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Background: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. Methods: A total of 18 adult female mice (Parkes strain), aged 4–5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. Results: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. Conclusion: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS. [ABSTRACT FROM AUTHOR]

Despite being some of the most anecdotally well‐known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end‐organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Opioids can be used for medical and non‐medical purposes. Chronic pain such as cancer, as well as the frequent use of such drugs in places such as operating rooms and intensive care units, and in non‐medical areas like drug abuse the effects and side effects of these drugs need to be examined in more detail. For this purpose, the effects of fentanyl and remifentanil drugs on neuroinflammation, oxidative stress and cholinesterase metabolism were investigated. Neuron cells (CRL‐10742) were used for the evaluation of the toxicity of fentanyl and remifentanil. MTT, PON1 activity and total thiol levels for its effect on oxidative stress, AChE and BChE activities for its effect on the cholinergic system, and TNF, IL‐8 and IL‐10 gene levels for its neuroinflammation effect were determined. The highest neurotoxic dose of fentanyl and remifentanil was determined as 10 μg/mL. It was observed that the rate of neuron cells in this dose has decreased by up to 61.80% and 56.89%, respectively. The IL‐8 gene expression level in both opioids was down‐regulated while IL 10 gene level was up‐regulated in a dose‐dependent manner compared to the control. In our results, the TNF gene expression level differs between the two opioids. In the fentanyl group, it was seen to be up‐regulated in a dose‐dependent manner compared to the control. Fentanyl and remifentanil showed an inhibitory effect against PON1, while remifentanil showed an increase in total thiol levels. PON1, BChE and total thiol activities showed similarity with MTT. [ABSTRACT FROM AUTHOR]

Aims Obesity is an epidemic that is a critical contributor to hypertension and other cardiovascular diseases. Current paradigms suggest that endothelial nitric oxide synthase (eNOS/NOS3) in the vessel wall is the primary regulator of vascular function and blood pressure. However, recent studies have revealed the presence of eNOS/NOS3 in the adipocytes of white adipose tissues and perivascular adipose tissues (PVATs). The current understanding of the role of adipocyte NOS3 is based mainly on studies using global knockout models. The present study aimed to elucidate the functional significance of adipocyte NOS3 for vascular function and blood pressure control. Methods and results We generated an adipocyte-specific NOS3 knockout mouse line using adiponectin promoter-specific Cre-induced gene inactivation. Control and adipocyte-specific NOS3 knockout (A-NOS3 KO) mice were fed a high-fat diet (HFD). Despite less weight gain, A-NOS3 KO mice exhibited a significant increase in blood pressure after HFD feeding, associated with exacerbated vascular dysfunction and remodelling. A-NOS3 KO mice also showed increased expression of signature markers of inflammation and hypoxia in the PVATs. Among the differentially expressed adipokines, we have observed an upregulation of a novel adipokine, chemerin, in A-NOS3 KO mice. Chemerin was recently reported to link obesity and vascular dysfunction. Treatment with chemerin neutralizing antibody normalized the expression of remodelling markers in the aorta segments cultured in serum from HFD-fed A-NOS3 KO mice ex vivo. Conclusion These data suggest that NOS3 in adipocytes is vital in maintaining vascular homeostasis; dysfunction of adipocyte NOS3 contributes to obesity-induced vascular remodelling and hypertension. [ABSTRACT FROM AUTHOR]

The development of atherosclerosis (AS) is closely linked to changes in the plaque microenvironment, which consists primarily of the cells that form plaque and the associated factors they secrete. The onset of inflammation, lipid deposition, and various pathological changes in cellular metabolism that accompany the plaque microenvironment will promote the development of AS. Numerous studies have shown that oxidative stress is an important condition that promotes AS. The accumulation of reactive oxygen species (ROS) is oxidative stress's most important pathological change. In turn, the effects of ROS on the plaque microenvironment are complex and varied, and these effects are ultimately reflected in the promotion or inhibition of AS. This article reviews the effects of ROS on the microenvironment of atherosclerotic plaques and their impact on disease progression over the past five years and focuses on the progress of treatment strategies based on scavenging ROS of nanoparticles for AS. Finally, we also discuss the prospects and challenges of AS treatment. [ABSTRACT FROM AUTHOR]

Human serum paraoxonase-1 (PON-1) is a critical antioxidant defence system against lipid oxidation. Decreased PON-1 activity has been associated with systemic oxidative stress in several disease states. We conducted a systematic review and meta-analysis of plasma/serum concentrations of PON-1 in asthma, a chronic inflammatory airway disease. The electronic databases PubMed, Web of Science, Scopus and Google Scholar were searched from inception to February 2022. In total, 8 studies in 355 asthmatic patients and 289 healthy controls were included in the meta-analysis. Serum PON-1 concentrations were significantly lower in asthmatic patients (SMD = −1.58, 95% CI −2.53 to −0.63; p = 0.001). The pooled SMD values were not substantially altered in sensitivity analysis. There was no publication bias. There were non-significant differences in PON-1 concentrations in patients with severe vs. mild-to-moderate asthma (SMD = − 0.39, 95% CI − 1.00 to 0.22, p = 0.21). Our meta-analysis has shown that serum PON-1 concentrations are significantly lower in patients with asthma, suggesting the presence of an impaired antioxidant defense in this group. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that the gut microbiota affects the cardiovascular system directly and indirectly via biologically active molecules. TMAO, a key metabolite produced by gut bacteria is implicated in atherosclerosis and chronic endothelial dysfunction, but with an unclear effect on vascular tone, oxidative stress, and inflammation. Our study aimed to evaluate the acute effects of TMAO on vascular contractility in relation with oxidative stress markers and inflammation. Aortic rings were harvested from laboratory rats and placed in a tissue bath system containing TMAO in concentrations of 300, 100, 10 µM, and control. Vascular tone under the influence of vasoconstrictor phenylephrine and non-endothelial-dependent vasodilator sodium nitroprusside was assessed using force transducers connected to a computer-based acquisition system. Oxidative stress and inflammation were quantified by vascular assessment of the activity of NF-κB, NRF2, SOD1, and iNOS by western-blotting and MDA by spectrofluorimetry. After the incubation of the aortic rings in TMAO solutions for 1 h, there was no difference in vasoconstrictor and non-endothelial vasodilator response between the studied doses. TMAO acutely induced oxidative stress and inflammation, significantly increasing levels of MDA and the expression of NF-κB, NRF2, SOD1, and iNOS, mostly in a dose-dependent manner. Our study showed the lack of a short-term effect of studied TMAO doses on vascular contractility, but demonstrated an acute prooxidative effect and activation of major inflammatory pathways, which can partially explain the detrimental effects of TMAO in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Hypothyroidism is the most common endocrine disorder diagnosed in dogs, leading to deleterious effects on a dog's life quality. This study aims to evaluate changes in the redox status in canine hypothyroidism. For this purpose, a comprehensive panel of antioxidants and oxidants biomarkers were measured in serum and saliva of 23 dogs with hypothyroidism, 21 dogs with non-thyroidal illness, and 16 healthy dogs. Among the antioxidants, cupric reducing antioxidant capacity (CUPRAC), ferric reducing ability of plasma (FRAP), Trolox equivalent antioxidant capacity (TEAC), thiol, paraoxonase type 1 (PON-1) and glutathione peroxidase (GPx) were determined in serum and CUPRAC, ferric reducing ability of saliva (FRAS) and TEAC in saliva. The oxidant biomarkers included were total oxidant status (TOS), peroxide-activity (POX-Act), reactive oxygen-derived compounds (d-ROMs), advanced oxidation protein products (AOPP), and thiobarbituric acid reactive substances (TBARS) in serum and AOPP and TBARS in saliva. Results: Results showed a significantly higher TEAC, PON-1, GPx, TOS, POX-Act, and d-ROMs, and a significantly lower AOPP in serum of dogs with hypothyroidism. Meanwhile, significantly lower FRAS and AOPP were observed in saliva of dogs with hypothyroidism. Once salivary concentrations were corrected based on their total protein concentrations, the only analyte showing significant changes was TBARS which was significantly higher in dogs with hypothyroidism. Conclusions: Our results show that dogs with hypothyroidism present alterations in the redox status in both serum and saliva. This study should be considered a preliminary study and further research addressing these changes should be made using larger populations. [ABSTRACT FROM AUTHOR]

Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double‐edged sword in disease progression suggest two different therapeutic strategies to treat redox‐relevant diseases, in which targeting ROS sources and redox‐related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox‐relevant diseases. [ABSTRACT FROM AUTHOR]

Paraoxonase (PON)1 is a HDL-associated enzyme with esterase (lipolactonase)- and peroxidase-like activities that exhibits antiatherogenic properties. PON1 deficiency in mice was shown to be associated with enhanced atherosclerosis development, whereas the overexpression of human PON1 resulted in a significant reduction in atherosclerotic lesion size. Human atherosclerotic lesions contain macrophages and a variety of oxidized lipids, which can facilitate further lesion progression and arterial macrophage oxidation. PON1 interacts with the atherosclerotic lesion and with macrophages to attenuate their atherogenic properties, whereas the oxidized lesion inactivates PON1. It is of interest that, similarly to HDL-associated PON1 antioxidant properties, PON2 (which is not present in the circulation) possesses similar antioxidant/antiatherogenic characteristics towards arterial macrophage foam cells, the hallmark of early atherogenesis. [ABSTRACT FROM AUTHOR]

Mitochondria are vital cellular organelles associated with energy production as well as cell signaling pathways. These organelles, responsible for metabolism, are highly abundant in hepatocytes that make them key players in hepatotoxicity. The literature suggests that mitochondria are targeted by various environmental pollutants. Arsenic, a toxic metalloid known as an environmental pollutant, readily contaminates drinking water and exerts toxic effects. It is toxic to various cellular organs; among them, the liver seems to be most affected. A growing body of evidence suggests that within cells, arsenic is highly toxic to mitochondria and reported to cause oxidative stress and alter an array of signaling pathways and functions. Hence, it is imperative to highlight the mechanisms associated with altered mitochondrial functions and integrity in arsenic-induced liver toxicity. This review provides the details of mechanistic aspects of mitochondrial dysfunction in arsenic-induced hepatotoxicity as well as various ameliorative measures undertaken concerning mitochondrial functions. [ABSTRACT FROM AUTHOR]

Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also demonstrated the significance of PON2 in the manifestation of cardiovascular and several other diseases, and hence, it is considered an important biomarker. Recent findings of its expression in brain tissue suggest its potential protective effect on oxidative stress and neuroinflammation. Polymorphisms of PON2 in humans are a risk factor in many pathological conditions, suggesting a possible mechanism of its anti-oxidative property probably through lactonase activity. However, exogenous factors may also modulate the expression and activity of PON2. Hence, this review aims to report the mechanism by which PON2 expression is regulated and its role in oxidative stress disorders such as neurodegeneration and tumor formation. The role of PON2 owing to its lactonase activity in bacterial infectious diseases and association of PON2 polymorphism with pathological conditions are also highlighted. [ABSTRACT FROM AUTHOR]

Differentially methylated regions (DMR) are genomic regions with different methylation status. The aim of this research was to identify DMRs in subjects with obesity that predict the response to a weight-loss dietary intervention and its association with metabolic variables. Based on the change in body mass index (BMI), 201 subjects with overweight and obesity were categorized in tertiles according to their response to a hypocaloric diet: Responders (R; n = 64) and Non-Responders (NR; n = 63). The R group lost 4.55 ± 0.91 BMI units (kg/m2) and the NR group lost 1.95 ± 0.73 kg/m2 (p < 0.001). DNA methylation was analysed in buffy coat through a methylation array at baseline. DMRs were analysed using a function of ChAMP (Chip Analysis Methylation Pipeline) in R software. Baseline DNA methylation analysis between R and NR exhibited a DMR located at paraoxonase 3 gene (PON3) consisting of 13 CpG sites, eleven of them significantly hypermethylated in R. To analyse the implication of these 11 CpGs on weight loss, a z-score was performed as a measure of DMR methylation. This analysis showed a correlation between PON3 DNA methylation and BMI loss. This z-score negatively correlated with PON3 protein serum levels. Total paraoxonase activity in serum was not different between groups, but PON enzymatic activity positively correlated with oxidized LDL levels. The present study identified a DMR within PON3 gene that is related to PON3 protein levels in serum, and that could be used as a potential biomarker to predict the response to weight-loss dietary interventions. [ABSTRACT FROM AUTHOR]

Background: Acute pancreatitis caused by hyperlipidemia is a severe life-threatening condition. Therefore, it is urgent to develop new therapeutic methods to treat this disease. Methods: Cell viability was determined by the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to detect the expression levels of apoptotic and endoribonuclease inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway-associated proteins. The induction of cell apoptosis was determined using flow cytometry. The expression levels of the oxidative stress indicators were measured by an enzyme-linked immunosorbent assay. Results: WB analysis and the CCK-8 assay demonstrated that trimethylamine-N-oxide (TMAO) decreased cell viability and facilitated apoptosis of MPC-83 cells in a dose-dependent manner. Furthermore, the induction of oxidative stress was assessed by evaluating the levels of specific markers, including hydrogen peroxide, reactive oxygen species, nitric oxide, and superoxide dismutase. The levels of the aforementioned markers were increased in the TMAO-treated group. Subsequently, the IRE1α/XBP-1 pathway-associated proteins were analyzed by WB analysis and the data demonstrated that the regulatory effects of TMAO on MPC-83 cells were meditated by the IRE1α/XBP-1 signaling pathway. Subsequently, rescue experiments were performed to further assess the effects of TMAO. Conclusion: The present study provides evidence on the application of TMAO as a potential diagnostic and therapeutic strategy for the therapeutic intervention of hyperlipidemic acute pancreatitis. [ABSTRACT FROM AUTHOR]

Among gut microbiota-derived metabolites, trimethylamine-N-oxide (TMAO) is receiving increased attention due to its possible role in the carcinogenesis of colorectal cancer (CRC). In spite of numerous reports implicating TMAO with CRC, there is a lack of empirical mechanistic evidences to concretize the involvement of TMAO in the carcinogenesis of CRC. Possible mechanisms such as inflammation, oxidative stress, DNA damage, and protein misfolding by TMAO have been discussed in this review in the light of the latest advancements in the field. This review is an attempt to discuss the probable correlation between TMAO and CRC but this linkage can be concretized only once we get sufficient empirical evidences from the mechanistic studies. We believe, this review will augment the understanding of linking TMAO with CRC and will motivate researchers to move towards mechanistic study for reinforcing the idea of implicating TMAO with CRC causation. Key points: • TMAO is a gut bacterial metabolite which has been implicated in CRC in recent years. • The valid mechanistic approach of CRC causation by TMAO is unknown. • The article summarizes the possible mechanisms which need to be explored for validation. [ABSTRACT FROM AUTHOR]

