The aim of this study was to investigate fatty acids, lipid mediator levels, and the desaturase index rates on different acute coronary syndrome types and their possible relationship with routine lipid parameters. The study included 81 patients with myocardial infarction (MI), 20 patients with unstable angina pectoris, and 31 healthy people. Fatty acids, CD59, lipoxin A4, 8-isoprostane, serum lipids, albumin, C-reactive protein (CRP), and high sensitive troponin levels were measured in all participants. When the fatty acid groups were evaluated as a ratio of albumin, MUFA/albumin and SFA/albumin ratios were significantly higher in the MI group compared to the control group. Although CD59 and lipoxin A4 levels were higher in the control group, there was no significant differences between the groups. When lipoxin A4/CRP and CD59/CRP ratios were evaluated, the results were significantly lower than those in the control group. Lipid mediators may be useful in treating atherosclerosis by contributing to the resolution of inflammation.

Lung protective effect of Ticagrelor in endotoxemia.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. This study aimed to investigate the potential protective effect of the lungs in sepsis by modulating inflammatory and oxidative stress markers. Twenty-four adult male Swiss-albino mice, aged 8-12 weeks and weighing 20-30 g, were divided into four equal groups (n=6): sham (laparotomy only), CLP (laparotomy plus cecal ligation and puncture), vehicle (DMSO administered one hour before CLP), and Ticagrelor (50 mg/kg IP administered one hour before CLP). Tissue levels of pro-inflammatory and oxidative stress markers in the lung were assessed using ELISA. F2 isoprostane levels were significantly higher in the sepsis group (p<0.05) compared to the sham group, while Ticagrelor significantly decreased the inflammatory and oxidative stress markers compared to the sepsis group. All mice in the sepsis group had considerable (p=0.05) lung tissue damage, but Ticagrelor considerably decreased lung tissue injury (p=0.05). Furthermore, Ticagrelor was found to reduce tissue cytokine levels of the lung (IL-1, TNF a, IL-6, F2 isoprostane, GPR 17, MIF) in male mice during CLP-induced polymicrobial sepsis by modulation of pro-inflammatory and oxidative stress cascade signaling pathways.

Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti-inflammatory effect of L-carnitine.

Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L-carnitine (L-car) deficiency, compound that has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro- and anti-inflammatory cytokines, as well as the L-car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L-car levels in the patients under treatment. Inverse correlation between Phe versus L-car and nitrate plus nitrite versus L-car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)-1β, interferons (IFN)-gamma, IL-2, tumor necrosis factor (TNF)-alpha, IL-8 and IL-6 in the patients at late diagnosis compared to controls, and IL-8 in the patients at early diagnosis and treatment compared to controls. Increased IL-2, TNF-alpha, IL-6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL-6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN-gamma and L-car in treated patients. Otherwise, it was observed that there were increased IL-4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8-isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro-oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L-car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.

Hepatocyte-specific deletion of thromboxane-prostanoid receptor has protective effects on alcohol-associated liver disease

