Effect of supplementation with polyphenol extract of Thymus atlanticus on paraoxonase-1 activity, insulin resistance, and lipid profile in high-fat diet-fed hamsters.

Thymus atlanticus has been used by Moroccan people to treat a variety of health problems, particularly metabolic disorders. In this study, hamsters fed a high-fat diet daily received distilled water (a positive control) or a single dose of Thymus atlanticus polyphenols (Pp) for 63 days. The negative control was fed a normal diet and received distilled water. Results showed that the supplementation of HFD with Pp significantly (p < .001) reduced the levels of MDA and LDL cholesterol, restored insulin level, and increased the activities of serum paraoxonase-1 and HDL cholesterol levels, but did not affect (p > .05) the activity of superoxide dismutase and glutathione peroxidase when compared with the group feeding HFD alone. Thymus atlanticus could be an effective agent against dyslipidemia, oxidative stress, and insulin resistance. PRACTICAL APPLICATIONS: HFD consumption is a risk factor for oxidative stress and the development of metabolic disorders, such as hyperlipidemia and insulin resistance, which may result in atherosclerosis and related cardiovascular diseases, the leading causes of death globally. The management of these alterations is an important strategy to prevent and treat heart complications. Our results showed thatT. atlanticus effectively alleviated HFD-induced hyperlipidemia and insulin resistance and improved PON1 activity. T. atlanticus is a source of biomolecules that may be an effective supplement for controlling HFD-related metabolic disorders. Therefore, the findings of this study may be helpful in the preparation of effective supplements from T. atlanticus to control metabolic disorders and related complications.

Cloning, sequence analysis, and tissue expression of marmoset paraoxonase 1.

Paraoxonase (PON) plays roles in the metabolism of organophosphate xenobiotics and drugs. Despite the importance of marmosets for research into drug metabolism and pharmacokinetics, marmoset paraoxonase has not yet been fully characterized. Consequently, we identified the PON1 gene in the marmoset genome by sequence homology analysis. Marmoset PON1 cDNA containing an open reading frame (1065 bp) was successfully cloned from marmoset liver by reverse transcription-polymerase chain reaction. The deduced amino acid sequence (355 amino acids) has approximately 93% identity with the human ortholog and contains important amino acid residues for substrate binding and calcium ion coordination. According to a phylogenetic tree of PON1 amino acid sequences constructed using data from seven animal species, marmoset PON1 is closer to human PON1 than it is to the PON1 orthologs of experimental animals such as pigs, rabbits, rats, and mice. Marmoset PON1 mRNA was predominantly expressed in liver among the five tissues examined. Marmoset PON1 protein secreted into plasma was detected by immunoblotting. The paraoxon-hydrolyzing activity in plasma was higher in marmosets than in humans. Based on these data, we concluded that marmoset and human PON1 have similar characteristics with regard to genomic structure, amino acid sequences, and tissue distribution.

Quercetin ameliorates the hepatic apoptosis of foetal rats induced by in utero exposure to fenitrothion via the transcriptional regulation of paraoxonase-1 and apoptosis-related genes.

BACKGROUND & PURPOSE: Exposure to organophosphorus during different phases of pregnancy induces many adverse impacts on the developing foetuses due to their immature detoxification system. We have estimated the potential amelioration role of quercetin against hepatic injury-induced apoptosis in rat foetuses following gestational exposure to fenitrothion and probable involvement of paraoxonase-1. METHODS: Forty pregnant rats were allocated into four groups; the first one kept as control, the second intubated with quercetin (100 mg/kg), the third orally administrated fenitrothion (4.62 mg/kg) and the last group received quercetin two hours before fenitrothion intoxication. RESULTS: Fenitrothion significantly elevated the foetal hepatic levels of thiobarbituric acid reactive substances, protein carbonyl, and nitric oxide, but it reduced the enzymatic activities of glutathione-S-transferase, superoxide dismutase, catalase, and acetylcholinesterase. Furthermore, fenitrothion provoked many histopathological changes in the foetal liver and markedly up-regulated the mRNA gene expression of p53, caspase-9 along with elevation in the immunoreactivity of Bax and caspase-3, but it down-regulated the expression level of paraoxonase-1. Remarkably, quercetin co-treatment successfully ameliorated the hepatic oxidative injury and apoptosis prompted by fenitrothion. CONCLUSIONS: Dietary supplements with quercetin can be used to reduce the risk from organophosphorus exposure probably through paraoxonase-1 up-regulation and enhancement of the cellular antioxidant system.

