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Paraoxonase 1 (PON1) is one of the most significant antioxidative enzymes associated with high-density lipoprotein (HDL). It has been proved that is involved in the pathogenesis of many diseases including chronic kidney disease (CKD). The association between PON1 and CKD seems to be mutual, such that the disease produces a significant decrease in PON1 activity levels, while the genetics of PON1 may affect the risk of susceptibility to CKD. Recent studies reveal that the decrease in serum PON1 activity observed in non-dialyzed and dialyzed CKD patients as well as in renal transplant (RT) patients is linked to an increased vulnerability to atherosclerosis. We intend to summarize current literature concerning PON1 activity in CKD, highlighting on the main determinants of PON1 activity, its association with oxidative stress, the impact of its genetic polymorphism on the disease development, the effect of drugs and nutritional state. Furthermore, evidence supporting the implication of reduced PON1 activity in the incident of cardiovascular disease in CKD patients, is also examined. It appears that despite the lack of standardization of PON1 activity measurement, PON1 remains a valuable biomarker for the researchers through the last decades, which contributes to the assessment of the antioxidant status having prognostic benefit on adverse clinical outcomes at various stages and etiologies of kidney disease.

In our study, we aimed to evaluate the effects of Moringa oleifera leaves extract on rat paraoxonase 1 (rPON1) and catalase (rCAT) activities in alloxan-induced diabetic rats. Our study included three groups; group C (control, n = 5); group D (diabetic, n = 5); and group DM (M. oleifera extract-supplemented diabetic rats, n = 5). Daily oral administration of M. oleifera extract at 200 mg/kg doses produced an increase in endogenous antioxidants. Serum rPON1 (lactonase) and liver cytosol catalase activities were determined by a spectrophotometric assay using progress curve analysis. We found a decrease in the Vm value of rPON1 in diabetic rats, but dihydrocoumarin (DHC) affinity (Km) was slightly increased. The value of Vm for the DM group was found to be reduced approximately by a factor of 3 compared with those obtained for group C, whereas Km was largely changed (96 times). Catalase activity was significantly higher in the DM group. These data suggest that the activation of rPON1 and rCAT activities by M. oleifera extracts may be mediated via the effect of the specific flavonoids on the enzyme structure. In addition, through molecular blind docking analysis, rPON1 was found to have two binding sites for flavonoids. In contrast, flavonoids bound at four sites in rCAT. In conclusion, the data suggest that compounds from M. oleifera leaves extract were able to influence the catalytic activities of both enzymes to compensate for the changes provoked by diabetes in rats.

Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated protein that endows its carrier with (lipo-)lactonase-dependent antioxidative features. Low levels of PON1 activity have been observed in association with obesity, a major risk factor for cardiovascular disease (CVD). Considering the well-recognized atheroprotective role of PON1, exogenous/endogenous factors that might modulate its levels/activity are raising great interest. Since adipokines represent a molecular link between obesity and CVD, we here explored the possible impact of these substances on PON1 activity/expression. The levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha, monocyte chemoattractant protein-1, hepatocyte growth factor, resistin, leptin, and adiponectin were measured along with arylesterase, paraoxonase, and lactonase activities of PON1 in 107 postmenopausal women. Moreover, the direct effect of resistin on PON1 expression was evaluated in vitro. Multivariate analysis revealed that only resistin was significantly and inversely correlated with PON1-lactonase activities (r = −0.346, p < 0.001) regardless of confounding factors such as age or HDL-cholesterol. It is worth noting that no statistical link was found between adipokine and arylesterase or paraoxonase, the two promiscuous activities of PON1. Notably, resistin down-regulated PON1 expression occurred in hepatocellular carcinoma cultures. Our study suggests that resistin might be a negative modulator of PON1 expression and anti-oxidative activity.

ObjectiveParaoxonase 1 (PON1), a calcium-dependent serum enzyme, has been shown to be involved in lipid metabolism. In this study, we examined the putative correlation of the serum PON1 level of Hanwoo, Korean native cattle, with gender and meat quality grade.MethodsPON1 levels were estimated by determining the arylesterase and paraoxonase activities (AE and PO, respectively) in serum samples from Hanwoo individuals (n = 56). Serum PON1 levels were analyzed in different gender groups (female [n = 21], castrated male [n = 17], and male [n = 18]), and meat quality grades (≥1 [n = 23], 2 [n = 21], and 3 [n = 12]).ResultsSerum PON1 levels were similar in female (AE = 120±55 U/mL, PO = 84±43 mU/mL) and castrated male (123±44 U/mL, PO = 89±30 mU/mL), while male showed a significantly lower level (AE = 65±43 U/mL, PO = 44±34 mU/mL). Furthermore, analysis of serum PON1 levels in three different grades of meat quality showed similar levels in the grades ≥1 (AE = 118±49 U/mL, PO = 84±37 mU/mL) and 2 (AE = 116±54 U/mL, PO = 82±43 mU/mL), while the level was significantly lower in the grade 3 (AE = 58±35 U/mL, PO = 39±27 mU/mL) of lower meat quality.ConclusionWe discovered the gender-dependent differences in serum PON1 levels of Hanwoo and a positive association of the serum PON1 level with meat quality. Results in this study suggest that PON1 would be a useful serum marker for preliminary screening of Hanwoo individuals with high-quality meat and applicable for genetic improvement.

