Arylesterase Activity Research Articles

Temporal proteomic and phosphoproteomic profiling of the left ventricle in a novel rat model of ischemia/reperfusion with or without ischemic preconditioning

Abstract Background The relationship between ischemic preconditioning (IPC) and myocardial stunning is incompletely understood. Preconditioning has been shown to protect against ischemic injury, whereas myocardial stunning, i.e. transient contractile dysfunction in the setting of ischemia, can lead to severe heart failure and has been considered a deleterious process. To understand this relationship, we recently developed a novel rat model of ischemia-reperfusion (I/R) injury in the presence or absence of IPC. In the presence of IPC (2 cycles of 5 min of I/R followed by 13.5 min of ischemia), we observe a profound myocardial stunning at 4h of reperfusion which completely resolves at 48h. In the absence of IPC, we observe necrosis at 4h of reperfusion and sustained injury at 48h. Despite extensive studies on IPC and myocardial stunning in the setting of I/R, the molecular basis of the relationship between these phenomena are still unknown. Purpose To investigate alterations in protein expression after IPC and myocardial stunning in a novel rat model of I/R injury. Methods We utilized tandem mass tags and mass spectrometry to identify temporal changes in the proteomic- and phosphoproteomic-profiles in left ventricular (LV) tissue from rat hearts following 13.5 min of ischemia and 4h of reperfusion in the presence of absence of IPC. Results Proteomics analysis of the LV tissues collected at baseline showed that 115 proteins were differentially expressed between IPC and non-IPC groups. We observed abundant changes in sarcoplasmic proteins, sarcoplasmic reticulum-related proteins, and actin-based cell projection proteins. Most of these proteins are implicated in arylesterase activity, haemoglobin binding, and nitrogen metabolism. At 4h, differentially expressed proteins were predominantly related to wound healing, coagulation, and lipase activity. Phosphoproteomic analysis at baseline showed that 686 phosphosites were differentially regulated between IPC and non-IPC groups. Aberrant phosphorylation patterns mostly occurred in sarcomere proteins, Z-disc, I-band, contractile fiber associated with actin binding, and the thyroid hormone signalling pathway. At 4h, 520 phosphosites differed between IPC and non-IPC rats; these phosphosites were abundant in contractile fiber proteins, myofibril proteins, and sarcomere proteins associated with calcium signalling and cardiomyopathies. Conclusions This study demonstrates marked changes in proteins and phosphosites related to lipase activity, haemoglobin binding, calcium signalling, and the cardiac contractile apparatus in IPC versus non-IPC groups. This extensive catalogue of novel proteins and phosphosites associated with IPC and myocardial stunning in the setting of I/R injury sets the stage for future manipulation of myocardial stunning and preconditioning in both experimental and clinical settings.

Oxidant and antioxidant balance in children with bacteremia.

There is a crucial balance between oxidant and antioxidant defense mechanisms. We aimed to evaluate the role of the balance of these systems in children with bloodstream infection. We analyzed prospectively oxidant and antioxidant stress parameters from serum samples of children with BSI besides demographic and clinical data of children. Serum levels of the total antioxidant status (TAS), total oxidant status (TOS), albumin, plasma thiol, disulphide, catalase (CAT), myeloperoxidase (MPO), ischemia-modified albumin (IMA) levels, ferroxidase and arylesterase (ARES) activity were evaluated in both patients and healthy controls. A total of 113 children were evaluated, 50 of them had bacteremia and the remaining 63 were healthy subjects. The median TOS values were 18.5 µmol H<inf>2</inf>O<inf>2</inf>/L and 13.1 µmol H<inf>2</inf>O<inf>2</inf>/L in patient and control groups, respectively with a statistically significant difference between groups. The mean serum IMA levels were 0.8±0.1 absorbance unit (ABSU) in patients and 0.5±0.09 ABSU in control, the difference between groups was statistically significant. The native thiol, total thiol levels and the disulphide levels were significantly lower in the patient group as compared with the control group. The myeloperoxidase level was 136 U/L in patients and 107 in controls with a statistically significant difference between groups. TOS, IMA, MPO, and particularly plasma thiols seem good candidates for accurate diagnosis of bacteremia in children.