The investigation of antioxidant and anti-inflammatory potentials of apitherapeutic agents on heart tissues in nitric oxide synthase inhibited rats via Nω-nitro-L-arginine methyl ester.

BACKGROUND: High blood pressure effects heart and vessels. Development of pathogenesis is the result of oxidative stress. We aimed to investigate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE), and pollen on the hearts of rats which chronic nitric oxide synthase (NOS) inhibited through Nω-nitro-L-arginine methyl ester (L-NAME). Paraoxonase 1 (PON1), total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), asymmetric dimethylarginine (ADMA), and nuclear factor-κB (NF-κB) were analyzed on the heart. MATERIAL AND METHODS: Sprague-Dawley rats were divided five groups of seven rats in every group; Group I: Control, Group II: L-NAME, Group III: L-NAME+propolis, Group IV: L-NAME+CAPE and Group V: L-NAME+pollen. L-NAME become dissolved in regular saline (0.9% NaCl w/v). The ethanolic extract of propolis (200 mg/kg/days, gavage), pollen (100 mg/kg/days, by gavage), CAPE (50 µM/kg/days, intraperitoneally), and the NOS inhibitor L-NAME (40 mg/kg, intraperitoneally) had been administered. RESULTS: Blood pressure (BP) of rats treated with propolis, CAP,E and pollen statistically significant decreased. Decreasing in BP of the rats of pollen group was more than CAPE and propolis groups (P < .05). PON1 and TAS levels decreased in L-NAME-treated groups (P < .05), but ranges have been better in propolis, CAPE and pollen groups. TOS, ADMA and NF-κB levels increased (P < .05) in L-NAME group; however, these parameters were lower (P < .05) in propolis and CAPE groups (P < .05). CONCLUSIONS: Vasorelaxant properties and free radical scavenging actions of propolis, CAPE, and pollen may reduce the oxidative stress and blood pressure in the rats chronic NOS inhibited through L-NAME.

Microencapsulated Pomegranate Modifies the Composition and Function of High-Density Lipoproteins (HDL) in New Zealand Rabbits.

Previous studies demonstrated that pomegranate, which is a source of several bioactive molecules, induces modifications of high-density lipoproteins (HDL) lipid composition and functionality. However, it remains unclear whether the beneficial effects of pomegranate are related to improvement in the lipid components of HDL. Therefore, in this placebo-controlled study, we characterized the size and lipid composition of HDL subclasses and assessed the functionality of these lipoproteins after 30 days of supplementation with a pomegranate microencapsulated (MiPo) in New Zealand white rabbits. We observed a significant decrease in plasma cholesterol, triglycerides, and non-HDL sphingomyelin, as well as increases in HDL cholesterol and HDL phospholipids after supplementation with MiPo. Concomitantly, the triglycerides of the five HDL subclasses isolated by electrophoresis significantly decreased, whereas phospholipids, cholesterol, and sphingomyelin of HDL subclasses, as well as the HDL size distribution remained unchanged. Of particular interest, the triglycerides content of HDL, estimated by the triglycerides-to-phospholipids ratio, decreased significantly after MiPo supplementation. The modification on the lipid content after the supplementation was associated with an increased resistance of HDL to oxidation as determined by the conjugated dienes formation catalyzed by Cu2+. Accordingly, paraoxonase-1 (PON1) activity determined with phenylacetate as substrate increased after MiPo. The effect of HDL on endothelial function was analyzed by the response to increasing doses of acetylcholine of aorta rings co-incubated with the lipoproteins in an isolated organ bath. The HDL from rabbits that received placebo partially inhibited the endothelium-dependent vasodilation. In contrast, the negative effect of HDL on endothelial function was reverted by MiPo supplementation. These results show that the beneficial effects of pomegranate are mediated at least in part by improving the functionality of HDL, probably via the reduction of the content of triglycerides in these lipoproteins.

