Alteration of the intestinal microbiota and serum metabolites in a mouse model of Pon1 gene ablation.

Mutations in the Paraoxonase 1 (Pon1) gene underlie aging, cardiovascular disease, and impairments of the nervous and gastrointestinal systems and are linked to the intestinal microbiome. The potential role of Pon1 in modulating the intestinal microbiota and serum metabolites is poorly understood. The present study demonstrated that mice with genomic excision of Pon1 by a multiplexed guide RNA CRISPR/Cas9 approach exhibited disrupted gut microbiota, such as significantly depressed alpha-diversity and distinctly separated beta diversity, accompanied by varied profiles of circulating metabolites. Furthermore, genomic knock in of Pon1 exerted a distinct effect on the intestinal microbiome and serum metabolome, including dramatically enriched Aerococcus, linoleic acid and depleted Bacillus, indolelactic acid. Specifically, a strong correlation was established between bacterial alterations and metabolites in Pon1 knockout mice. In addition, we identified metabolites related to gut bacteria in response to Pon1 knock in. Thus, the deletion of Pon1 affects the gut microbiome and functionally modifies serum metabolism, which can lead to dysbiosis, metabolic dysfunction, and infection risk. Together, these findings put forth a role for Pon1 in microbial alterations that contribute to metabolism variations. The function of Pon1 in diseases might at least partially depend on the microbiome.

Increased oxidative stress in shoe industry workers with low-level exposure to a mixture of volatile organic compounds.

This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, ethers, and carboxylic acids. All measured VOCs were below the permitted occupational exposure limits. The control group included 50 unexposed participants (25 men and 25 women). The following plasma parameters were analysed: superoxide anion (O2 •-), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidant-antioxidant balance (PAB), oxidative stress index (OSI), superoxide dismutase (SOD) and paraoxonase-1 (PON1) enzyme activity, total SH group content (SHG), and total antioxidant status (TAS). Trace metal levels (copper, zinc, iron, magnesium, and manganese) were analysed in whole blood. All oxidative stress and antioxidative defence parameters were higher in the exposed workers than controls, except for PON1 activity. Higher Fe, Mg, and Zn, and lower Cu were observed in the exposed vs control men, while the exposed women had higher Fe and lower Mg, Zn, and Cu than their controls. Our findings confirm that combined exposure to a mixture of VOCs, even at permitted levels, may result in additive or synergistic adverse health effects and related disorders. This raises concern about current risk assessments, which mainly rely on the effects of individual chemicals, and calls for risk assessment approaches that can explain combined exposure to multiple chemicals.

The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis.

The incidence and prevalence of cardiovascular diseases are still rising. The principal mechanism that drives them is atherosclerosis, an affection given by dyslipidemia and a pro-inflammatory state. Paraoxonase enzymes have a protective role due to their ability to contribute to antioxidant and anti-inflammatory pathways, especially paraoxonase 1 (PON1). PON1 binds with HDL (high-density lipoprotein), and high serum levels lead to a protective state against dyslipidemia, cardiovascular diseases, diabetes, stroke, nonalcoholic fatty liver disease, and many others. Modulating PON1 expression might be a treatment objective with significant results in limiting the prevalence of atherosclerosis. Lifestyle including diet and exercise can raise its levels, and some beneficial plants have been found to influence PON1 levels; therefore, more studies on herbal components are needed. Our purpose is to highlight the principal roles of Praoxonase 1, its implications in dyslipidemia, cardiovascular diseases, stroke, and other diseases, and to emphasize plants that can modulate PON1 expression, targeting the potential of some flavonoids that could be introduced as supplements in our diet and to validate the hypothesis that flavonoids have any effects regarding PON1 function.

Effect of fentanyl and remifentanil on neuron damage and oxidative stress during induction neurotoxicity.

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.

Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery-A Randomized, Controlled Clinical Trial.