Introduction: There is no consensus on an ideal marker of oxidative stress (OS). Disruption of the balance between free radical and antioxidant activity production by increasing oxidative markers results in OS. In this study, we aimed to investigate how OS, which increases mortality and morbidity due to various reasons, is affected by keto/amino therapy in patients with hypoalbuminemia undergoing peritoneal dialysis. Materials and Method: Twenty patients who underwent peritoneal dialysis were included in the study. Before starting keto/amino acid therapy, primary kidney diseases were determined, body mass indexes, serum total protein, albumin, C‐reactive protein, ferritin, calcium, phosphorus, parathyroid hormone, paraoxonase‐1 (PON‐1), sialic acid levels, arylesterase (ARE) activities, and malondialdehyde (MDA) levels were measured, and Kt/V values were calculated. Keto/amino acid treatment was initiated for those with an albumin level of <3.5 g/dL. The same parameters of the patients, followed up for 3 months, were checked again at the end of the third month. Results: Paraoxonase‐1 and ARE activities, which are antioxidant enzyme activities, were found to be statistically significantly increased compared to the initial period (59 ± 59, 135 ± 69, 15.8 ± 19.7, and 44.7 ± 16.4, respectively; p < 0.00). MDA and sialic acid levels were significantly lower than the initial values (109 ± 99, 23 ± 9, 2.26 ± 0.44, and 2.04 ± 0.39, respectively; p < 0.01). Conclusion: In our study, after the initiation of keto/amino acid treatment, PON‐1, which is a significant antioxidant marker, and ARE plasma activities increased and tissue destruction product MDA and sialic acid significantly decreased. In the light of all these data, we think that this treatment can reduce OS, improve hypoalbuminemia, which causes both mortality and morbidity in patients, improve survival in PD patients, and may be an antioxidant treatment in suitable patients. [ABSTRACT FROM AUTHOR]

Naturally occurring Babesia bigemina infection in cattle is associated with changes in the status of oxidative stress, trace elements, sialic acid, and cholinesterase activity in blood. However, to date there is no description of hepatic damage in the infected animals. More importantly, the majority of the above-mentioned causative factors are synthesized or stored in the liver. Therefore, this study was undertaken to evaluate biomarkers of hepatic function, paraoxonase-1 activity, and lipid profile in 13 cattle infected with B. bigemina which did not respond to standard treatment. The animals were necropsied and the histopathology of the liver and DNA damage of hepatocytes were examined. Blood analysis revealed a significant parasitemia burden-dependent increase in the activities of hepatic enzymes and total bilirubin and a decrease in albumin concentrations in the infected cattle compared to the control ones. Paraoxonase-1 activity was remarkably lower in the infected animals than the control. A significant decrease in the blood concentrations of total cholesterol, low density lipoprotein, and high density lipoprotein and a significant increase in the triglyceride concentration were observed in the infected animals. Severe oxidative damages were also recorded in the haptic tissue evidenced by significant alterations in the activities of antioxidant enzymes, suppression of total antioxidant capacity, and oxidation of biomolecules. Congestion of blood vessels, bile duct hyperplasia, and hepatocyte necrosis were the evident histopathologic findings. Our results revealed significant changes in the indices of liver function in the diseased cattle, leading to the conclusion that the parasite can potentially cause liver dysfunction. [ABSTRACT FROM AUTHOR]

There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: to compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (–SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, and total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n = 40) and non-deficit (n = 40) schizophrenia and healthy controls (n = 40). Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered –SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (odds ratio = 3.15, p < 0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, and IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas –SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. When overall severity of schizophrenia increases, multiple immune and oxidative (especially protein oxidation indicating chlorinative stress) neurotoxicities and impairments in immune-protective resilience become more prominent and shape a distinct nosological entity, namely deficit schizophrenia. The nomothetic network psychiatry approach allows building causal-pathway-phenotype models using machine learning techniques. [ABSTRACT FROM AUTHOR]

Copyright of Turkiye Klinikleri Journal of Internal Medicine / Türkiye Klinikleri İç Hastalıkları Dergisi is the property of Turkiye Klinikleri and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Psoriasis, a chronic inflammatory skin disease, is associated with oxidative stress of serum lipoproteins. In psoriatic children we evaluated the activity and levels of myeloperoxidase, the activity of paraoxonase-1 (PON1) and biochemical markers of lipid peroxidation, to investigate wether an unbalance between oxidant–antioxidants occurs very early in psoriasis. A total of 52 patients affected by psoriasis and 48 sex–age-matched healthy controls were enrolled. Serum MPO levels were measured using ELISA method. MPO and PON1 activities (paraoxonase, arylesterase and lactonase) were evaluated by spectroscopic methods. Our results demonstrated a significant increase of MPO levels and activity in psoriatic subjects. PON1 activities were found to be significantly decreased. A positive correlation has been established between the MPO/PON1 ratio and levels of lipid peroxides in all psoriatic patients. These results suggest that an unbalance between MPO and PON1 can reflect in higher oxidative stress in serum lipoproteins. [ABSTRACT FROM AUTHOR]

Introduction: The atherosclerosis process is highly accelerated in patients with chronic kidney disease (CKD). Oxidative stress is considered as one of the pro-atherogenic factors involved in accelerating the atherosclerosis process of the carotid artery. The aim of the present study was to determine the relationship between oxidative stress markers and the progression of carotid atherosclerosis in CKD patients. Material and methods: The study was conducted on 162 patients with CKD and 40 controls, and the disease stage was scored between 2 and 5D. Blood samples were taken and advanced oxidative protein product, myeloperoxidases, malondialdehyde, nitric oxide, glutathione, and oxidised low-density lipoprotein were measured. Furthermore, we studied the correlations between these biomarkers and clinical and para-clinical cardiovascular complications. Results: The average age of patients was 56.5 years. The oxidative stress markers average ± SD levels in CKD groups compared to the control were as follows: advanced oxidation protein product (61.89 ±1.4 vs. 26.65 ±1.05 µmol/l), myeloperoxidase (59.89 ±1.98 vs. 38.45 ±1.98 UI/ml), malondialdehyde (6.1 ±0.12 vs. 3.26 ±0.03 µmol/l), nitric oxide (65.82 ±1.06 vs. 52.19 ±2.1 µmol/l), glutathione (52.21 ±1.3 vs. 89.4 ±2.6 IU/ml), and oxLDL (15.57 ±1.07 vs. 1.72 ±0.82 µmol/l). While the glutathione level decreased significantly in advanced CKD stage (p < 0.05), the concentrations of all the other biomarkers increased significantly in accordance with CKD score (p < 0.05). Conclusions: Cardiovascular diseases, mainly atherosclerosis, can be diagnosed indirectly by measuring oxidative stress markers. Furthermore, theses markers can be used to predict the progression of CKD, for better management of the disease. [ABSTRACT FROM AUTHOR]