Nicotinamide reduces inflammation and oxidative stress via the cholinergic system in fructose-induced metabolic syndrome in rats.

AIMS: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have been associated with risk factors for metabolic syndrome (MetS). Our objective was to evaluate the effect of nicotinamide (NAM) on the activities, expression and protein content of cholinesterases in a MetS model. MAIN METHODS: MetS was induced in male rats administrating 40% fructose to the drinking water for 16 weeks. Additionally, from 5th week onward, the carbohydrate solution was replaced by NAM, at several concentrations for 5 h each morning for the next 12 weeks. In the 15th week, the glucose tolerance test was conducted, and blood pressure was measured. After the treatment period had concluded, the biochemical profile; oxidant stress; proinflammatory markers; and the activity, quantity and expression of cholinesterases were evaluated, and molecular docking analysis was performed. KEY FINDINGS: The MetS group showed anthropometric, hemodynamic and biochemical alterations and increased cholinesterase activity, inflammation and stress markers. In the liver, cholinesterase activity and mRNA, free fatty acid, tumor necrosis factor-alpha (TNF-α), and thiobarbituric acid-reactive substance (TBARS) levels were increased, while reduced glutathione (GSH) levels were decreased. NAM partially or totally decreased risk factors for MetS, markers of stress and inflammation, and the activity (serum and liver) and expression (liver) of cholinesterases. Molecular docking analysis showed that NAM has a greater affinity for cholinesterases than acetylcholine (ACh), suggesting NAM as an inhibitor of cholinesterases. SIGNIFICANCE: Supplementation with 40% fructose induced MetS, which increased the activity and expression of cholinesterases, oxidative stress and the inflammation. NAM attenuated these MetS-induced alterations and changes in cholinesterases.

The effect of resveratrol supplementation on serum levels of asymmetric de-methyl-arginine and paraoxonase 1 activity in patients with type 2 diabetes: A randomized, double-blind controlled trial.

The present study sought to investigate the effect of micronized resveratrol supplementation on serum levels of asymmetric de-methyl-arginine (ADMA) and paraoxonase-1 (PON1) activity in patients with type 2 diabetes (T2D). In this double-blinded randomized trial, 76 patients with T2D were recruited. Participants were randomly assigned to consume 1,000 mg resveratrol or placebo capsules (methylcellulose) per day, for 8 weeks. Serum levels of ADMA and PON1 enzyme activity were measured at the beginning and end of the intervention using the enzyme-linked immunosorbent assay method. In total, 71 participants completed the study. Our results showed that resveratrol significantly decreased serum levels of ADMA (-0.16 ± 0.11, p < .001) and improved PON1 enzyme activity (15.39 ± 13.99, p < .001) compared with placebo, after adjusting for confounding factors (age, sex, and baseline body mass index). Our findings suggest that 8-week resveratrol supplementation may produce beneficial effects on serum levels of ADMA and PON1 enzyme activity in patients with T2DM. However, further research is needed to confirm the veracity of these results.

African Walnuts (Tetracarpidium conophorum) Modulate Hepatic Lipid Accumulation in Obesity via Reciprocal Actions on HMG-CoA Reductase and Paraoxonase.

BACKGROUND: Obesity is characterized by increased body fat and involves an imbalance between the synthesis and degradation of lipids. OBJECTIVE: The study aimed to investigate the effect of African walnuts (Tetracarpidium conophorum) on lipids storage and the regulatory enzymes of hepatic lipid metabolism in obese rats. METHODS: Nuts were extracted in ethanol (WE) and further separated to obtain the ethyl-acetate fraction (ET) and the residue (RES). These were administered orally to 3 groups of monosodium glutamate- obese rats (n = 6), respectively, for 6 weeks. Other groups in the study were: normal (NC), obese control (OC) and standard control (SC) which received orlistat. Hepatic total lipids, total phospholipids, triacylglycerol (TG), total cholesterol (TCHOL), 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase and paraoxonase were studied. RESULTS: Total lipids, TG and TCHOL which increased in OC compared to NC group, decreased. HMG-CoA reductase activity decreased in the 3 study groups relative to OC. Paraoxonase activity which decreased in OC was up-regulated, while the magnitude of hepatic cholesterol decreased from 94.32 % in OC to 52.19, 65.43 and 47.04 % with WE, ET and RES, respectively. Flavonoids, alkaloids, glycosides, tannins and saponins were detected in the nut. GC-MS analysis revealed 16, 18 and 10 volatile components in WE, ET and RES, respectively. Unsaturated fatty acids (linolenic acids: 33.33, 47.95 and 50.93 %, and α-linolenic acids: 25, 19.66 and 26.63 %) in WE, ET and RES, respectively, are the most abundant, and likely to be responsible for the observed activity. CONCLUSION: African walnuts can prevent hepatic lipid accumulation through reciprocal actions on HMG-CoA reductase and paraoxonase in obesity.