Assessment of amino-terminal C-type natriuretic peptide serum level and its correlation with high-density lipoprotein structure and function in patients with end stage renal disease before and after kidney transplantation

We aimed to investigate serum amino-terminal C-type natriuretic peptide (NT-proCNP) and its relationship with quantitative and qualitative HDL-parameters in patients with end-stage renal disease (ESRD) before, then 1 and 6 months after kidney transplantation (TX). Seventy patients (47 males, 23 females, mean age 51.7 ± 12.4 years) were enrolled in a prospective follow-up study. We examined serum creatinine, C-reactive protein, procalcitonin, fasting glucose and lipid parameters before, then 1 and 6 months after TX. High-density lipoprotein- (HDL)-associated paraoxonase-1 (PON1) paraoxonase and arylesterase activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. NT-proCNP and oxidized low-density lipoprotein (oxLDL) levels were measured by ELISA. Mean NT-proCNP was 45.8 ± 21.9 pmol/L before renal transplantation and decreased markedly 1 month and 6 months after transplantation (5.3 ± 2.5 and 7.7 ± 4.9 pmol/L, respectively, P = 1 × 10−4). During the 6 months’ follow-up, PON1 arylesterase, paraoxonase and salt-stimulated paraoxonase activities improved. NT-proCNP positively correlated with procalcitonin and creatinine and negatively with GFR, LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C). There was a negative correlation between serum NT-proCNP and PON1 arylesterase activity. According to the multiple regression analysis, the best predicting variables of NT-proCNP were serum procalcitonin, creatinine and PON1 arylesterase activity. NT-proCNP might be a novel link between HDL dysfunction and impaired vascular function in ESRD, but not after kidney transplantation. Further studies in larger populations are needed to clarify the exact role of NT-proCNP in the risk prediction for cardiovascular comorbidities and complications in ESRD.

Myeloperoxidase/paraoxonase ratio as a prognostic marker for post-COVID syndrome in patients undergoing hemodialysis: A cross-sectional cohort study

The present study aimed to assess the impact of post-COVID syndrome on the oxidative status and activity of paraoxonase 1 (PON-1), myeloperoxidase (MPO), and leukocyte elastase in the blood of patients undergoing hemodialysis (HD).&#x0D; Methods. In this cross-sectional cohort study, 290 patients undergoing HD were included. The oxidative status was assessed based on the levels of blood malondialdehyde (MDA), ceruloplasmin, thiol compounds (SH-groups), and the serum activities of myeloperoxidase (MPO), paraoxonase-1 (PON-1), and elastase were determined.&#x0D; Results. It was found that HD patients exhibited an elevation in oxidative processes, characterized by increased blood concentrations of MDA, MPO, elastase activity, and a decrease in the levels of SH-groups and arylesterase activity of PON-1. Patients with post-COVID syndrome showed further increases in MPO activity and a decrease in arylesterase activity of PON-1. Additionally, a statistically significant elevation in the MPO/PON-1 ratio was observed in HD patients with post-COVID syndrome compared to the control group and patients examined before the onset of the pandemic (p &lt; 0.0001). The MPO/PON-1 ratio exhibited a direct correlation with serum MDA levels (p &lt; 0.0001) and inversely correlated with the concentration of ceruloplasmin (p = 0.0008). The MPO/PON-1 value surpassing 9.06 units was identified as a predictive marker for PCS, demonstrating a specificity of 68.4% and a sensitivity of 88.5%.&#x0D; Conclusions. Our study highlights a significant impact of post-COVID syndrome on oxidative processes in HD patients, as evidenced by elevated MDA levels and MPO activity, along with reduced levels of antioxidants and arylesterase activity of PON-1. The MPO/PON-1 ratio emerges as a promising predictive marker for post-COVID syndrome, underlining its potential clinical relevance in identifying at-risk patients.