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote oxidative stress and inflammation in the peripheral tissues, contributing to the pathogenesis of many diseases. Here we examined whether pre-existing higher circulating TMAO would influence cognitive function in aged rats after anesthetic sevoflurane exposure. Aged rats received vehicle or TMAO treatment for 3 weeks. After 2 weeks of treatment, these animals were exposed to either control or 2.6% sevoflurane for 4 h. One week after exposure, freezing as measured by fear conditioning test, microglia activity, proinflammatory cytokine expression and NADPH oxidase-dependent reactive oxygen species (ROS) production in the hippocampus (a key brain structure involved in learning and memory) were comparable between vehicle-treated rats exposed to control and vehicle-treated rats exposed to sevoflurane. TMAO treatment, which increased plasma TMAO before and 1 week after control or sevoflurane exposure, significantly reduced freezing to contextual fear conditioning, which was associated with increases in microglia activity, proinflammatory cytokine expression and NADPH oxidase-dependent ROS production in the hippocampus in rats exposed to sevoflurane but not in rats exposed to control. Moreover, hippocampal expression of antioxidant enzyme methionine sulfoxide reductase A (MsrA) was reduced by TMAO treatment in both groups, and TMAO-induced reduction in MsrA expression was negatively correlated with increased proinflammatory cytokine expression in rats exposed to SEV. These findings suggest that pre-existing higher circulating TMAO downregulates antioxidant enzyme MsrA in the hippocampus, which may sensitize the hippocampus to oxidative stress, resulting in microglia-mediated neuroinflammation and cognitive impairment in aged rats after sevoflurane exposure. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the immune-inflammatory, metabolic, and nitro-oxidative stress (IM&NO) biomarkers as predictors of disability in multiple sclerosis (MS) patients. A total of 122 patients with MS were included; their disability was evaluated using the Expanded Disability Status Scale (EDSS) and IM&NO biomarkers were evaluated in peripheral blood samples. Patients with EDSS ≥3 were older and showed higher homocysteine, uric acid, advanced oxidized protein products (AOPP) and low-density lipoprotein (LDL)-cholesterol and higher rate of metabolic syndrome (MetS), while high-density lipoprotein (HDL)-cholesterol was lower than in patients with EDSS <3; 84.6% of all patients were correctly classified in these EDSS subgroups. We found that 36.3% of the variance in EDSS score was explained by age, Th17/T regulatory (Treg) and LDL/HDL ratios and homocysteine (all positively related) and body mass index (BMI) (inversely related). After adjusting for MS treatment modalities, the effects of the LDL/HDL and zTh17/Treg ratios, homocysteine and age on disability remained, whilst BMI was no longer significant. Moreover, carbonyl proteins were associated with increased disability. In conclusion, the results showed that an inflammatory Th17 profile coupled with age and increased carbonyl proteins were the most important variables associated with high disability followed at a distance by homocysteine, MetS and LDL/HDL ratio. These data underscore that IM&NO pathways play a key role in increased disability in MS patient and may be possible new targets for the treatment of these patients. Moreover, a panel of these laboratory biomarkers may be used to predict the disability in MS. [ABSTRACT FROM AUTHOR]

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Key points: Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases.To investigate whether age‐related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad‐spectrum, poorly‐absorbed antibiotics in drinking water for 3–4 weeks.In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation.To provide insight into age‐related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine N‐oxide.The results of the present study provide the first proof‐of‐concept evidence that the gut microbiome is an important mediator of age‐related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. Oxidative stress‐mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age‐related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3–4 weeks of treatment with broad‐spectrum, poorly‐absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age‐related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut‐derived metabolite trimethylamine N‐oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area‐under‐the‐curve carotid artery dilatation to acetylcholine in young: 345 ± 16 AU vs. old control (OC): 220 ± 34 AU, P < 0.01; vs. old antibiotic‐treated (OA): 334 ± 15 AU; P < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m s−1 vs. OC: 4.43 ± 0.38 m s−1; vs. OA: 3.52 ± 0.35 m s−1; P = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6 ± 0.4 μmol L−1  vs. OC: 7.2 ± 2.0 μmol L−1; P < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 μmol L−1; P < 0.0001 vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age‐related arterial dysfunction and oxidative stress and suggest that therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans. Key points: Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases.To investigate whether age‐related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad‐spectrum, poorly‐absorbed antibiotics in drinking water for 3–4 weeks.In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation.To provide insight into age‐related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine N‐oxide.The results of the present study provide the first proof‐of‐concept evidence that the gut microbiome is an important mediator of age‐related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effects of atorvastatin and simvastatin on behavioral manifestations that followed hyperhomocysteinemia induced by special dietary protocols enriched in methionine and deficient in B vitamins (B6, B9, B12) by means of alterations in anxiety levels in rats. Simultaneously, we investigated the alterations of oxidative stress markers in rat hippocampus induced by applied dietary protocols. Furthermore, considering the well-known antioxidant properties of statins, we attempted to assess their impact on major markers of oxidative stress and their possible beneficial role on anxiety-like behavior effect in rats. The 4-week-old male Wistar albino rats were divided (eight per group) according to basic dietary protocols: standard chow, methionine-enriched, and methionine-enriched vitamins B (B6, B9, B12) deficient. Each dietary protocol (30 days) included groups with atorvastatin (3 mg/kg/day i.p.) and simvastatin (5 mg/kg/day i.p.). The behavioral testing was performed in the open field and elevated plus maze tests. Parameters of oxidative stress (index of lipid peroxidation, superoxide dismutase, catalase activity, glutathione) were determined in hippocampal tissue samples following decapitation after anesthesia. Methionine-load dietary protocols induced increased oxidative stress in rat hippocampus, which was accompanied by anxiogenic behavioral manifestations. The methionine-enriched diet with restricted vitamins B intake induced more pronounced anxiogenic effect, as well as increased oxidative stress compared to the methionine-load diet with normal vitamins B content. Simultaneous administration of statins showed beneficial effects by means of both decreased parameters of oxidative stress and attenuation of anxiety. The results obtained with simvastatin were more convincible compared to atorvastatin. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging. Cardiovascular risk factors like hypertension and atherosclerosis increase the risk for AD. Polymorphic alleles of apolipoprotein E (ApoE) are one of the main genetic determinants of AD.Objective: Mice, double-knockout (DKO) for ApoE (major cholesterol carrier in brain) and PON1 (paroxonase1, reduces oxidative stress), showed severe age-dependent atherosclerosis of the arteries carrying blood to the brain even on normal diet. This prompted us to investigate the possibility of an AD pathology resulting from the deficiency of ApoE and the induction of oxidative stress.Methods: Atherosclerotic lesions were quantified by ImageJ. The brain hippocampus of young and old ApoE-PON1 DKO mice and control mice were harvested. RT-PCR analysis was performed for mRNA levels of AD specific markers. Blood levels of S100 calcium-binding protein B (S100B) protein were measured by ELISA. H&E as well as immunostaining was performed to detect amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in brain tissues. Evans blue dye was used to evaluate the vascular permeability and blood-brain barrier (BBB) dysfunction.Results: Results showed that the older DKO mice had severe carotid atherosclerosis, increased mRNA levels of AD markers in brain tissue, and elevated levels of serum S100B protein. Immunological staining confirmed the characteristics of AD. Ex-vivo imaging showed higher levels of Evans blue dye in the ApoE-PON1 DKO mice brain tissues, pointing toward impaired vasculature.Conclusion: Aged ApoE-PON1 DKO mice displaying AD specific markers along with Aβ plaques, NFTs, and disrupted BBB suggests the animals are suffering from AD. [ABSTRACT FROM AUTHOR]

ROS are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. In the vascular system, physiological levels of ROS are essential for normal vascular functions including endothelial homeostasis and smooth muscle cell contraction. In contrast, uncontrolled overproduction of ROS resulting from an imbalance of ROS generation and elimination leads to the development of vascular diseases. Excessive ROS cause vascular cell damage, the recruitment of inflammatory cells, lipid peroxidation, activation of metalloproteinases and deposition of extracellular matrix, collectively leading to vascular remodelling. Evidence from a large number of studies has revealed that ROS and oxidative stress are involved in the initiation and progression of numerous vascular diseases including hypertension, atherosclerosis, restenosis and abdominal aortic aneurysm. Furthermore, considerable research has been implemented to explore antioxidants that can reduce ROS production and oxidative stress in order to ameliorate vascular diseases. In this review, we will discuss the nature and sources of ROS, their roles in vascular homeostasis and specific vascular diseases and various antioxidants as well as some of the pharmacological agents that are capable of reducing ROS and oxidative stress. The aim of this review is to provide information for developing promising clinical strategies targeting ROS to decrease cardiovascular risks.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