Zinc source modulates zootechnical characteristics, intestinal features, humoral response, and paraoxonase (PON1) activity in broilers.

The current experiment was performed to find the potential effect of inorganic and organic forms of zinc (Zn) on growth, intestinal histomorphology, immune response, and paraoxonase (PON1) activity in broiler. In this experiment, a total of 450 broiler chickens were assigned to four experimental and control groups. The birds received organic Zn at the rate of 50 mg/kg (OZ-50) and 60 mg/kg (OZ-60) or inorganic Zn at the rate of 50 mg/kg (IZ-50) and 60 mg/kg (IZ-60) for an experimental period of 30 days. Significantly (P < 0.05) higher feed consumption, body weight, feed conversion ratio, and production efficiency factor (PEF) were recorded in OZ-50. Similarly, antibody titer against infectious bronchitis (IB) and PON1 activity was higher (P < 0.05) in OZ-50 compared with the control group. In addition, significantly (P < 0.05) higher villus dimensions and goblet cell count were recorded for the group OZ-50 compared with other treatments. It was concluded that the organic form of Zn was superior in improving the growth, histological features of intestines, humoral response, and PON1 activity in broiler.

Propolis relieves the cardiotoxicity of chlorpyrifos in diabetic rats via alleviations of paraoxonase-1 and xanthine oxidase genes expression.

Pesticides cardiotoxicity in case of diabetic-induced cardiac complications is unidentified. The probable amelioration role of propolis is gauged against the cardiotoxic effects of chlorpyrifos in the diabetic rats through paraoxonase-1 (PON1) and xanthine oxidase (XO) genes dysregulation. Fifty-six male rats were distributed (n = 7) into eight groups. The first one saved as control whereas the 2nd, 3rd, and 4th were kept for propolis aqueous extract (100 mg/kg), diabetes (60 mg/kg streptozotocin) and chlorpyrifos (2.5 mg/kg), respectively. The 5th was diabetes/chlorpyrifos combination, while 6th, 7th, and 8th were intubated with propolis for four weeks after diabetic induction, chlorpyrifos intoxication, and their combination, respectively. The plasma glucose, lipid profiles, cardiac enzymes and interleukin-6 (IL-6) significantly elevated, while insulin decreased in the diabetic and combination groups. Although the cardiac acetylcholinesterase, total thiols, and PON1 significantly reduced after diabetic and/or chlorpyrifos gavage, the protein carbonyl, superoxide dismutase, catalase, and XO significantly elevated. The mRNA genes expression of PON1 and XO have also confirmed the enzymatic activities. Interestingly, propolis significantly restored the hyperglycemia, hypoinsulinemia, hyperlipidemia, IL-6 elevations, and antioxidant defense system disorder. These records revealed that the immunomodulatory, anti-diabetic and antioxidant tasks are fine pointers for the cardiovascular defender of propolis especially during diabetes and/or pesticides exposure.

Therapeutic potentials of propolis and pollen on biochemical changes in reproductive function of L-NAME induced hypertensive male rats.