Combined western diet and bisphenol A exposure induces an oxidative stress-based paraoxonase 1 response in larval zebrafish

Paraoxonase 1 (PON1) is an antioxidant enzyme linked to metabolic disorders by genome-wide association studies in humans. Exposure to metabolic disrupting chemicals (MDCs) such as bisphenol A (BPA), together with genetic and dietary factors, can increase the risk of metabolic disorders. The objective of this study was to investigate how PON1 responds to the metabolic changes and oxidative stress caused by a western diet, and whether exposure to BPA alters the metabolic and PON1 responses. Zebrafish larvae at 14 days post fertilization were fed a custom-made western diet with and without aquatic exposure to two concentrations of BPA for 5 days. A combination of western diet and 150 μg/L BPA exposure resulted in a stepwise increase in weight, length and oxidative stress, suggesting that BPA amplifies the western diet-induced metabolic shift. PON1 arylesterase activity was increased in all western diet and BPA exposure groups and PON1 lactonase activity was increased when western diet was combined with exposure to 1800 μg/L BPA. Both PON1 activities were positively correlated to oxidative stress. Based on our observations we hypothesize that a western diet caused a shift towards fatty acid-based metabolism, which was increased by BPA exposure. This shift resulted in increased oxidative stress, which in turn was associated with a PON1 activity increase as an antioxidant response. This is the first exploration of PON1 responses to metabolic challenges in zebrafish, and the first study of PON1 in the context of MDC exposure in vertebrates.

Revealing mechanism of Methazolamide for treatment of ankylosing spondylitis based on network pharmacology and GSEA

Methazolamide is a carbonic anhydrase (CA) inhibitor with satisfactory safety. Our previous studies have demonstrated the elevation of CA1 expression and the therapeutic effect of Methazolamide in Ankylosing spondylitis (AS). In this study, we explored the pathogenic role of CA1 and the pharmacological mechanism of Methazolamide in AS through Gene Set Enrichment Analysis (GSEA) and network pharmacology. Seven out of twelve CA1 related gene sets were enriched in AS group. CA1 was core enriched in above seven gene sets involving zinc ion binding, arylesterase activity and one carbon metabolic process. Functional analysis of the candidate target genes obtained from the intersection of AS associated genes and Methazolamide target genes indicated that Methazolamide exerts therapeutic effects on AS mainly through inflammatory pathways which regulate the production of tumor necrosis factor, IL-6 and nitric oxide. PTGS2, ESR1, GSK3β, JAK2, NOS2 and CA1 were selected as therapeutic targets of Methazolamide in AS. Molecular docking and molecular dynamics simulations were performed successfully. In addition, we innovatively obtained the intersection of Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and GSEA results, and found that 18 GO terms and 5 KEGG terms were indicated in the pharmacological mechanism of Methazolamide in AS, involving bone mineralization, angiogenesis, inflammation, and chemokine signaling pathways. Nevertheless, validation for these mechanisms is needed in vivo/vitro experiments.

High-density lipoprotein dysfunction in carotid artery stenosis.

Background: High density lipoprotein (HDL) is well established to have an athero-protective role under normal conditions; however, pro-inflammatory alteration of HDL proteins may transform the HDL particle into a dysfunctional molecule. Our aim was to investigate HDL dysfunction by measuring enzyme-based markers in carotid artery stenosis (CAS). Patients and methods: All participants underwent duplex ultrasound and 52 subjects diagnosed with CAS and 51 subjects who had no significant stenosis (as controls) were enrolled in this study. Serum lipid profiles and serum parameters associated with dysfunctional HDL including myeloperoxidase (MPO), paraoxonase 1 (PON1), arylesterase (ARE) activity, and lipid hydroperoxide (LOOH) levels were measured. Results: It was found that the patients with CAS had increased levels of MPO and LOOH while PON1 activity was decreased. There was no significant difference between the CAS and non-CAS groups in terms of HDL levels. MPO/PON1, MPO/ARE, and LOOH/PON1 ratios were significantly increased in the CAS group. MPO/PON1 and MPO/ARE ratios both demonstrated significant correlations with degree of stenosis (%). Conclusions: The MPO/PON1 and MPO/ARE ratios may be potential serum markers that can enable the monitoring of HDL functionality and the assessment of atherosclerotic disease risks. Additionally, monitoring the oxidative balance of lipids on HDL molecules by LOOH/PON1 ratio may have value in the early detection of pro-atherosclerotic transformation of the HDL particle.

Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with l-carnitine under systemic inflammation

The current study was conducted to examine the effect of l-carnitine (LC) supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase/protein kinase B pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). In addition to comparing the responses in cows with or without LC, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an LC-supplemented group (CAR; 25 g LC/cow per day; d 42 ante partum to d 126 postpartum (PP), n = 27). On d 111 PP, each cow was injected intravenously with LPS (Escherichia coli O111:B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary LC supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of LC. Dietary LC supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary LC than the outer mitochondrial membrane translocase (TOM complex).

Paraoxonase 1 Activity and Renal Replacement Therapy for Chronic Renal Failure: A Meta-Analysis.

Chronic renal failure (CRF) is associated with the development of cardiovascular disease (CVD). Paraoxonase 1 (PON1), an antioxidant enzyme, shows cardioprotective properties and has been proposed as a therapeutic marker for CRF. A systematic analysis of the literature assessing the association between PON1 activity and renal replacement therapy (RRT) of CRF is currently lacking. Therefore, we set out to perform a meta-analysis of the available data on PON1 in RRT of CRF. We searched three electronic databases for studies on PON1 activity in CRF patients with RRT such as hemodialysis (HD), peritoneal dialysis (PD), or renal transplantation (RTx), published before June 2023. A random-effects and network meta-analysis were performed. A total of 53 studies were eligibly identified. Compared to CRF patients without RRT, RTx patients had higher paraoxonase activity (standard mean difference (SMD), 1.76, 95% confidence interval (CI), 0.76-2.75), followed by HD (SMD, 0.73; 95% CI, 0.02-1.45) and PD patients. Likewise, RTx patients had higher arylesterase activity (SMD, 1.84, 95% CI, 0.18-3.50), followed by HD and PD patients. Also, paraoxonase activity was increased after HD (SMD, 0.59, 95% CI, 0.16-1.03). In conclusion, the overall data demonstrated that PON1 activity is higher in CRF patients with RRT, particularly RTx, followed by that of HD and PD. Measuring PON1 activity can also be included to the paraclinical toolbox for the management of RRT, in addition to the understanding of CRF-related pathophysiology. Regarding the selection of RRT types and their potential to prevent CVD, more research is required.

Expression of paraoxonase 1 in HEK293 cells and its effect on lactonase and arylesterase activity in samples containing human serum and/or prooxidant or antioxidant agents - a preliminary study

Expression of recombinant paraoxonase 1 (PON1) in the human embryonic kidney (HEK293F) cell line was evaluated. Two recombinant human PON1 proteins were investigated: PON1-Fc, which has an Fc-tag on its C-terminal, and His-PON1-Fc, which has an Fc-tag on its C-terminal and histidine on its N-terminal. The influence of high and low-density lipoproteins, copper ions, iron ions, and thiolactone homocysteine, on arylesterase and lactonase activities of PON1 in human serum was examined. Two activities of PON1, arylesterase and lactonase, were measured using earlier elaborated kinetic spectrophotometric method with temperature control at 37°C using the water thermostated cuvette holder. It was demonstrated that the HEK293F expression platform is useful for obtaining recombinant human PON1 protein. Also, addition of high-density lipoprotein increased serum arylesterase and lactonase activity of PON1 to a greater extent than the addition of PON1-Fc or HisPON1-Fc recombinant proteins. In contrast, the addition of high-density lipoprotein to samples containing PON1-Fc or His-PON1-Fc did not increase PON1 activities, while low-density lipoprotein, copper ions, and iron ions, depressed PON1 arylesterase and lactonase activity. Obtained results indicated that it may be advantageous to stimulate PON1 activities rather than supplement with endogenous PON1 protein and HDL, which could be an interesting direction for further study. Furthermore, the work has highlighted some potential research directions for the use of PON1 as a therapeutic molecules. Nevertheless, the study had some limitations and should therefore be treated as a preliminary study.

Paraoxonase/Arylesterase Activity of Serum Paraoxonase-1 and Schizophrenia: A Systematic Review and Meta-Analysis.