OBJECTIVES: Cardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role whose activity is decreased in systemic inflammation and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by upregulating PON1 gene expression. The authors aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: The University Medical Center Ljubljana, Slovenia. PARTICIPANTS: Forty adult patients who underwent complex cardiac surgery on CPB between February 2016 and December 2017 were randomized into methylprednisolone and control groups (n = 20 each). INTERVENTIONS: Patients in the methylprednisolone group received 1 g of methylprednisolone in the CPB priming solution, whereas patients in the control group were not given methylprednisolone during CPB. MEASUREMENTS AND MAIN RESULTS: The effect of methylprednisolone from the CPB priming solution was compared with standard care during CPB on PON1 activity until postoperative day 5. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed also. No significant differences were found between study groups for PON1 activity, high-density lipoprotein, and low-density lipoprotein in any of the measurement intervals (p > 0.016). The methylprednisolone group had significantly lower tumor necrosis factor alpha (p < 0.001) and interleukin-6 (p < 0.001), as well as C-reactive protein and procalcitonin (p < 0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and tumor necrosis factor alpha, interleukin-6, and CPB duration. CONCLUSIONS: Methylprednisolone does not influence PON1 activity during cardiac surgery on CPB.

Contribution of the Paraoxonase-2 Enzyme to Cancer Cell Metabolism and Phenotypes.

Paraoxonase-2 (PON2) is a ubiquitously expressed intracellular protein that is localized in the perinuclear region, the endoplasmic reticulum (ER), and mitochondria, and is also associated with the plasma membrane. PON2 functions as an antioxidant enzyme by reducing the levels of reactive oxygen species (ROS) in the mitochondria and ER through different mechanisms, thus having an anti-apoptotic effect and preventing the formation of atherosclerotic lesions. While the antiatherogenic role played by this enzyme has been extensively explored within endothelial cells in association with vascular disorders, in the last decade, great efforts have been made to clarify its potential involvement in both blood and solid tumors, where PON2 was reported to be overexpressed. This review aims to deeply and carefully examine the contribution of this enzyme to different aspects of tumor cells by promoting the initiation, progression, and spread of neoplasms.

Role of paraoxonase 3 in regulating ENaC-mediated Na+ transport in the distal nephron.

Paraoxonase 3 (PON3) is expressed in the aldosterone-sensitive distal nephron, where filtered Na+ is reabsorbed mainly via the epithelial Na+ channel (ENaC) and Na+ -coupled co-transporters. We previously showed that PON3 negatively regulates ENaC through a chaperone mechanism. The present study aimed to determine the physiological role of PON3 in renal Na+ and K+ homeostasis. Pon3 knockout (KO) mice had higher amiloride-induced natriuresis and lower plasma [K+ ] at baseline. Single channel recordings in split-open tubules showed that the number of active channels per patch was significantly higher in KO mice, resulting in a higher channel activity in the absence of PON3. Although whole kidney abundance of ENaC subunits was not altered in Pon3 KOs, ENaC gamma subunit was more apically distributed within the connecting tubules and cortical collecting ducts of Pon3 KO kidneys. Additionally, small interfering RNA-mediated knockdown of PON3 in cultured mouse cortical collecting duct cells led to an increased surface abundance of ENaC gamma subunit. As a result of lower plasma [K+ ], sodium chloride co-transporter phosphorylation was enhanced in the KO kidneys, a phenotype that was corrected by a high K+ diet. Finally, PON3 expression was upregulated in mouse kidneys under dietary K+ restriction, potentially providing a mechanism to dampen ENaC activity and associated K+ secretion. Taken together, our results show that PON3 has a role in renal Na+ and K+ homeostasis through regulating ENaC functional expression in the distal nephron. KEY POINTS: Paraoxonase 3 (PON3) is expressed in the distal nephron of mouse kidneys and functions as a molecular chaperone to reduce epithelial Na+ channel (ENaC) expression and activity in heterologous expression systems. We examined the physiological role of PON3 in renal Na+ and K+ handling using a Pon3 knockout (KO) mouse model. At baseline, Pon3 KO mice had lower blood [K+ ], more functional ENaC in connecting tubules/cortical collecting ducts, higher amiloride-induced natriuresis, and enhanced sodium chloride co-transporter (NCC) phosphorylation. Upon challenge with a high K+ diet, Pon3 KO mice had normalized blood [K+ ] and -NCC phosphorylation but lower circulating aldosterone levels compared to their littermate controls. Kidney PON3 abundance was altered in mice under dietary K+ loading or K+ restriction, providing a potential mechanism for regulating ENaC functional expression and renal Na+ and K+ homeostasis in the distal nephron.

Oxidative stress in polycystic ovary syndrome: a case-control study.