ObjectiveBile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.DesignSerum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.ResultsSerum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.ConclusionsThe serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

The objective here is to examine the role of overall oxidative stress in the etiopathogenesis of gluten-sensitive enteropathy disease and its relationship with gluten free diet and autoantibodies. Eighty gluten-sensitive enteropathy patients and 80 control group participants were included in the study. As oxidative stress parameters, we researched total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), paraoxonase-1 and arylesterase parameters in the serum samples of gluten-sensitive enteropathy patients. In comparison to the control group, gluten-sensitive enteropathy patients had lower TAS, paraoxonase-1 and arylesterase levels and gluten-sensitive enteropathy patients had considerable TOS and OSI levels. In contrast, patients who agreed to the gluten free eating routine had a higher OSI proportion and patients who did not conform to the gluten free eating regimen had a lower paraoxonase-1 level. An affirming reciprocation was de tected amidst TOS and OSI proportion and gluten-sensitive enteropathy autoantibodies and C-reactive protein levels and a negative correlation was found between arylesterase level and gluten-sensitive enteropathy autoantibodies. We observed oxidative stress levels to be higher in gluten-sensitive enteropathy patients contrasted with the control group. Oxidative stress level showed differences in gluten-sensitive enteropathy patients depending on gluten diet content and autoantibody positivity. In point of fact, C-reactive protein and gluten-sensitive enteropathy autoantibodies are identified with oxidative anxiety parameters resulting in the possibility that oxidative stress might be successful in the gluten-sensitive enteropathy pathogenesis.

Coronavirus disease 2019 (COVID-19) pandemic is affecting millions of patients worldwide. The consequences of initial exposure to SARS-CoV-2 go beyond pulmonary damage, with a particular impact on lipid metabolism. Decreased levels in HDL-C were reported in COVID-19 patients. Since HDL particles display antioxidant, anti-inflammatory and potential anti-infectious properties, we aimed at characterizing HDL proteome and functionality during COVID-19 relative to healthy subjects. HDLs were isolated from plasma of 8 severe COVID-19 patients sampled at admission to intensive care unit (Day 1, D1) at D3 and D7, and from 16 sex- and age-matched healthy subjects. Proteomic analysis was performed by LC-MS/MS. The relative amounts of proteins identified in HDLs were compared between COVID-19 and controls. apolipoprotein A-I and paraoxonase 1 were confirmed by Western-blot analysis to be less abundant in COVID-19 versus controls, whereas serum amyloid A and alpha-1 antitrypsin were higher. HDLs from patients were less protective in endothelial cells stiumalted by TNFα (permeability, VE-cadherin disorganization and apoptosis). In these conditions, HDL inhibition of apoptosis was blunted in COVID-19 relative to controls. In conclusion, we show major changes in HDL proteome and decreased functionality in severe COVID-19 patients.

Mammals evolved in terrestrial environments. Those that now live in the marine environment have had to adapt to the particular selective pressures that this environment imposes. Meyer et al. surveyed the genomes of several marine mammal species to identify regions of convergent change. Multiple losses of the Paraoxonase 1 gene are evident in marine mammals, likely resulting from remodeling of lipid metabolism or antioxidant networks. The multiple occurrences of this loss of function across taxa indicate an evolutionary benefit. However, Paraoxonase 1 is the primary mammalian defense against organophosphorus toxicity. Marine mammals may be at a great disadvantage in the Anthropocene if run-off of this agricultural product into the marine environment continues. Science , this issue p. 591 Convergent loss of Paraoxonase 1 may leave marine mammals unable to metabolize organophosphates. Mammals diversified by colonizing drastically different environments, with each transition yielding numerous molecular changes, including losses of protein function. Though not initially deleterious, these losses could subsequently carry deleterious pleiotropic consequences. We have used phylogenetic methods to identify convergent functional losses across independent marine mammal lineages. In one extreme case, Paraoxonase 1 ( PON1 ) accrued lesions in all marine lineages, while remaining intact in all terrestrial mammals. These lesions coincide with PON1 enzymatic activity loss in marine species’ blood plasma. This convergent loss is likely explained by parallel shifts in marine ancestors’ lipid metabolism and/or bloodstream oxidative environment affecting PON1’s role in fatty acid oxidation. PON1 loss also eliminates marine mammals’ main defense against neurotoxicity from specific man-made organophosphorus compounds, implying potential risks in modern environments.

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

Current diagnoses of mood disorders are not cross validated. The aim of the current paper is to explain how machine learning techniques can be used to a) construct a model which ensembles risk/resilience (R/R), adverse outcome pathways (AOPs), staging, and the phenome of mood disorders, and b) disclose new classes based on these feature sets. This study was conducted using data of 67 healthy controls and 105 mood disordered patients. The R/R ratio, assessed as a combination of the paraoxonase 1 (PON1) gene, PON1 enzymatic activity, and early life time trauma (ELT), predicted the high-density lipoprotein cholesterol – paraoxonase 1 complex (HDL-PON1), reactive oxygen and nitrogen species (RONS), nitro-oxidative stress toxicity (NOSTOX), staging (number of depression and hypomanic episodes and suicidal attempts), and phenome (the Hamilton Depression and Anxiety scores and the Clinical Global Impression; current suicidal ideation; quality of life and disability measurements) scores. Partial Least Squares pathway analysis showed that 44.2% of the variance in the phenome was explained by ELT, RONS/NOSTOX, and staging scores. Cluster analysis conducted on all those feature sets discovered two distinct patient clusters, namely 69.5% of the patients were allocated to a class with high R/R, RONS/NOSTOX, staging, and phenome scores, and 30.5% to a class with increased staging and phenome scores. This classification cut across the bipolar (BP1/BP2) and major depression disorder classification and was more distinctive than the latter classifications. We constructed a nomothetic network model which reunited all features of mood disorders into a mechanistically transdiagnostic model.