The presence of a pro-oxidant state in patients with schizophrenia may account for the increased risk of atherosclerosis and cardiovascular disease in this group and supports the potential utility of circulating biomarkers of oxidative stress for risk stratification and management. We investigated this issue by conducting a systematic review and meta-analysis of the association between the circulating concentrations of paraoxonase-1, an antioxidant calcium-dependent high-density lipoprotein (HDL)-associated esterase, with paraoxonase and arylesterase activity in schizophrenia. We searched electronic databases from inception to 31 May 2023 for studies investigating paraoxonase-1 in patients with schizophrenia and healthy controls and assessed the risk of bias and the certainty of evidence (PROSPERO registration number: CRD42023435442). Thirteen studies were identified for analysis. There were no significant between-group differences in paraoxonase (standard mean difference, SMD = 0.12, 95% CI -0.23 to 0.48, p = 0.50; extremely low certainty of evidence) or arylesterase activity (SMD = -0.08, 95% CI -0.39 to 0.23, p = 0.61; very low certainty of evidence). However, in meta-regression and subgroup analysis we observed significant associations between the SMD of paraoxonase and age (p = 0.003), HDL-cholesterol (p = 0.029), and study country (p = 0.04), and the SMD of arylesterase and age (p = 0.007), body mass index (p = 0.012), HDL-cholesterol (p = 0.002), and pharmacological treatment for schizophrenia (p < 0.001). In the absence of overall between-group differences, our systematic review and meta-analysis suggests that alterations in paraoxonase-1 may reflect a pro-oxidant state in specific subgroups of patients with schizophrenia that require further assessment in appropriately designed studies.

Antioxidant Potential of Thymus willdenowii Boiss &amp; Reut. Aqueous Extract and Effect of its Supplementation on Hyperlipidemia and Paraoxonase-1 Arylesterase Activity in High-Fat Diet-Fed Rats

Background: Thymus willdenowii Boiss &amp; Reut. (T. willdenowii) is a medicinal plant that grows in the Moroccan High Atlas Mountains. It is used in local folk medicine to treat several disorders including cardiovascular disease. Objective: In this study, we aimed to evaluate the antioxidant and anti-hyperlipidemic effects of the traditionally used aqueous extract of T. willdenowii. Methods: The extraction of the plant was assessed using the traditionally used decoction method. Total contents of polyphenols (TPC), flavonoids (TFC), and tannins (TTC) were estimated and in vitro antioxidant assays namely DPPH, FRAP, and TAC were carried out to evaluate its antioxidant potential. Moreover, the anti-hyperlipidemic activity was tested on rats fed a high-fat diet (HFD) containing sucrose (15%), lard (15%), and cholesterol (2%). Thyme extract was given daily at 500 mg/kg. Results: After 2 months of treatment, lipid profile parameters and arylesterase activity were determined. The findings showed that T. willdenowii extract is rich in phenolic compounds (TPC = 127.34 GAE mg/gE; TFC = 105.43 RE mg/gE; TTC = 24.08 CE mg/gE) and exhibits important antioxidant activity (DPPH IC50 = 0.41 mg/mL; FRAP value = 1.31 Fe2+E mM; TAC value = 322.13 AAE µg/gE). Moreover, T. willdenowii extract significantly reduced the alterations caused by HFD intake by decreasing blood lipids (TC: -28.19 %; TGs: -22.82 %; LDL-C: -35.11 %) and increasing paraoxonase-1 arylesterase activity (+12.83 %). Conclusion: We conclude that the traditional use of T. willdenowii is effective in the treatment of hyperlipidemia.

