Paraoxonase 1 Arylesterase Activity Research Articles

Investigation of the effects of Terminalia chebula seed hydroalcoholic extract on Paraoxonase1 enzyme activity in rats

Background and aims: Paraoxonase 1 (PON1) is related to high-density lipoprotein (HDL) in serum and protects against low-density lipoprotein (LDL) oxidation. This study aimed to investigate the effects of Terminalia chebula on PON1 in hyperlipidemic rats and the molecular docking effects of some compounds of this medical plant on PON1 activity. Methods: Overall, 40 male rats (200–250 gr) were randomly divided into four groups, including the control group, the hyperlipid group, the hyperlipid group receiving 400 mg/kg of the hydroalcoholic extract of T. chebula seeds, and the hyperlipid group receiving 800 mg/kg of the hydroalcoholic extract of T. chebula seeds. The PON1 arylesterase activity in serum and the PON1 gene expression in the liver tissue underwent investigation. Then, the molecular docking effects of its compounds were studied on PON1 through in-silico studies using the AutoDock software (version 4.2.0). Results: T. chebula decreased (P<0.001) the serum triglycerides from 105.88±10.15 mg/dL in the hyperlipidemic group to 66.88±14.90 and 74.25±9.51 mg/dL in hyperlipidemic groups receiving 400 and 800 mg/kg of the hydroalcoholic extract of T. chebula seeds, respectively. In addition, the PON1 serum aryl esterase activity increased from 202.12±6058 in hyperlipidemic rats to 224.34±58.74 (P=0.83) and 235.80±37.05 (P=0.6) in hyperlipidemic groups receiving 400 mg/kg and 800 mg/kg of the hydroalcoholic extract of T. chebula seeds, respectively. It also demonstrated a significant effect on PON1 gene expression (P<0.001). In addition, the in-silico and docking results revealed that the main antioxidant compounds of T. chebula, such as catechin, kaempferol, and quercetin, could bind to the PON1 enzyme directly and influence the enzyme activity. Conclusion: T. chebula increased PON1 activity and PON1 gene expression. However, among the plant’s compounds, catechin, kaempferol, and quercetin played the most substantial role in the PON1 activity. It seems that these compounds can be useful as co-treatments in hyperlipidemia therapies.

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.

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

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. 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. 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. We conclude that the supplementation with the aqueous extract of T. atlanticus could potentially protect against hyperlipidemia and consequently, the development of atherosclerosis.

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).
 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.
 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 < 0.0001). The MPO/PON-1 ratio exhibited a direct correlation with serum MDA levels (p < 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%.
 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.

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.

Antioxidant Potential of Thymus willdenowii Boiss & 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 & 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.

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.

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.

HDL cholesterol efflux capacity and phospholipid content are associated with the severity of acute ischemic stroke and predict its outcome

Background/AimsImpaired high-density lipoprotein (HDL) function and composition are more strongly related to cardiovascular morbidity than HDL concentration. However, it is unclear whether HDL function and composition predict ischemic stroke severity and outcome. We aimed to evaluate these associations. MethodsWe prospectively studied 199 consecutive patients who were admitted with acute ischemic stroke. The severity of stroke was evaluated at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥ 5. The outcome was assessed with dependency at discharge (modified Rankin scale 2–5) and in-hospital mortality. Cholesterol efflux capacity (CEC), phospholipid levels, lecithin:cholesterol acyl transferase (LCAT)-phospholipase activity, paraoxonase-1 (PON1)-arylesterase activity and serum amyloid A1 (SAA1) content of HDL were measured. ResultsCEC, phospholipid levels and LCAT-phospholipase activity of HDL were lower and SAA1 content of HDL was higher in patients with severe stroke. Patients who were dependent at discharge had lower CEC, PON1-arylesterase activity, phospholipid content and LCAT-phospholipase activity of HDL and higher HDL-SAA1 content. Independent predictors of dependency at discharge were the NIHSS at admission (RR 2.60, 95% CI 1.39–4.87), lipid-lowering treatment (RR 0.17, 95% CI 0.01–0.75), HDL-CEC (RR 0.21, 95% CI 0.05–0.87) and HDL-associated PON1-arylesterase activity (RR 0.95, 95% CI 0.91–0.99). In patients who died during hospitalization, phospholipids, LCAT-phospholipase and PON1-arylesterase activities of HDL were lower. ConclusionsChanges in CEC and composition of HDL appear to be associated with the severity and outcome of acute ischemic stroke and could represent biomarkers that may inform risk stratification and management strategies in these patients.

Paraoxonase 1 and atrial fibrillation: Is there a relationship?