BACKGROUND: Hypertension is described as increased blood pressure based on changed hemodynamics and associated with an increased oxidative damage to reproductive function. This work is to determine therapeutic and protective effects of apitherapy products (propolis and pollen) on reproductive functions of L-NAME-induced hypertensive male rats. METHODS: Experimental animals were indiscriminately separated into four groups of seven rats in each group: (I) Control, (II) L-NAME, (III) L-NAME+ propolis and (IV) L-NAME+ pollen. At the end of the experimental applications, the rats were decapitated by anesthesia and biochemical analyzes were performed on the removed testicular tissues. RESULTS: The levels of TOS, NF-κB and MDA in the L-NAME group compared to control have increased (p < 0.05). The levels of these parameters in L-NAME+ propolis and L-NAME+ pollen groups compared to the L-NAME group have decreased (p < 0.05). TAS levels, PON1 and CAT activities were significantly decreased in testis tissue samples in the L-NAME-induced group (p < 0.05). However, these parameters were significantly lower in the L-NAME plus propolis and pollen groups (p < 0.05) compared with rats administered L-NAME alone (p < 0.05). NO level significantly reduced (p < 0.05) in L-NAME group compared with control group. There was no statistically significant changes in the NO level of the L-NAME+ propolis group compared with the L-NAME-treated group (p > 0.05). CONCLUSION: It has been determined that ethanolic extracts of propolis and pollen, which are natural bee products in the regulation of rising blood pressure. Propolis or pollen is thought to help regulate reproductive function by inhibiting the functioning of inflammatory pathways leading to hypertension.

Effects of Panax Notoginseng Saponins on Esterases Responsible for Aspirin Hydrolysis In Vitro.

Herb⁻drug interactions strongly challenge the clinical combined application of herbs and drugs. Herbal products consist of complex pharmacological-active ingredients and perturb the activity of drug-metabolizing enzymes. Panax notoginseng saponins (PNS)-based drugs are often combined with aspirin in vascular disease treatment in China. PNS was found to exhibit inhibitory effects on aspirin hydrolysis using Caco-2 cell monolayers. In the present study, a total of 22 components of PNS were separated and identified by UPLC-MS/MS. Using highly selective probe substrate analysis, PNS exerted robust inhibitory potency on human carboxylesterase 2 (hCE2), while had a minor influence on hCE1, butyrylcholinesterase (BChE) and paraoxonase (PON). These effects were also verified through molecular docking analysis. PNS showed a concentration-dependent inhibitory effect on hydrolytic activity of aspirin in HepaRG cells. The protein level of hCE2 in HepaRG cells was suppressed after PNS treatment, while the level of BChE or PON1 in the extracellular matrix were elevated after PNS treatment. Insignificant effect was observed on the mRNA expression of the esterases. These findings are important to understand the underlying efficacy and safety of co-administration of PNS and aspirin in clinical practice.

Zingiber officinale extract administration diminishes steroyl-CoA desaturase gene expression and activity in hyperlipidemic hamster liver by reducing the oxidative and endoplasmic reticulum stress.

BACKGROUND: Stearoyl CoA desaturases (SCD) are enzymes that convert saturated to monounsaturated fatty acids and have increased activity in hepatic steatosis. PURPOSE: We aimed to investigate the potential of ginger extract (GIN) to modulate the liver SCD1 expression and activity in hyperlipidemic (HL) conditions, in order to lower lipid accumulation in the steatotic liver. STUDY DESIGN/METHODS: Male Golden Syrian hamsters were divided in three groups: (i) fed with standard chow (N), (ii) fed with standard chow plus 3% cholesterol and 15% butter for 21 weeks (HL), (iii) HL treated with GIN (800 µg/kg body weight/day) in the last 5 weeks of fat diet (HL-GIN). Cholesterol (C), triglycerides (TG), non-esterified fatty acids (NEFA), SCD1 estimated activity (C16:1n7/C16:0; C18:1n9/C18:0) and gene expression, acetyl-CoA carboxylase (ACC), thiobarbituric acid reactive substances (TBARS), paraoxonase1 (PON1) and myeloperoxidase (MPO) were determined in the plasma and liver of all hamsters. We measured protein expression of endoplasmic reticulum stress (ERS) markers, gene and protein expression of liver X receptor α/ß (LXRα/ß), peroxisome proliferator-activated receptor γ (PPARγ), ATP-binding cassette sub-family G member 5/8 (ABCG5/G8) and 7α-hydroxylase1 (CYP7A1) in all hamsters' livers. RESULTS: In plasma, in HL-GIN versus HL hamsters, SCD1 estimated activity was lower (27%; 15%, p < 0.05), NEFA levels decreased by 91%, p < 0.001, while C and TG levels did not vary; the oxidative stress expressed as MPO and TBARS levels decreased (15%; 11%, p < 0.01), while PON1 protein increased (75%, p < 0.05). In the liver of HL-GIN versus HL, C, TG, NEFA, MPO and TBARS levels decreased (8-40%, p < 0.05) and PON1 protein levels increased (30%, p < 0.05), SCD1 estimated activity decreased (8%; 9%, p < 0.05), in parallel with the reduced gene expression of SCD1 and ACC (70-80%, p < 0.05). The protein expression of the ERS sensors decreased (30-65%, p < 0.05), while that of ABCG5/G8, CYP7A1, LXRα/ß and PPARγ increased in HL-GIN (20-30%, p < 0.05) versus HL liver. CONCLUSION: GIN reduces SCD1 estimated activity and expression, as well as the lipids accumulated in the livers of HL hamsters. This is achieved through a mechanism involving the decrease of the oxidative and ERS, and the enhancement of cholesterol efflux.