Oxidative stress and peri-implantitis: The role of oxidants and antioxidants

Background: Peri-implantitis is the main cause of implant failure and is associated with augmented oxidative stress or tissue destruction. In this study, it was aimed to investigate the oxidant-antioxidant balance parameters in individuals with peri-implantitis, considering the clinical findings and the control group. Methods: Peri-implantitis (n=30) and healthy (n=30) individuals participated in the study. Peri-implant clinical parameters, including probing depth (PD), gingival index (GI), plaque index (PI), bleeding on probing (BoP), and keratinized mucosa width (KMW), were recorded. The levels of total antioxidant capacity (TAC), total oxidant capacity (TOC), oxidative stress index (OSI), and arylesterase (ARE) in saliva were examined. To identify the relationship between oxidative stress biomarkers and clinical parameters was used Spearman’s correlation coefficient. Results: TOC values were higher in peri-implantitis, and they correlated with BoP, GI, PD, and PI (P=0.004, r=0.370; P=0.010, r=0.328; P=0.038, r=0.268; P=0.007, r=0.342, respectively). TAC values were higher in healthy and correlated with PI, BoP, and GI (P=0.021, r=-0.297; P=0.035, r=-0.273; P=0.012, r=-0.321, respectively). OSI showed a negative correlation with the KMW (mm) (P=0.046, r=-0.259). Conclusion: Increased TOC and decreased TAC and ARE activity could be predictors of peri-implantitis development. Adequate KMW is important in the production of antioxidants.

Relationship Between Paraoxonase-1 Genotype and Activity, and Major Adverse Cardiovascular Events and Malignancies in Patients with Rheumatoid Arthritis Receiving Tofacitinib.

This post hoc analysis investigated the relationship between paraoxonase-1 (PON1) genotype and activity, and risk of major adverse cardiovascular events (MACE) and malignancies in tofacitinib rheumatoid arthritis (RA) clinical studies. Data were pooled from 9 phase II/III studies and the associated long-term extension studies (all completed by October 2017). PON1 activities in plasma were measured using paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity), and phenylacetate (arylesterase activity) as substrates. PON1 Q192R genotype effect on baseline PON1 activity was assessed using linear regression for each study, with fixed-effects meta-analysis across studies. MACE and malignancy risk by time-varying enzyme activity was determined using Cox proportional hazards regression. The analysis included 1,969 patients with RA. Compared with the QQ genotype, RR had a significant positive association with baseline paraoxonase activity and a significant negative association with baseline lactonase and arylesterase activity (all p < 0.001). Time-varying models demonstrated a significant association of increased paraoxonase activity over time with lower risk of MACE (p < 0.001) and malignancies (excluding non-melanoma skin cancer [NMSC]; p ≤ 0.05), even after controlling for risk factors identified in univariate analysis and RA disease activity. A similar trend was observed for lactonase and arylesterase for MACE. Higher paraoxonase activity over time was associated with significantly reduced risk of future MACE and malignancies (excluding NMSC), but not NMSC, in patients with RA receiving tofacitinib. Further investigation of PON1 as a novel functional lipid biomarker of MACE/malignancy risk in patients with RA is warranted.

Glyphosate Suppresses the Ability of PON1 to Hydrolyse Oxidized-LDL in the Exposed Farm Workers in Pahang, Malaysia

INTRODUCTION: Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme which is known to hydrolyse most pesticides including organophosphates (OPs) and prevent atherosclerosis by inhibiting oxidative modification of low-density lipoprotein (LDL). Glyphosate is one of the common organophosphate pesticides used in agriculture in many developing countries including Malaysia. The aim of this study to is to assess the PON1 ability to hydrolyse oxidized LDL in glyphosate exposed farm workers. MATERIALS AND METHODS: In this cross-sectional comparative study, a total of 103 subjects (53 Glyphosate-exposed and 50 non-exposed) were recruited. Fasting serum samples were analysed for PON1 activities towards substrates paraoxon, phenylacetate, and diazoxon, as well as for lipid profiles and oxidized-LDL (ox-LDL). RESULTS: The results showed lower basal paraoxonase activity [156.96 (58.87) vs 177.06 (66.78)], arylesterase activity [90.06 (17.14) vs 96.92 (23.87)] and diazoxonase activity [850.93 (206.75) vs 990.48 (248.73)] in glyphosate-exposed compared to non-exposed, however, only diazoxonase activity was statistically significant (p&lt;0.05). PON1 activity is not significantly different with different length of period of exposure except for arylesterase. There was also significantly higher (p&lt;0.05) ox-LDL in the exposed group but no significant differences in lipid profiles (p&gt;0.05) between the two groups. The PON1 to ox-LDL ratio which probably reflects the ability of PON1 to hydrolyse ox-LDL were also significantly lower (p&lt;0.05) among the glyphosate-exposed group. CONCLUSION: The results suggested that the decreased PON1 activity in glyphosate-exposed individuals could predispose them to the development of atherosclerosis and coronary artery disease through decreased PON1 ability to hydrolyse ox-LDL.