Atrial fibrillation (AF) is associated with oxidative stress and inflammation. Paraoxonase-1 (PON1), circulates in blood bound to high-density lipoproteins and reduces systemic oxidative stress. The aim of this study was to evaluate PON1 serum concentration and PON1 arylesterase activity (AREase) in patients with AF. We studied a group of 67 patients with symptomatic paroxysmal or persistent AF admitted for cardioversion and a control group of 59 patients without AF. Clinical parameters, lipid profile, PON1 concentration and AREase were evaluated. A significant difference in serum PON1 concentration and in AREase was found among the two groups. In a multivariate linear regression model, the presence of AF was associated with low PON1 concentration (P = .022). The body mass index was also independently associated with PON1 values (P < .001). Only the high-density lipoproteins-cholesterol level was independently associated with AREase (P = .002). PON1 serum concentrations and AREase were diminished in patients with AF, and the presence of AF was independently associated with low PON1 values.

Sphingosine 1-Phosphate and Apolipoprotein M Levels and Their Correlations with Inflammatory Biomarkers in Patients with Untreated Familial Hypercholesterolemia.

High-density lipoprotein (HDL)-bound apolipoprotein M/sphingosine 1-phosphate (ApoM/S1P) complex in cardiovascular diseases serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. To date, S1P and ApoM in patients with untreated heterozygous familial hypercholesterolemia (HeFH) have not been extensively studied. Eighty-one untreated patients with HeFH and 32 healthy control subjects were included in this study. Serum S1P, ApoM, sCD40L, sICAM-1, sVCAM-1, oxLDL, and TNFα concentrations were determined by ELISA. PON1 activities were measured spectrophotometrically. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly higher serum S1P and ApoM levels were found in HeFH patients compared to controls. S1P negatively correlated with large HDL and positively with small HDL subfractions in HeFH patients and the whole study population. S1P showed significant positive correlations with sCD40L and MMP-9 levels and PON1 arylesterase activity, while we found significant negative correlation between sVCAM-1 and S1P in HeFH patients. A backward stepwise multiple regression analysis showed that the best predictors of serum S1P were large HDL subfraction and arylesterase activity. Higher S1P and ApoM levels and their correlations with HDL subfractions and inflammatory markers in HeFH patients implied their possible role in endothelial protection.

Paraoxonase 1 rs662 polymorphism, its related variables, and COVID-19 intensity: Considering gender and post-COVID complications.

In this study, we aimed to investigate the effect of paraoxonase 1 (PON1) rs662 polymorphism, arylesterase (ARE) activity, and the serum lipid profile in patients with coronavirus disease 2019 (COVID-19) in different stages of the disease considering post-COVID outcomes. A total of 470 COVID-19 patients (235 female and 235 male patients) were recruited into the study, and based on the World Health Organization (WHO) criteria, the patients were divided into three groups: moderate, severe, and critical. PON1 rs662 polymorphism was determined by the Alw 1 enzyme followed by agarose gel electrophoresis. Moreover, serum levels of triglycerides (TG), cholesterol (Chol), high-density lipoprotein-cholesterol (HDL-c), and low-density lipoprotein-cholesterol (LDL-c), as well as the level of the ARE activity of PON1 in the sera of patients were measured at the time of infection and one and three months after hospitalization. There was a significant relationship between the G allele and the severity of the disease. In addition, the probability of death in homozygous individuals (GG) was higher than in heterozygous patients (GA), and it was higher in heterozygous patients than in wild-type individuals (AA). There was also a significant relationship between the decrease in serum lipids and the intensity of COVID-19. On the contrary, at the onset of the disease, the HDL-c level and serum ARE activity were reduced compared to one and three months after COVID-19 infection. The findings of this study indicated the significant impact of PON1 rs662 polymorphism on ARE activity, lipid profiles, disease severity, and mortality in COVID-19 patients.

Lyso-DGTS Lipid Derivatives Enhance PON1 Activities and Prevent Oxidation of LDL: A Structure-Activity Relationship Study.

Paraoxonase 1 (PON1) plays a role in regulating reverse cholesterol transport and has antioxidative, anti-inflammatory, antiapoptotic, vasodilative, and antithrombotic activities. Scientists are currently focused on the modulation of PON1 expression using different pharmacological, nutritional, and lifestyle approaches. We previously isolated a novel active compound from Nannochloropsis microalgae—lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS)—which increased PON1 activity, HDL-cholesterol efflux, and endothelial nitric oxide release. Here, to explore this important lipid moiety’s effect on PON1 activities, we examined the effect of synthesized lipid derivatives and endogenous analogs of lyso-DGTS on PON1 lactonase and arylesterase activities and LDL oxidation using structure–activity relationship (SAR) methods. Six lipids significantly elevated recombinant PON1 (rePON1) lactonase activity in a dose-dependent manner, and four lipids significantly increased rePON1 arylesterase activity. Using tryptophan fluorescence-quenching assay and a molecular docking method, lipid–PON1 interactions were characterized. An inverse correlation was obtained between the lactonase activity of PON1 and the docking energy of the lipid–PON1 complex. Furthermore, five of the lipids increased the LDL oxidation lag time and inhibited its propagation. Our findings suggest a beneficial effect of lyso-DGTS or lyso-DGTS derivatives through increased PON1 activity and prevention of LDL oxidation.