Consuming a Mediterranean diet rich in minimally processed plant foods has been associated with a reduced risk of developing multiple chronic diseases and increased life expectancy. Data from several randomized clinic trials have demonstrated a beneficial effect in the primary and secondary prevention of cardiovascular disease, type 2 diabetes, atrial fibrillation, and breast cancer. The exact mechanism by which an increased adherence to the traditional Mediterranean diet exerts its favorable effects is not known. However, accumulating evidence indicates that the five most important adaptations induced by the Mediterranean dietary pattern are: (a) lipid-lowering effect, (b) protection against oxidative stress, inflammation and platelet aggregation, (c) modification of hormones and growth factors involved in the pathogenesis of cancer, (d) inhibition of nutrient sensing pathways by specific amino acid restriction, and (e) gut microbiota-mediated production of metabolites influencing metabolic health. More studies are needed to understand how single modifications of nutrients typical of the Mediterranean diet interact with energy intake, energy expenditure, and the microbiome in modulating the key mechanisms that promote cellular, tissue, and organ health during aging. [ABSTRACT FROM AUTHOR]

Coronary artery disease, the leading cause of death in the developed and developing countries, is prevalent in diabetes mellitus with 68% cardiovascular disease (CVD)-related mortality. Epidemiological studies suggested inverse correlation between HDL and CVD occurrence. Therefore, low HDL concentration observed in diabetic patients compared to non-diabetic individuals was thought to be one of the primary causes of increased risks of CVD. Efforts to raise HDL level via CETP inhibitors, Torcetrapib and Dalcetrapib, turned out to be disappointing in outcome studies despite substantial increases in HDL-C, suggesting that factors beyond HDL concentration may be responsible for the increased risks of CVD. Therefore, recent studies have focused more on HDL function than on HDL levels. The metabolic environment in diabetes mellitus condition such as hyperglycemia-induced advanced glycation end products, oxidative stress, and inflammation promote HDL dysfunction leading to greater risks of CVD. This review discusses dysfunctional HDL as one of the mechanisms of increased CVD risks in diabetes mellitus through adversely affecting components that support HDL function in cholesterol efflux and LDL oxidation. The dampening of reverse cholesterol transport, a key process that removes cholesterol from lipid-laden macrophages in the arterial wall, leads to increased risks of CVD in diabetic patients. Therapeutic approaches to keep diabetes under control may benefit patients from developing CVD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Atherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury. Endogenous anti-oxidants function as checkpoints to avoid these untoward consequences of ROS, and an imbalance in the oxidant/anti-oxidant mechanisms leads to a state of oxidative stress. In this review, we discuss the role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and highlight potential anti-oxidant therapeutic strategies relevant to atherosclerosis. Recent Findings: There is growing evidence on how traditional risk factors translate into oxidative stress and contribute to atherosclerosis. Clinical trials evaluating anti-oxidant supplements had failed to improve atherosclerosis. Current studies focus on newer ROS scavengers that specifically target mitochondrial ROS, newer nanotechnology-based drug delivery systems, gene therapies, and anti-miRNAs. Synthetic LOX-1 modulators that inhibit the effects of Ox-LDL are currently in development. Summary: Research over the past few decades has led to identification of multiple ROS generating systems that could potentially be modulated in atherosclerosis. Therapeutic approaches currently being used for atheroslcerotic vascular disease such as aspirin, statins, and renin-angiotensin system inhibitors exert a pleiotropic antioxidative effects. There is ongoing research to identify novel therapeutic modalities to selectively target oxidative stress in atherosclerosis. [ABSTRACT FROM AUTHOR]

Coronary artery disease and low-density lipoprotein (LDL) levels in the blood have long been known to be associated with peripheral vascular diseases. Paraoxonase-1 (PON1) enzyme is related to serum levels of high-density lipoprotein (HDL) and protects LDL from oxidation which may result in development of microvascular disease in diabetes. The enzyme has a major role in the prevention of atherosclerosis besides antioxidant properties. Additionally, PON1 is important in the detoxification of organophosphate insecticides from the body. In this study, we aimed to synthesize highly active new compounds which can be a drug candidate and evaluate their effects on PON1 activity. Nine novel triazole compounds bearing thioacetamide moiety (5a-i) were synthesized and their in vitro PON1 activity was investigated. The PON1 enzyme was purified from human serum using ammonium sulfate precipitation method. Also, it was further purified using Sepharose 4B-L-tyrosine-1-naphthylamine affinity chromatography. Among the synthesized triazole compounds, 5b, 5c, 5f and 5h have been determined to increase PON1 activity, remarkably. Compounds 5b, 5c, 5f and 5h bearing 5-nitrothiazole, benzothiazole, 6-ethoxybenzothiazole and 6-florobenzothiazole moieties could be considered to proceed in vivo investigations which is a further stage for a drug candidate. [ABSTRACT FROM AUTHOR]

Background: Cisplatin is widely used chemotherapeutic agent for cancer treatment with limited uses due to its neurotoxic side effect. The aim of this study was to determine the potential preventive effects of rutin on the brain of cisplatin- neurotoxic rat model. Methods: Forty rats were divided into four groups. Group-1 (control group) was intra-peritoneal (IP) injected with 2.5 ml/kg saline. Group-2 (rutin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days. Group-3 (cisplatin group) was IP received 5 mg/kg cisplatin single dose. Group-4 (rutin and cisplatin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days with a single dose of 5 mg/kg cisplatin IP on day ten. Brain tissues from frontal cortex was used to extract RNA, the gene expression levels of paraoxonase-1 (PON-1), PON-2, PON-3, peroxisome proliferator-activated receptor delta (PPAR-δ), and glutathione peroxidase (GPx) was investigated by Real-time PCR. Results: Cisplatin significantly decreased the expression levels of PON-1, PON-3, PPAR-δ and GPX whereas significantly increased PON-2 expression levels. Co-administration of Rutin prevented the cisplatin-induced toxicity by restoring the alteration in the studied genes to normal values as in the control group. Conclusion: This study showed that Rutin has neuroprotective effect and reduces cisplatin-neurotoxicity with possible mechanism via the antioxidant pathway. [ABSTRACT FROM AUTHOR]

Objectives: Otosclerosis is a disease involving abnormal bone turnover in the human otic capsule that results in hearing loss. Several hypotheses have been suggested for the etiopathogenesis of otosclerosis; however, its etiology remains unclear. Methods: This study evaluated the correlation between otosclerosis and levels of paraoxonase-1 (PON1), arylesterase, total antioxidant status, total oxidant status (TOS), oxidative stress index (OSI), total sulfhydryl (-SH) groups, lipid hydroperoxide, and ceruloplasmin in the serum of otosclerosis patients and healthy subjects with respect to oxidative stress. Results: In our study, TOS and OSI levels were higher in the otosclerosis patients than in the controls. The PON1 levels showed that oxidative stress was severe, and as a result, antioxidants were consumed and depleted. Discussion: When an imbalance between oxygen free radical production and antioxidative defense mechanisms occurs, reactive oxygen species levels may increase, which in turn may damage cells and tissues through the peroxidation of phospholipid membrane structures. The body initially responds with increased antioxidant production, but if the oxidative stress is severe, decreased antioxidant levels may result. This study reports expression levels of oxidative stress species in otosclerosis patients. [ABSTRACT FROM PUBLISHER]