OBJECTIVE: To compare the serum levels of biochemical and oxidative stress markers i.e., malondialdehyde (MDA) and paraoxonase-1(PON1) in polycystic ovary syndrome (PCOS) patients and healthy female individuals of reproductive age group (18-40 years). METHODS: This case-control study was conducted in Dow University of Health Sciences (DUHS), Karachi from June 2019 to October 2020. Seventy Subjects including 35 PCOS patients that have primary subfertility problem (cases) and 35 healthy and fertile females (controls) were recruited. Serum samples were collected for analysis of insulin, sex hormone-binding globulin, testosterone, fasting blood glucose and lipid profile. PON 1 and MDA levels were estimated by ELISA. Comparison between the two groups was done using independent t-test. RESULTS: The patients had significantly increased mean body mass index (28.5+4.6 kg/m2 vs 25.7+4.5 kg/m2, p=0.014), systolic (129.6±13.9 mm of Hg vs 113±7.7 mm of Hg, p<0.001) and diastolic (78.7±8.8 mm of Hg vs 74.6±6.7 mm of Hg, p=0.032) blood pressures compared to controls. The high-density lipoprotein cholesterol levels were significantly lower in PCOS (42.2±8.6mg/dl) than controls (48.8±11.8mg/dl, p=0.009, p=0.009). Serum insulin (14.3±5.8 uIU/mL) vs (10.0±5.2 uIU/mL), p=0.002 and testosterone levels (1.3±0.9 nmol/L) vs (0.82±0.3 nmol/L), p<0.001 were significantly higher whereas sex hormone binding globulin (SHBG) levels (35.2±19.7nmol/L vs 58.8±31.0 nmol/L) were significantly lower in patients than healthy controls (p<0.001). Both oxidative stress markers, paraoxonase 1 (7.7±2.4 vs 6.4±2.6 µg/mL, p=0.04) and malondialdehyde (2.5±1.0 vs 1.9+0.51µg/mL, p=0.034) levels were significantly elevated in PCOS patients than controls. No significant correlation was found between dietary habits and life style between cases and controls. CONCLUSIONS: The study reported significantly elevated levels of oxidative stress markers in PCOS patients.

The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and response in the Emirati population.

BACKGROUND: Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel. METHODS: Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes. RESULTS: Our data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel's transport, enzymatic clearance, and receptor performance. CONCLUSIONS: Recognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles.

Active site engineering of Zn-doped mesoporous ceria toward highly efficient organophosphorus hydrolase-mimicking nanozyme.

Hydrolase-mimicking nanozymes have received increasing attention in recent years, but the effective rational design and development of these materials has not been realized, as they are not at present considered a critical research target. Herein, we report that Zn-doped mesoporous ceria (Zn-m-ceria) engineered to have an abundance of two different active sites with different functions-one that allows both co-adsorption binding of organophosphate (OP) and water and another that serves as a general base-has significant organophosphorus hydrolase (OPH)-like catalytic activity. Specifically, Zn-m-ceria exhibits a catalytic efficiency over 75- and 25-fold higher than those of m-ceria and natural OPH, respectively. First-principles calculations reveal the importance of Zn for the OPH-mimicking activity of the material, promoting substrate adsorption and proton-binding. The OPH-like Zn-m-ceria catalyst is successfully applied to detect a model OP, methyl paraoxon, in spiked tap water samples with excellent sensitivity, stability, and detection precision. We expect that these findings will promote research based on the rational engineering of the active site of nanozymes and efficient strategies for obtaining a diverse range of catalysts that mimic natural enzymes, and hence the utilization in real-world applications of enzyme-mimicking catalysts with properties superior to their natural analogs should follow.

Association of PON1, APOE and SDF-1 Gene Polymorphisms with Treatment Response to Intravitreal Anti-VEGF Treatment in Patients with Retinal Vein Occlusion.