Alcohol-associated liver disease (ALD) is a major health issue worldwide with limited effective treatment options. Thromboxane-prostanoid receptor (TP-R), a G-protein-coupled receptor, is widely expressed in liver. Previous studies reported that an alcohol diet increased levels of TP-R ligands, thromboxane A2 and 8-isoprostane, in mouse liver. However, the role of TP-R signaling in ALD still remains unknown. Here, to test the hypothesis that deleting hepatocyte TP-R ameliorates liver injury caused by an alcohol diet, nine-week female hepatocyte-specific TP-R knock-out mice (KO) and their wild-type (WT) littermate control mice were fed the Lieber-DeCarli control (CONT) or 5% (v/v) ethanol (ET) diet for 4 weeks. Mice were divided into four groups: WT-CONT (n=8), KO-CONT (n=8), WT-ET (n=10), and KO-ET (n=8). Real-time PCR analyses showed that deleting hepatocyte TP-R attenuated alcohol-induced increase in mRNA levels of inflammatory markers including interleukin 6 ( P&lt;0.01) and lipocalin 2 ( P&lt;0.01). In addition, mRNA levels of other inflammatory markers including C-C motif chemokine ligand 2 ( P&lt;0.05) and interleukin 1β ( P&lt;0.01) were increased significantly only in WT-ET mice but not in KO-ET mice compared with controls. Of note, both real-time PCR and immunohistochemistry analyses showed that deleting TP-R in hepatocytes attenuates alcohol-induced increase in the expression of cluster of differentiation 36 (CD36, P&lt;0.05), a fatty acid transport protein. Previous studies documented that chronic alcohol consumption led to hepatic steatosis through promoting CD36-mediated fatty acid uptake. Interestingly, the gas chromatographic analysis of liver lipids revealed a remarkable increase in linoleic acid ( P&lt;0.05) level in liver triglyceride (TG) in WT-ET mice and this effect was blunted in KO-ET group. Additionally, the alcohol diet increased the levels of arachidonic acid ( P&lt;0.01), dihomo-gamma-linoleic acid ( P&lt;0.05), and docosatetraenoic acid ( P&lt;0.05) in liver TG of WT mice, but these fatty acids were not altered by alcohol diet in KO-ET group. Chronic alcohol feeding is known to elicit an oxidative stress in mouse livers though increasing the activity of cytochrome P450 family 2 subfamily E member 1 (CYP2E1). Accordingly, we noted that ablation of hepatocyte TP-R inhibited liver CYP2E1 activity in mice fed an alcohol diet ( P&lt;0.01). Moreover, the alcohol diet increased liver malondialdehyde level in WT mice ( P&lt;0.01) but not in KO mice. These findings suggest that hepatocyte TP-R plays an important role in regulating lipid metabolism and oxidative stress, thereby contributing to the development of AALD. This study was supported by R21 awards from NIH-National Institute on Alcohol Abuse and Alcoholism (R21- AA025445 and R21-AA027367) and a Merit Award from the Department of Veterans Affairs (I01CX002084). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association of functional superoxide gene polymorphism with chlamydia trachomatis-associated recurrent spontaneous abortion

Oxidative stress generated by Chlamydia trachomatis infection is associated with reproductive complications such as recurrent spontaneous abortion. Aim of prospective study was to evaluate whether single nucleotide polymorphisms (SNPs) of SOD1 and SOD2 gene are associated with C. trachomatis-infected recurrent spontaneous abortion (RSA). 150 patients with history of RSA and 150 patients with history of successful deliveries were recruited from Department of Obstetrics and Gynecology, Safdarjung hospital, New Delhi, India. Urine and non-heparinized blood samples were collected and C. trachomatis was detected by polymerase chain reaction (PCR). Using qualitative real time PCR, SNPs rs4998557 (SOD1) and rs4880 (SOD2) were screened in enrolled patients. Level of 8-hydroxyguanosine (8-OHdG), 8-isoprostane (8-IP), progesterone and estrogen was determined by enzyme-linked immunosorbent assays and correlated with SNPs. Significant differences were found in frequency of AA genotype of SOD1 gene among RSA patients versus controls, (82% and 54.66%, respectively; p = 0.02; OR 0.40; CI 95%). Frequency of AA genotype of SOD1 gene among RSA patients with C. trachomatis infection was 87.33%, while in uninfected RSA patients was 71.33% (p < 0.0001; OR 8; CI 95%). No significant relation was found between SOD2 (rs4880) genotype and RSA. Furthermore, significant increase in 8-OHdG, 8-IP and estrogen and significant decrease in progesterone was observed among patients carrying AA genotype. Findings suggest the clinical importance of AA genotype along with 8-OHdG, 8-IP and estrogen and progesterone in screening C. trachomatis-infected RSA women.

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.