Introduction: Anthrax is a bacterial disease caused by the aerobic sporeforming bacterium Bacillus anthracis. It has been suggested that oxidative stress plays an important role in the pathogenesis of B. anthracis. The aim of this study was to investigate serum paraoxonase 1 (PON1) activity, catalase activity, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) levels in patients with cutaneous anthrax. Materials and methods: Fifteen patients with cutaneous anthrax and 15 healthy controls were enrolled in this study. The serum MDA levels, SOD levels, paraoxonase, arylesterase, and catalase activities were measured using a spectrophotometer. Results: The serum SOD levels, paraoxonase, arylesterase, and catalase activities were significantly lower in patients with cutaneous anthrax than in controls (for all, p < 0.001), whereas MDA levels were significantly higher (p < 0.001). No significant correlation was found between serum paraoxonase activity, arylesterase activity, SOD levels, and MDA levels (all, p > 0.05) in patients with cutaneous anthrax. Conclusions: The current study was the first to show decreased antioxidant levels and increased oxidant levels in patients with cutaneous anthrax. Therefore, decreased PON1 activity may play a role in the pathogenesis of cutaneous anthrax. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are major contributors to global deaths and disability-adjusted life years, with hypertension a significant risk factor for all causes of death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions, such as vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of obtaining measurements of endothelial function, the clinical techniques for its determination, the mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunction. Since vascular oxidative stress and inflammation are major determinants of endothelial function, we have also addressed current antioxidant and anti-inflammatory therapies. In the light of recent data that dispute the prognostic value of endothelial function in healthy human cohorts, we also discuss alternative diagnostic parameters such as vascular stiffness index and intima/media thickness ratio. We also suggest that assessing vascular function, including that of smooth muscle and even perivascular adipose tissue, may be an appropriate parameter for clinical investigations.Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]

Aim:To investigate peripheral blood monocytes/macrophages (Mo/Mᴓ) paraoxonase 2 (PON2) in diabetes and the factors modulating its activity. Methods:One hundred and eighteen patients with newly diagnosed uncomplicated type 2 diabetes mellitus were compared regarding clinical, biochemical and oxidative stress parameters with 80 healthy subjects. The capacity of the peripheral blood mononuclear cells (PBMNC) to release pro-oxidants and to neutralise them was determined by measuring the respiratory burst (RB) and the intracellular antioxidant enzyme PON2.In vitroexperiments were conducted on a differentiated monocytes cell line (dU937) that was exposed to serum deprivation followed by addition of isolated lipoproteins (VLDL or LDL). Results:Paraoxonase 2 activity in Mo/Mᴓ was significantly lower in type 2 diabetes patients (0.042 ± 0.044 vs 0.165 ± 0.133U lactonase activity/mg protein in controls,p < .0005) and decreased in the obese in all groups. It was inversely correlated to parameters of adiposity (BMI and Waist Circumference), of glucose control (blood glucose, fructosamine and HbA1c) and insulin resistance (HOMA-IR). In multivariate regression models, 15–34% of the PON2 variance was explained by diabetes. Thein vitroaddition of VLDL normalised the RB of serum deprived dU937 cells, S− (to 82 ± 18% of the cells incubated with serum, S+) and PON2 activity (from 0.524 ± 0.061 in S − to 0.298 ± 0.048 U/mg protein). In contrast, when LDL was added, the RB remained lower (61 ± 12% of S+,p = .03) and PON2 higher (0.580 ± 0.030 U/mg protein,p = .003). Conclusions:The decrease in monocyte/macrophage PON2 enzymatic activity observed in type 2 diabetes cannot be totally explained by abdominal obesity and insulin resistance. The underlying molecular mechanisms need to be identified. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is both the prevailing malignancy and the most common cause of cancer death among women. Many factors may play a role in the susceptibility to the breast cancer and Oxygen Free Radicals may be one of these. There are various known antioxidant systems against oxidative stress, including ParaoxonaseI. The aim of this study was to investigate the association between rs854560 polymorphism in the PON1 gene in patients with breast cancer. Materials and Methods: We performed genotyping analysis using polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) assay in a case–control study of 83 confirmed breast cancer patients and 100 cancer-free controls in Markazi Province. Results: In our study of the PON1 gene L55M polymorphism, the LL genotype was found in 2 (2.40%) patients, whereas the LM genotype was found in 69 (83.13%) patients. The MM genotype was present in 12 (14.45%) patients. In the control group, LL, LM and MM genotypes were found in 4 (4%), 81 (81%), and 15 (15%) subjects, respectively. There was no statistically significant difference between patient and control groups in terms of the PON1 gene L55M polymorphism (p= 0.825). Allele distributions were different but this difference did not reach statistical significance (p= 0.920). Conclusion: We found no association between M55L polymorphism and breast cancer. [ABSTRACT FROM AUTHOR]

Paraoxonase 1 (PON1), an antioxidant enzyme, is believed to play a critical role in many diseases, including cancer. PCBs are widespread environmental contaminants known to induce oxidative stress and cancer and to produce changes in gene expression of various pro-oxidant and antioxidant enzymes. Thus, it appeared of interest to explore whether PCBs may modulate the activity and/or gene expression of PON1 as well. In this study, we compared the effects of dioxin-like and non-dioxin-like PCBs and of various aryl hydrocarbon receptor (AhR) ligands on PON1 regulation and activity in male and female Sprague-Dawley rats. Our results demonstrate that (i) the non-dioxin-like PCB154, PCB155, and PCB184 significantly reduced liver and serum PON1 activities, but only in male rats; (ii) the non-dioxin-like PCB153, the most abundant PCB in many matrices, did not affect PON1 messenger RNA (mRNA) level in the liver but significantly decreased serum PON1 activity in male rats; (iii) PCB126, an AhR ligand and dioxin-like PCB, increased both PON1 activities and gene expression; and (iv) even though three tested AhR ligands induced CYP1A in several tissues to a similar extent, they displayed differential effects on the three PONs and AhR, i.e., PCB126 was an efficacious inducer of PON1, PON2, PON3, and AhR in the liver, while 3-methylcholantrene induced liver AhR and lung PON3, and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), the most potent AhR agonist, increased only PON3 in the lung, at the doses and exposure times used in these studies. These results show that PCBs may have an effect on the antioxidant protection by paraoxonases in exposed populations and that regulation of gene expression through AhR is highly diverse. [ABSTRACT FROM AUTHOR]

Purpose: Patients with oral squamous cell carcinomas (OSCC) often receive radiotherapy to preferentially induce apoptosis of cancer cells through generation of overwhelming DNA damage. This is amplified by generation of reactive oxygen species (ROS), thereby causing oxidative stress and cell death. However, tumors resist through different mechanisms, including upregulation of anti-apoptotic factors and enhanced ROS resistance. We recently reported that the antioxidative enzyme PON2 significantly enhances cellular stress resistance by attenuating mitochondrial ROS-mediated apoptosis. Further, PON2 is often upregulated in cancer. This prompted us to investigate its yet unknown role in the protection of OSCC against irradiation-induced cell death. Methods: PON2 expression was determined after 7 Gy singular irradiation in four OSCC cell lines (PCI-13, PCI-52, SCC-4, SCC-68) accompanied by the detection of caspase 3/7 activity. A direct role of PON2 was tested by siRNA-mediated knockdown. In vivo PON2 expression was tested in five patients with oral carcinoma and compared with healthy mucosa for the evaluation of clinical significance. Results: PON2 is variably expressed in OSCC in vitro and in vivo. Compared with the other cell lines, SCC-4 cells showed twofold more basal PON2 ( p ≤ 0.05) and the lowest caspase 3/7 activity after singular irradiation ( p ≤ 0.05). Contrarily, irradiation led to 1.2-fold induction of PON2 in PCI-13 with no effect on SCC-4 (≤0.05), suggesting that PON2 levels reflect the cells' irradiation sensitivity. In agreement, PON2 knockdown resulted in significant higher apoptosis rates ( p ≤ 0.05). Conclusion: Our findings give first evidence that upregulation of PON2 may protect OSCC against irradiation-induced apoptosis. [ABSTRACT FROM AUTHOR]