PURPOSE: The purpose of this study was to determine whether specific genetic polymorphisms affect the response to intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with macular oedema secondary to retinal vein occlusion (RVO). METHODS: Participants in this prospective study were 50 patients with macular oedema secondary to RVO, who were treated with intravitreal ranibizumab or aflibercept, and were followed-up for 12 months after initiation of treatment. Five single nucleotide polymorphisms (SNPs) from three different genes (APOE, PON1, SDF-1) were examined as potential predictors for treatment response to intravitreal anti-VEGF agents. RESULTS: Patients with the LL genotype of the PON1 L55M SNP had significantly higher reduction in central subfield thickness (CST) at month 12 after initiation of intravitreal anti-VEGF treatment (101.63 ± 56.80 µm in LL vs. 72.44 ± 39.41 µm in LM vs. 40.25 ± 19.33 µm in MM, p = .026). Patients with the M allele of the PON1 L55M SNP were significantly associated with lower reduction in CST compared to non-carriers (68.29 ± 38.77 µm in LM + MM vs. 101.63 ± 56.80 µm in LL, p = .032). CONCLUSION: PON1 L55M SNP may serve as a promising genetic biomarker for predicting response to intravitreal anti-VEGF treatment in patients with macular oedema due to RVO.

Prognostic Impact of Serum Homocysteine-Lowering Therapy on Patients with Hemorrhagic Stroke and Its Influence on National Institutes of Health Stroke Scale and China Stroke Scale Scores.

Objective: This study aimed to investigate the prognostic impact of serum homocysteine-lowering therapy on patients with hemorrhagic stroke (HS) and its influence on their National Institutes of Health Stroke Scale (NIHSS) and China Stroke Scale (CSS) scores. Methods: A double-blind study involving 120 patients with HS and hyperhomocysteinemia (Hhcy) who were admitted to our hospital was conducted in 2021. They were evenly divided into two groups: the control group (n=60) received low-dose folic acid, methylcobalamin, and vitamin B6 as part of serum homocysteine-lowering therapy, while the study group (n=60) received high-dose folic acid, methylcobalamin, and vitamin B6. The prognosis of each group was compared using the NIHSS and CSS to assess the neurological function of the patients. Results: Before treatment, the levels of oxidative stress markers and vascular endothelial function markers were comparable between the two groups (t = 0.051, 0.015, 0.010, 0.011, 0.013, 0.022, P = .960, .988, .992, 0.991, .989, 0.982). However, after treatment, the study group exhibited higher levels of MDA and ET-1 compared to the control group (t = 3.418, 1.978, P < .001). Additionally, SOD, GSH-Px, and PON1 levels were lower in the study group (t = 3.435, 3.783, 2.735, 3.893, P < .001). The NIHSS scores before treatment were comparable among patients (t = 0.058, P = 0.954), but after treatment, the study group showed significantly lower NIHSS scores (t = 20.105, P < .001). Similarly, the CSS scores before treatment were comparable (t = 0.046, P = .963), but the CSS scores in the study group after treatment were significantly lower (t = 5.027, P < .001). Conclusions: High-dose folic acid, methylcobalamin, and vitamin B6 as part of serum homocysteine-lowering therapy can improve oxidative stress and vascular endothelial function in HS patients. This treatment also enhances prognosis and ameliorates neurological deficits. Therefore, it holds significant clinical potential and should be considered for broader adoption.

Integrative Multianalytical Model Based on Novel Plasma Protein Biomarkers for Distinguishing Lung Adenocarcinoma and Benign Pulmonary Nodules.

Given the pressing clinical problem of making a decision in diagnosis for subjects with pulmonary nodules, we aimed to discover novel plasma protein biomarkers for lung adenocarcinoma (LUAD) and benign pulmonary nodules (BPNs) and then develop an integrative multianalytical model to guide the clinical management of LUAD and BPN patients. Through label-free quantitative plasma proteomic analysis (data are available via ProteomeXchange with identifier PXD046731), 12 differentially expressed proteins (DEPs) in LUAD and BPN were screened. The diagnostic abilities of DEPs were validated in two independent validation cohorts. The results showed that the levels of three candidate proteins (PRDX2, PON1, and APOC3) were lower in the plasma of LUAD than in BPN. The three candidate proteins were combined with three promising computed tomography indicators (spiculation, vascular notch sign, and lobulation) and three traditional markers (CEA, CA125, and CYFRA21-1) to construct an integrative multianalytical model, which was effective in distinguishing LUAD from BPN, with an AUC of 0.904, a sensitivity of 81.44%, and a specificity of 90.14%. Moreover, the model possessed impressive diagnostic performance between early LUADs and BPNs, with the AUC, sensitivity, specificity, and accuracy of 0.868, 65.63%, 90.14%, and 82.52%, respectively. This model may be a useful auxiliary diagnostic tool for LUAD and BPN by achieving a better balance of sensitivity and specificity.