Low HDL Cholesterol Efflux Capacity Indicates a Fatal Course of COVID-19.

Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels.

Correlation between paraoxonase-1 arylesterase activities and clopidogrel drug in patients with coronary artery disease

Background: Coronary artery disease (CAD) is one of the leading causes of death worldwide. Clopidogrel, antiplatelet drug, has been widely used for management of CAD. Arylesterase, the activity of Paraoxonase-1 (PON-1), is mainly contributed in the biotransformation of clopidogrel to its active thiol form. The purpose of this study was to investigate the effect of receiving clopidogrel drug on the arylesterase activities in CAD patients. The effect of receiving clopidogrel drug on the antioxidant activity of arylesterase was also monitored by determination of malondialdehyde (MDA) level. Methods: One hundred CAD patients, who were followed-up for 5 days after reciving clopidogrel, and 50 healthy volunteers were included in our study. The activities of arylesterase using two (phenyl acetate and p-nitrophenyl acetate) substrates, lipid profile, MDA, and total protein concentration (Tp) were determined spectrophotometrically. Results: PON-1 arylesterase activities, HDL-C, and Tp were significantly decreased (P&lt;0.0001) in patients with CAD before receiving clopidogrel drug (CAD-pre-Clp) compared to baseline (non-CAD) and the levels of these parameters were returned to baseline (P&gt;0.05) after 5 days of receiving clopidogrel (CAD-post-Clp).

Usefulness of the Measurement of Serum Paraoxonase-1 Arylesterase Activity in the Diagnoses of COVID-19.

The development of inexpensive, fast, and reliable screening tests for COVID-19 is, as yet, an unmet need. The present study was aimed at evaluating the usefulness of serum arylesterase activity of paraoxonase-1 (PON1) measurement as a screening test in patients with different severity levels of COVID-19 infection. We included 615 COVID-19-positive patients who were classified as asymptomatic, mildly symptomatic, severely symptomatic, or fatally symptomatic. Results were compared with 50 healthy volunteers, 330 patients with cancer, and 343 with morbid obesity. Results showed PON1 activity greatly decreased in COVID-19 compared to healthy volunteers; a receiver operating characteristics plot showed a high diagnostic accuracy. The degree of COVID-19 severity did not influence PON1 levels. Our results indicated that PON1 determination was efficient for disease diagnosis, but not for prognosis. Furthermore, patients with obesity or cancer presented alterations similar to those of COVID-19 patients. As such, elevated levels of PON1 indicate the absence of COVID-19, but low levels may be present in various other chronic diseases. The assay is fast and inexpensive. We suggest that PON1 measurement could be used as an initial, high cut-off point screening method, while lower values should be confirmed with the more expensive nucleic acid amplification test.

Occupational exposure to pesticides in farmworkers and the oxidative markers.

Organophosphate (OPPs) and organochlorine pesticides (OCPs) are the two predominant forms of pesticides extensively used all around the world and are being reconsidered as environmental pollutants. The current study sought to assess the role of socioeconomic factors on the level of pesticides residues and the oxidative effects of exposure to OPPs and OCPs among the farmworkers of southeast Iran. In this cross-sectional study, 192 farmworkers and 74 non-farmworkers (controls) were involved. Gas chromatography (GC) was performed to measure the serum levels of organochlorine chemicals (2,4-DDT, 4,4-DDT, 2,4-DDE, 4,4-DDE, α-HCH, β-HCH, and γ-HCH). Furthermore, acetylcholinesterase (AChE) activity, arylesterase activity of paraoxonase-1 (PON-1), and several oxidative stress (OS) markers were assessed. In addition, the impact of several parameters such as home to farm distance, education level, ventilation status, and personal protective equipment (PPE) on pesticide levels was analyzed. The levels of OCPs in the farmworkers were significantly higher than the control subjects. In addition, AChE activity, arylesterase activity of PON-1, and total antioxidant capacity in farmworkers were significantly less, and MDA levels were higher than the controls. Education level was associated with farmworkers' protective behavior. The current findings suggested that some phased out OCPs can still be measured in human samples in the southeast of Iran. Furthermore, the current study demonstrated that exposure to OCPs and OPPs was accompanied by adverse consequences regarding OS parameters and subsequent health problems. In addition, the findings of the present study suggest that improving farmworkers' education might be associated with reduced exposure to pesticides and less adverse health effects.