Previous evidence has demonstrated that chemical classes of pesticides, including organophosphates (OP), can induce oxidative stress in exposed workers. The resulting increase in free radicals causes damage to biological macromolecules, and promotes the formation of novel compounds, including advanced glycation end products (AGE) and advanced oxidation protein products (AOPP). The present study aimed to evaluate the common genetic polymorphisms of the paraoxonase 1 (PON1) gene in a group of 55 farmers exposed to pesticides, as well as the association between these polymorphisms and serum levels of AGE and AOPP. The 192Q wild-type (WT) allele was present at a significantly higher frequency, compared with the 192R mutated allele (0.74 and 0.26, respectively). The WT allele was predominantly represented by the homozygote 192QQ genotype (51%). The mutated 192QR heterozygotic allele was prevalent, at a frequency of 45.4%, whereas the mutated homozygotes were present at a frequency of 3.6%. A significant decrease in the levels of AGE and AOPP was observed in farmers exhibiting the homozygotic 192RR mutated genotype (14,7221 AU/ml and 0.64 nmol/ml, respectively), compared with the WT genotype (16,1400 AU/ml and 1.76 nmol/ml, respectively), and 192QR genotype (15,2312 AU/ml and 1.60 nmol/ml, respectively). Therefore, due to the high catalytic activity of PON1, the 192RR genotype provides an important genetic predictor of the toxic effects associated with OP pesticide exposure. It determines a minor risk of developing oxidative damage following pesticide exposure, and measuring the levels of AOPP may provide a novel biomarker for oxidative damage in subjects exposed to OP. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is associated with oxidative damage of low density lipoproteins (ox-LDL). In order to investigate whether higher levels of ox-LDL are related to alterations of the activity of enzymes involved in lipid metabolism, we studied the activity of paraoxonase-1 (PON1) and platelet activating factor acetylhydrolase (PAF-AH) in AD patients and the relationship between biochemical markers and severity of the disease. Levels of ox-LDL, PON1 (paraoxonase, arylesterase, and lactonase activities), and PAF-AH activity were evaluated in plasma from 49 patients affected by AD and from 34 control subjects matched for gender and age. Our results demonstrated alterations in the activities of PON1 and PAF-AH in AD patients compared to controls and showed, for the first time, a relationship between the activities of these enzymes, ox-LDL levels, and severity of the disease. A significant negative correlation was observed between the ratio PON1/PAF-AH and ox-LDL. Whatever the causes that contribute to a systemic oxidative stress in AD, our results have shown that AD patients exhibit higher PAF-AH activity than control subjects and higher ox-LDL. This phenomenon, in combination with diminished PON1 in these patients and, consequently, the relatively lower ratio PON1/PAF-AH activity, could contribute to inflammation and oxidative stress of plasma lipoproteins. [ABSTRACT FROM AUTHOR]

Introduction: The enzyme paraoxonase-1 (PON1) represents an endogenous defense mechanism against vascular oxidative stress, thereby contributing to the prevention of atherosclerosis. Several polymorphisms have been reported in the PON1 gene, including Q192R. PON1 phenotype is commonly expressed as the paraoxonase/arylesterase ratio (PON/ARE). The major aim of this study was to investigate the association between PON1 Q192R polymorphism, PON1 phenotypes and the incidence of early-onset acute myocardial infarction (AMI) in Egyptians. Material and methods: The study subjects consisted of 102 AMI patients and 72 age-matched healthy controls. Genotyping and enzyme activities were determined using PCR-RFLP and kinetic spectrophotometric assays, respectively. Results: The genotype distribution for the PON1 gene was significantly different between AMI patients (QQ = 38.24%, QR = 49.02%, RR = 12.75%) and controls (QQ = 66.67%, QR = 25%, RR = 8.33%). Allele frequencies were also significantly different between patients (Q = 62.75%, R = 37.25%) and controls (Q = 79.17%, R = 20.83%). The genotypes QR and RR showed higher risk for AMI compared to the homozygous QQ (odds ratio (OR) = 3.231, p < 0.001). The average PON/ARE ratio in MI patients (1.187 ±0.1) did not differ significantly from controls (1.118 ±0.26). However, it showed a significant difference among different genotypes in both AMI patients (QQ = 0.91 ±0.11, QR = 1.09 ±0.11 and RR = 2.65 ±0.4) (p = 0.0002) and controls (QQ = 0.68 ±0.1, QR = 1.07 ±0.11 and RR = 4.89 ±2.84) (p < 0.0001). Conclusions: PON1 192R allele represents an independent risk factor for early-onset AMI in Egyptians, and PON1 Q192R polymorphism modulates the paraoxonase phenotype. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a state of augmented oxidative stress and diminished antioxidant capacity. High density lipoprotein (HDL) particles were shown to possess antioxidant and anti-inflammatory properties, as well as Paraoxonase 1 (PON1), which is an enzyme that is also protective against HDL oxidation. Previous studies suggested a possible role of decreased PON1 activity or HDL levels in sepsis patients. Aims: The present study was designed to test a hypothesis that higher PON1 activity and HDL-cholesterol levels could predict a better survival in sepsis patients. Study Design: Observational study. Methods: Venous blood samples were collected from sepsis patients for HDL-cholesterol levels, PON1 activity and cytokine assays (TNF-α and IL-6) and Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores were calculated in order to weight patients' disease severity on the day of sepsis diagnosis. Patients were followed-up until the 28th day for any cause intra-hospital mortality. Data were statistically analyzed for effects of study parameters on patients' survival. Results: In total, 85 patients with sepsis were included in the study. The mean age was 65.2±17.9 years and 48 were male; at the end of the 28-day follow-up period, 46 survived. TNF-α (86.9±10.5 vs 118.6Ü6.4) and IL-6 levels (906.7±82.7 vs 1323.Ü54.3) were significantly higher in non-survivors, while PON1 activity (140.7±42.3 vs 66.7±46.6) and HDL-cholesterol levels (43.6±8.1 vs 34.5±8.9) were significantly higher in survivors (p<0.001 for all). TNF-α (r=-0.763) and IL-6 levels (r=-0.947) showed strong negative correlations, PON1 activity (r=0.644) and HDL-cholesterol levels (r=0.477) showed positive correlations with patient survival (p<0.001 for all). Survival estimates significantly favored TNF-α (Log Rank 59.5, p<0.001) and IL-6 levels (Log Rank 53.2, p<0.001) according to PON1 activity (Log Rank 5.4, p<0.03) and HDL-cholesterol levels (Log Rank 8.3, p<0.005). Regression analyses for relative contributions of parameters to survival showed that higher IL-6 levels (t:-16.489, p<0.001) were the most significant negative factor for survival, and TNF-α levels (t:-4.417, p<0.001), whereas PON1 activity had a positive effect (t:3.210, p<0.003). Conclusion: The present study showed that although low PON1 activity and HDL-cholesterol levels were related to mortality, higher levels were not found to be as predictive as cytokine levels for survival. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia (hHCy) is recognized as a co-morbid risk factor of human stroke. It also aggravates the ischemia-induced injury by increased production of reactive oxygen species, and by the homocysteinylation and thiolation of functional proteins. Ischemic preconditioning represents adaptation of the CNS to sub-lethal ischemia, resulting in increased brain tolerance to subsequent ischemia. We present here an overview of recent data on the homocysteine (Hcy) metabolism and on the genetic and metabolic causes of hHCy-related neuropathologies in humans. In this context, the review documents for an increased oxidative stress and for the functional modifications of enzymes involved in the redox balance in experimentally induced hHCy. Hcy metabolism leads also to the redox imbalance and increased oxidative stress resulting in elevated lipoperoxidation and protein oxidation, the products known to be included in the neuronal degeneration. Additionally, we examine the effect of the experimental hHCy in combination with ischemic insult, and/or with the preischemic challenge on the extent of neuronal degeneration as well as the intracellular signaling and the regulation of DNA methylation. The review also highlights that identification of the effects of co-morbid factors in the mechanisms of ischemic tolerance mechanisms would lead to improved therapeutics, especially the brain tissue. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) is important in the pathogenesis of atherosclerosis. Paraoxonase-1 (P0N1) is an enzyme found in the circulation associated with high-density lipoprotein (HDL). HDL-associated enzyme P0N1 has an important role in the attenuation of atherogenic low-density lipo-protein (LDL) oxidation.The aim of this study was to determine P0N1 and arylesterase (AREST) enzyme levels in relation to insulin resistance (IR) or obesity among children and adolescents. The study included healthy school children and adolescents. Blood was drawn for the determination of blood glucose, lipid, P0N1 and AREST enzyme levels. Overall, we observed a positive correlation between PON1 enzyme activity and high-density lipoprotein cholesterol (HDL-C) levels (r = 0.189, P = 0.014).The correlation appeared to be more significant in boys (r=0.271, P=0.009). For subjects with IR and obesity, PON1 enzyme activity did not correlate with HDL-C levels (r=0.038, P=0.790), instead PON1 levels correlated negatively with BMI (r = -0.309 and P = 0.026). Multiple linear regression analysis was performed to find the predictors of log PON1 activity. HDL-C level was the strongest predictor of PON1 activity in the lean control group, while BMI appeared to be the strongest predictor in the subjects with obesity or IR. In conclusion, determinants of PON1 enzyme activity are variable in children and adolescents based on IR and obesity. Future studies will shed light on the underlying mechanisms and biomarkers of OS in children and may reveal possible targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