Recombinant Organophosphorus acid anhydrolase (OPAA) enzyme-carbon quantum dot (CQDs)-immobilized thin film biosensors for the specific detection of Ethyl Paraoxon and Methyl Parathion in water resources.

Organophosphates pesticide (OP) toxicity through water resources is a large concern globally among all the emerging pollutants. Detection of OPs is a challenge which needs to be addressed considering the hazardous effects on the health of human beings. In the current research thin film biosensors of recombinant, Organophosphorus acid anhydrolase (OPAA) enzyme along with carbon quantum dots (CQDs) immobilized in thin films were developed. OPAA-CQDs thin film biosensors were used for the specific detection of two OPs Ethyl Paraoxon (EP) and Methyl Parathion (MP) in river water and household water supply. Recombinant OPAA enzyme was expressed in E. Coli, purified and immobilized on the CQD containing chitosan thin films. The CQDs used for this purpose were developed by a one-pot hydrothermal method from phthalic acid and Tri ethylene diamine. The properties of CQDs, OPAA and thin films were characterized using techniques like XPS, TEM, XRD, enzyme activity and CLSM measurements. Biosensing studies of EP and MP were performed by taking fluorescence measurements using a fiber optic spectrometer. The analytical parameters of biosensing were compared against an estimation carried out using the HPLC method. The biosensing performance indicates that the OPAA-CQDs thin film-based biosensors were able to detect both EP and MP in a range of 0-100 µM having a detection limit of 0.18 ppm/0.69 ppm for EP/MP, respectively with a response time of 5 min. The accuracy of estimation of EP/MP when spiked in water resources lie in the range of ∼100-102% which clearly indicates the OPAA-CQD based thin film biosensors can function as a point-of-use method for the detection of OP pesticides in complex water resources.

Unveiling the therapeutic potential of a mutated paraoxonase 2 in diabetic retinopathy: Defying glycation, mitigating oxidative stress, ER stress and inflammation.

Paraoxonase 2 (PON2) is an intracellular anti-oxidant protein ubiquitously expressed in all cells and reduces reactive oxygen species, endoplasmic reticulum (ER) stress, further improves mitochondrial function and thereby shows anti-apoptotic function. In diabetes and its complications this PON gets glycated and becomes in effective. The PON activity is reported to be reduced in diabetic retinopathy and we have earlier showed Carboxy methyl lysine (AGE) decreased PON2 expression and activity in Human retinal endothelial cells (HREC) . In this study, we have designed and developed a mutated PON2 by in silico and in vitro approach which can resist glycation. Where in glycation-prone residues in PON2 was predicted using in silico analyses and a mutated PON2 was developed using in vitro site directed mutagenesis (SDM) assay mPON2 (mutant PON2-PON2-K70A) and its efficacy was compared with wPON2 (wild type PON2). CML glycated wPON2 and reduced its activity when compared with mPON2 in HREC confirmed by immunoprecipitation and in vitro experiments. Additionally, mPON2 interaction efficiency with its substrates was higher than wPON2 by insilico assay and demonstrated enhanced inhibition against CML-induced oxidative stress, ER stress, pro-inflammation, and mitochondrial fission than wPON2 by invitro assay. Further mPON2 showed increased inhibition of phosphorylation of NFĸB induced by CML. Our investigation establishes that the over expression of mPON2 in HREC can defy glycation and therefore mitigate ER stress and inflammation against CML than endogenous wPON2. These findings imply that mPON2 can be a beneficial therapeutic target against diabetic retinopathy.

Paraoxonase and arylesterase activity of paraoxonase 1 and oxidative stress parameters in cervical intraepithelial neoplasia.