Effect of Exercise Repetitions on Arylesterase Activity of PON1 in Plasma of Average-Trained Men-The Dissociation between Activity and Concentration.

Exercise may increase the antioxidant capacity of plasma by stimulating antioxidant enzymes. The study aimed to measure the effect of three repetitions of acute exercise on arylesterase (ARE) activity of the paraoxonase 1 (PON1) enzyme. Eleven average-trained men (age 34.0 ± 5.2 years) completed three treadmill runs. ARE activity in plasma was evaluated spectrophotometrically and compared with PON1 concentration (PON1c), paraoxonase (PON) activity, and high-density lipoprotein cholesterol (HDL-C) at rest and after exercise. In all repetitions of the exercise, ARE activity remained stable, and ARE activity standardized for PON1c (ARE/PON1c) was lower post- than pre-exercise. The ARE/PON1c ratio changes returned to baseline levels during rest after each exercise session. Pre-exercise ARE activity correlated negatively with post-exercise C-reactive protein (CRP) (ρ = -0.35, p = 0.049), white blood cell count (WBC) (ρ = -0.35, p = 0.048), polymorphonuclear leukocytes (PMN) (ρ = -0.37, p = 0.037), and creatine kinase (CK) (ρ = -0.37, p = 0.036). ARE activity may be depleted under conditions of oxidative stress, as increases in PON1c during acute exercise did not result in parallel increases in ARE activity. No adaptation of the response of ARE activity to exercise was detected in subsequent exercise sessions. Individuals with lower pre-exercise ARE activity may develop a higher inflammatory response to strenuous exercise.

Paraoxonase 1 activity in patients with Alzheimer disease: Systematic review and meta-analysis

Cumulating evidence links environmental toxicants, such as organophosphate (OP) pesticides, to the pathogenesis of Alzheimer's disease (AD). The calcium-dependent Paraoxonase 1 (PON1) can neutralize these toxicants with good catalytic efficiency, thus protecting from OP-induced biological damage. Although different previous studies have already partially described an association between PON1 activity and AD, this intriguing relationship has not yet been comprehensively examined. To fill this gap, we performed a meta-analysis of existing data comparing the PON1 arylesterase activity in AD and healthy subjects from the general population. Data were obtained by searching MEDLINE, Embase and CENTRAL, Google Scholar, and SCOPUS electronic databases for all studies published at any time up to February 2023, reporting and comparing the PON1- paraoxonase activity between AD patients and controls. Seven studies, based on 615 subjects (281 AD and 356 controls) met the inclusion criteria and were included into the final analysis. A random effect model revealed that PON1 arylesterase activity was significantly lower in the AD group compared to controls, exhibiting low level of heterogeneity (SMD = – 1.62, 95% CI = -2.65 to −0.58, p = 0.0021, I2 = 12%). These findings suggest that PON1 activity might be reduced in AD reflecting a major susceptibility to OPs neurotoxicity. Further studies should be conducted to definitely ascertain this link and to establish the cause-effect relationship between PON1 reduction and AD onset.

Effects of PON1 QR192 genetic polymorphism and paraoxonase, arylesterase activities on deep vein thrombosis

Abstract Objectives We aimed to evaluate PON1 QR192 polymorphism’s (rs662) effects on levels of triglyceride, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, glucose, and c-reactive protein, and paraoxonase-arylesterase activities among deep vein thrombosis patients and healthy subjects. Methods Forty-five deep vein thrombosis patients and 45 healthy subjects participated in the study. Genetic analysis was performed by using polymerase chain reaction and sequencing. Paraoxonase and arylesterase enzyme activities were determined by a spectrophotometer. Serum levels of triglyceride, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, glucose, and c-reactive protein were measured by a similar method. Results There were no statistically significant differences between patients and controls regarding the frequency of variant allele for the PON1 QR192 polymorphism, activities of paraoxonase-arylesterase, and level of high-density lipoprotein-cholesterol. Triglyceride, total cholesterol, low-density lipoprotein-cholesterol, glucose, and c-reactive protein levels were significantly higher in patients compared to controls (p values were 0.005, 0.0002, 0.009, 0.0009, &lt;0.0001, respectively.) Paraoxonase activity was found to be associated with PON1 QR192 genetic polymorphism (p&lt;0.0001). However, we observed no association of PON1 QR192 polymorphism with arylesterase activity and, levels of triglyceride, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, glucose, and c-reactive protein. Conclusions There was no statistically significant difference between deep vein thrombosis patients and healthy subjects regarding variant allele frequency for the PON1 QR192 genetic polymorphism. In addition, paraoxonase and arylesterase activities were similar among the groups. These results indicate that PON1 QR192 genetic polymorphism and activity levels of paraoxonase-arylesterase have no effect on the development of deep vein thrombosis.