In our in vitro study, we analyzed the effects of incubation of J774A.1 macrophages with reduced glutathione (GSH) and quercetin on the extent of cellular cholesterol efflux by high-density lipoprotein (HDL) or apolipoprotein A1 (apoA1). This combination was the most potent one among other exogenous and endogenous antioxidant combinations, since it significantly increased the extent of HDL-mediated cholesterol efflux from macrophages by 47% versus control cells, whereas quercetin (20 μM) or GSH (200 μM) alone increased it by only 37% or 17%, respectively. Similarly, apoA1-mediated cholesterol efflux was increased by 11% or 22% in quercetin or quercetin + GSH-treated cells, respectively, versus control cells. These stimulatory effects were noted only after 20 h of cell incubation. The combination of quercetin + GSH demonstrated high scavenging capacity of free radicals versus quercetin or GSH alone. In addition, quercetin + GSH significantly decreased macrophage oxidative stress as measured by the scavenging capacity of free radicals in the cells, the formation of reactive oxygen species, and the levels of cellular glutathione and lipid peroxides. There was no significant effect of quercetin + GSH on cellular HDL binding, on ATP-binding cassette A1 (ABCA1) activity, or on ABCG1 messenger RNA (mRNA) levels. In contrast, mRNA levels for ABCA1 and peroxisome proliferator-activated receptor alpha (PPARα) were both significantly increased by 89% and 93%, respectively, in quercetin + GSH-treated cells versus control cells. Quercetin alone increased the mRNA levels for ABCA1 or PPARα by 42% or 77%, respectively, whereas GSH alone increased it by 22% or 28%, respectively. Mass spectra analysis revealed that oxidized quercetin reacts with GSH to form a new adduct product. We thus conclude that the stimulatory effects of quercetin + GSH on apoA1- or HDL-mediated macrophage cholesterol efflux are related to the ability of GSH to preserve quercetin in its reduced form. [ABSTRACT FROM AUTHOR]

Numerous experimental and epidemiologic studies shown that oxygen-free-radicals are elevated in uncontrolled diabetes mellitus (DM). Paraoxonase-1 (PON1) has been reported to confer antioxidant activities by decreasing the accumulation of lipid peroxidation products. This study was designed to investigate the role of PON1 activity, glutathione reductase (GR), and lipid peroxidation in patients with diabetic nephropathy (DN). 70 subjects were included in the study: 30 as a control, 20 with type 2 DM (T2DM) with nephropathy (DN), 20 T2DM without nephropathy. All studied groups are subjected to the following laboratory investigations after their consents: fasting and postprandial blood glucose, Serum triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL) and low density lipoprotein (LDL), HbA1c, blood urea, serum creatinine, urine microalbumin, serum PON1 activity, serum malondialdehyde (MDA), and serum GR activity. Fasting and postprandial blood glucose levels, and HbA1c was significantly higher in the DN group than the diabetic or control group (p=0.0001). Serum creatinine show a significant rise in the DN group than diabetic or control group (p=0.0001). Microalbuminuria show a significant rise in the DN group than the control or diabetic group as well as in the diabetic group than control group (p=0.0001). Serum PON1 activity and GR level showed significant decrease in diabetic patients with or without nephropathy compared to the control group with a significant decrease in its activity in the DN group while there was a significant a rise of MDA in diabetic groups than control with a significant rise in DN. The decreased antioxidant enzyme activities in DN patients, suggesting that oxidative stress may contribute to the development of DN and other microvascular complications beside chronic hyperglycemia and dyslipidemia. Measurement of PNO1, MDA and GR levels may be a helpful marker in the diagnosis and follow up DN. [ABSTRACT FROM AUTHOR]

Objective Oxidative stress and oxidized high-density lipoprotein (HDL) are implicated as risk factors for cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Yet, how HDL is oxidized and rendered dysfunctional in SLE remains unclear. Neutrophil extracellular traps (NETs), the levels of which are elevated in lupus, possess oxidant-generating enzymes, including myeloperoxidase (MPO), NADPH oxidase (NOX), and nitric oxide synthase (NOS). We hypothesized that NETs mediate HDL oxidation, impairing cholesterol efflux capacity (CEC). Methods Plasma MPO levels and CEC activity were examined in controls and lupus patients, and 3-chlorotyrosine (MPO specific) and 3-nitrotyrosine (derived from reactive nitrogen species) were quantified in human HDL. Multivariable linear models were used to estimate and test differences between groups. HDL was exposed to NETs from control and lupus neutrophils in the presence or absence of MPO, NOX, NOS inhibitors, and chloroquine (CQ). Murine HDL oxidation was quantified after NET inhibition in vivo. Results SLE patients displayed higher MPO levels and diminished CEC compared to controls. SLE HDL had higher 3-nitrotyrosine and 3-chlorotyrosine content than control HDL, with site-specific oxidation signatures on apolipoprotein A-I. Experiments with human and murine NETs confirmed that chlorination was mediated by MPO and NOX, and nitration by NOS and NOX. Mice with lupus treated with the NET inhibitor Cl-amidine displayed significantly decreased HDL oxidation. CQ inhibited NET formation in vitro. Conclusion Active NOS, NOX, and MPO within NETs significantly modify HDL, rendering the lipoprotein proatherogenic. Since NET formation is enhanced in SLE, these findings support a novel role for NET-derived lipoprotein oxidation in SLE-associated CVD and identify additional proatherogenic roles of neutrophils and putative protective roles of antimalarials in autoimmunity. [ABSTRACT FROM AUTHOR]