Introduction: Paraoxonase 1 (PON1) is the enzyme that removes carcinogenic radicals from lipids. The aim of the study was to investigate the differences in PON1 activity and oxidation stress parameters between patients with cervical intraepithelial neoplasia (CIN) and healthy controls. Materials and methods: The study included 65 women with CIN and 109 healthy women. Lipid parameters were determined on Cobas Integra 400 plus (Roche, Mannheim, Germany). Tiols and reduced glutathione (GSH) were determined spectrophotometric using Eliman reagent. Activity of PON1 was assessed with two substrates, paraoxon and phenylacetate by spectrophotometric method. Malondialdehyde (MDA) was determined by high performance liquid chromatography (Shimadzu Corporation, Kyoto, Japan). Mann-Whitney-test, t-test, χ2-test, correlation and logistic regression was used in statistical analysis. P < 0.05 was considered statistically significant. Results: The basal (P = 0.929) and NaCl-stimulated (P = 0.985) PON1 activity and activities standardised on the concentration of high-density lipoprotein (HDL; P = 0.076; P = 0.065, respectively) and apolipoprotein AI (apo AI; P = 0.444; P = 0.499, respectively) as well as PON1 phenotypes (P = 0.842) did not differ significantly between the groups. The PON1 arylesterase activity (53±19 kU/L vs. 77±17 kU/L; P < 0.001) and HDL-standardized activity (37 (28-44) kU/mmol vs. 43 (37-50) kU/mmol; P < 0.001) and apoAI (29±11 kU/g vs. 44±11 kU/g; P < 0.001) was significantly reduced in the CIN group. The concentration of the thiol groups was similar (P = 0.519), of MDA was lower (0.39 (0.27-0.55) µmol/L vs. 0.76 (0.57-1.15) µmol/L; P < 0.001) and of GSH was higher (112.0 (66.0-129.6) µg/mL vs. 53.4 (34.8-134.4) µg/mL; P < 0.001) in the CIN group. Conclusion: Reduced PON1 arylesterase activity, lower MDA and higher GSH concentration were observed in CIN patients.

Signature of paraoxonases in the altered redox homeostasis in Alzheimer's disease.

Paraoxonase (PON) enzymes (PON1, PON2 and PON3) exert antioxidant properties through arylesterase, lactonase and paraoxonase activities. Increasing findings suggested their potential involvement, particularly PON1 and PON2, in Alzheimer's disease (AD), a neurodegenerative pathology characterized by early oxidative stress. Specifically, decreased serum PON1-arylesterase and lactonase activities seem to be associated with an increased brain oxidative damage in early AD, leading to hypothesize that PON activity alterations might be an early event in AD. To address this hypothesis, the levels of 4-hydroxynonenal (4-HNE; i.e. a marker of oxidative stress damage) along with the protein expression and enzymatic activity of PON1 and PON2 have been investigated in the brain and serum of young [Postnatal day (PD)8-10, 20-25 and 60-65] asymptomatic 3xTg-AD female mice, one of the most used transgenic models of AD. At PD 8-10, there were no differences in hippocampus and prefrontal cortex (PFC) 4-HNE expression levels between 3xTg-AD mice compared to controls (Non-Tg mice). On the other hand, significant increased levels of 4-HNE were detected in PD 20-30 3xTg-AD mice hippocampus, while a significant reduction was observed in 3xTg-AD group at PD 60-65. In the PFC, 4-HNE levels were significantly reduced in 3xTg-AD mice brain at PD 20-30, while no differences in 4-HNE levels were detected at PD 60-65. No significant differences in arylesterase and lactonase activities were observed in the plasma of 3xTg-AD and Non-Tg mice at the different considered ages. Compared to Non-Tg mice, a reduction of brain arylesterase activity was found in 3xTg-AD female at PD 20-30 and PD 60-65, but it was significant only in the younger group. Finally, a similar trend was observed also for PON1 and PON2 protein levels, with both significantly, and solely, decreased in 3xTg-AD mice brain at PD 20-30. Overall, these findings suggest that the altered oxidative stress homeostasis in the 3xTg-AD female mice may be related to an early reduction in activity and expression of PONs enzymes most likely via a reduced brain arylesterases activity.

Investigation of serum ischemic-modified albumin, galectin-3, paraoxonase-1, and myeloperoxidase activity levels in patients with acute brucellosis.