Antioxidant Defense Enzymes in Multiple Sclerosis: A 5-Year Follow-up Study.

Oxidative stress biomarkers are increased in multiple sclerosis (MS) lesions. Antioxidant defense enzymes regulate reactive oxygen species that can cause tissue injury in MS. The study of 91 subjects included 64 relapsing-remitting MS (RR-MS, 72% female, baseline age 44.6±SD 11 years; disease duration: 13.3±8.8 years; median EDSS 2.0, IQR: 1.8) and 27 healthy controls (HC) subjects at baseline and 5-year follow-up (5YFU). Serum glutathione peroxidase (GPX), glutathione S-transferase (GST), glutathione reductase (GSHR), superoxide dismutase (SOD), and paraoxonase-1 (PON1) arylesterase and paraoxonase activities were measured using kinetic enzyme assays. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) and an apolipoprotein (Apo) panel with ApoA-I, ApoA-II, ApoB, ApoC-II and ApoE were obtained. Serum neurofilament (sNfL) was used to assess axonal injury. Disability was measured on the Expanded Disability Status Scale (EDSS). GSHR activity was lower in HC compared to RR-MS at baseline and 5YFU. GPX (p=0.008) and PON-1 arylesterase and paraoxonase activities (both p=0.05) increased between baseline and 5YFU in HC but did not increase in RR-MS. At baseline and 5YFU, GPX and GST were associated with TC, LDL-C, and ApoA-II; GSHR was associated with ApoA-II and ApoC-II. Antioxidant enzymes were not associated with sNfL or EDSS in RR-MS. RR-MS patients did not exhibit the changes in antioxidant enzyme activities over 5YFU found in HC; however, the differences were modest. Antioxidant enzyme activities are not associated with disability.

Paraoxonase 1 status is a major Janus-faced component of mild and moderate acute ischemic stroke and consequent disabilities.

This study aims to examine the associations between paraoxonase 1 (PON)1 status and acute ischemic stroke (AIS) and consequent disabilities. This study recruited 122 patients with AIS and 40 healthy controls and assessed the Q192R gene variants, arylesterase (AREase) and chloromethyl phenylacetate (CMPAase) activities, and high-density lipoprotein cholesterol (HDLc) in baseline conditions. AREase and CMPAase were measured 3 months later. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin score (mRS) were assessed at baseline and 3 and 6 months later. Reduced CMPAase and increased AREase activities are significantly associated with AIS and mRS and NIHSS scores (baseline and 3 and 6 months later). The best predictor of AIS/disabilities was a decrease in the z-unit-based composite zCMPAase-zAREase score. Serum high density lipoprotein cholsterol (HDLc) was significantly correlated with CMPAase, but not AREase, activity and a lowered zCMPAase + zHDLc score was the second best predictor of AIS/disabilities. Regression analysis showed that 34.7% of the variance in baseline NIHSS was explained by zCMPAase-zAREase and zCMPAase + zHDLc composites, HDLc, and hypertension. Neural network analysis showed that stroke was differentiated from controls with an area under the ROC curve of 0.975 using both new composite scores, PON1 status, hypertension, dyslipidemia, previous stroke as body mass index. The PON1 Q192R genotype has many significant direct and mediated effects on AIS/disabilities, however, its overall effect was not significant. PON1 status and the CMPAase-HDLc complex play key roles in AIS and its disabilities at baseline and 3 and 6 months later.