OBJECTIVES: Infection remains current as an important discussion topic in the etiological factors of atherosclerosis. Ischemic-modified albumin (IMA), galectin-3 (gal-3), paraoxonase-1 (PON-1), and myeloperoxidase (MPO) are biomolecules that play an important role in the pathogenesis of atherosclerosis. Our aim is to investigate serum IMA, gal-3, PON-1, and MPO activity in acute brucellosis infection. MATERIALS AND METHODS: Forty patients with acute brucellosis and 40 healthy individuals were included in the study. Serum IMA, gal-3, PON-1, and MPO activity were analyzed by the ELISA method. RESULTS: In acute brucellosis infection, serum gal-3, IMA, and MPO activities were found to be significantly increased compared to the control group, and PON-1 activity was found to be significantly decreased compared to the control group (p < 0.001). There was a positive correlation between serum IMA, and MPO activity (r = 0.707 p = 0.000) and a negative correlation (r = -0.943, p = 0.000) between PON-1 activity. There was a positive correlation between serum gal-3 and MPO activity (r = 0.683, p = 0.000) and IMA level (r = 0.927, p = 0.000) and a negative correlation between PON-1 activity (r = -0.951, p = 0.000).Conclusion, it was found that serum gal-3, IMA levels and MPO activity increased, while PON-1 activity decreased. These results showed that the oxidant-anti-oxidant balance is impaired in acute brucellosis infection. In addition, these results indicate that brucella infection may be increase the risk of atherosclerosis. Further studies are needed to support our findings.

Thymus atlanticus (Ball) Roussine Aqueous Extract Exerts Lipid-lowering and Anti-atherosclerotic Effects in Hyperlipidemic Guinea Pigs.

BACKGROUND: Thymus atlanticus (Ball) Roussine (T. atlanticus) is traditionally used in the Moroccan high Atlas Mountains to treat several disorders, including cardiovascular disease. In the present study, the lipid-lowering and anti-atherosclerotic activities of the traditionally used aqueous extract of T. atlanticus were evaluated on guinea pigs subjected to chronic hyperlipidemia. METHODS: Animals were given a diet containing 2% cholesterol and 20% lard for 12 weeks. Moreover, thyme extract was given daily at 400 mg/kg. At the end of the experiment, lipid levels and paraoxonase arylesterase activity were measured, and aorta histology was studied. RESULTS: Our findings revealed that there was an important elevation of blood lipids in the HFD group along with a significant decrease in paraoxonase arylesterase activity (-40.06%). Moreover, the consumption of fat altered the histology of aorta by thickening the intima media and forming atherosclerotic lesions and foam cells in these tissues. However, the administration of thyme extract attenuated HFD-caused alterations by decreasing blood lipids, elevating paraoxonase activity (+24.04%), and limiting the progression of atherosclerotic lesions. CONCLUSION: We conclude that the supplementation with the aqueous extract of T. atlanticus could potentially protect against hyperlipidemia and consequently, the development of atherosclerosis.

Regular Practice of Physical Activity Improves Cholesterol Transfers to High-Density Lipoprotein (HDL) and Other HDL Metabolic Parameters in Older Adults.

The effects of regular physical activity on two important anti-atherosclerosis functions of high-density lipoprotein (HDL), namely its capacity to receive both forms of cholesterol and its anti-oxidant function, were investigated in this study comparing older adults with young individuals. One-hundred and eight healthy adult individuals were enrolled and separated into the following groups: active older (60-80 yrs, n = 24); inactive older (60-79 yrs, n = 21); active young (20-34 yrs, n = 39); and inactive young (20-35 yrs, n = 24). All performed cardiopulmonary tests. Blood samples were collected in order to assess the following measures: lipid profile, HDL anti-oxidant capacity, paraoxonase-1 activity, HDL subfractions, and lipid transfer to HDL. Comparing active older and active young groups with inactive older and inactive young groups, respectively, the active groups presented higher HDL-C levels (p < 0.01 for both comparisons), unesterified cholesterol transfer (p < 0.01, p < 0.05), and intermediate and larger HDL subfractions (p < 0.001, p < 0.01) than the respective inactive groups. In addition, the active young group showed higher esterified cholesterol transfer than the inactive young group (p < 0.05). As expected, the two active groups had higher VO2peak than the inactive groups; VO2peak was higher in the two younger than in the two older groups (p < 0.05). No differences in unesterified and esterified cholesterol transfers and HDL subfractions were found between active young and active older groups. HDL anti-oxidant capacity and paraoxonase-1 activity were equal in all four study groups. Our data highlight and strengthen the benefits of regular practice of physical activity on an important HDL function, the capacity of HDL to receive cholesterol, despite the age-dependent decrease in VO2peak.