Long-Term Supplementation of Black Elderberries Promotes Hyperlipidemia, but Reduces Liver Inflammation and Improves HDL Function and Atherosclerotic Plaque Stability in Apolipoprotein E-Knockout Mice.

SCOPE: HDL particles are protective against atherosclerosis, but may become dysfunctional during inflammation and chronic disease progression. Anthocyanin-rich foods, such as the black elderberry, may improve HDL function and prevent disease development via antioxidant and/or anti-inflammatory effects. This study investigates the long-term consumption of black elderberry extract (BEE) on HDL function and atherosclerosis in apolipoprotein (apo) E-/- mice. METHODS AND RESULTS: ApoE-/- mice (n = 12/group) are fed a low-fat diet, supplemented with 0, 0.25%, or 1% (by weight) BEE (≈37.5-150 mg anthocyanins per kg body weight) for 24 weeks. Feeding 1% BEE increases total serum cholesterol (+31%) and non-HDL cholesterol (+32%) compared with the control diet. PON1 arylesterase (+32%) and lactonase (+45%) activities also increase with the 1% BEE diet. Both 0.25% BEE and 1% BEE diets strongly increase HDL cholesterol efflux capacity (CEC) by 64% and 85%, respectively. Further, BEE dose-dependently lowers serum liver enzymes and hepatic inflammatory gene expression. Although there is no change in neutral lipid accumulation in atherosclerotic lesions, BEE promotes connective tissue deposition in the aortic root. CONCLUSIONS: Chronic BEE supplementation in apoE-/- mice dose-dependently improves HDL function. Despite BEE promoting hyperlipidemia, which likely offsets HDL effects, BEE increases connective tissue content, suggesting improved atherosclerotic plaque stability.

Trace Elements and Paraoxonase-1 Activity in Lower Extremity Artery Disease.

Oxidative stress and inflammation are candidate mechanisms to explain the potential role of exposure to metals and reduced activity of paraoxonase-1 (PON1) in age-related diseases. Both may be risk factors contributing to atherosclerosis. In the present study, inductively coupled mass spectrometry was used to explore multiple trace elements, while in-house methods were employed to measure PON1-related variables in patients with lower extremity artery disease (LEAD). Healthy controls were matched for sex, age, body weight, and relevant genotype variants. Serum concentrations of As, Ba, Cu, and Sr were higher in patients than those in controls, with a strong predictive ability to discriminate between groups. Differences in serum Pb, Cd, and Zn were negligible. Serum Cu increased when the disease was more severe, but a negative trend was noted for serum As, B, Ba, and Zn. The only variable associated with ankle-brachial index was serum Zn. Serum PON1 activity was significantly lower in LEAD patients. When the ability of serum trace elements to modulate PON1 activity was explored, the analysis revealed a unique association with serum Zn. The current results strongly suggest that Zn may have a protective effect in non-coronary atherosclerosis and indicate that this element may exert its anti-inflammatory and antioxidant functions through interactions with PON1 activity. These findings deserve confirmation and further research. In particular, the periodic evaluation of serum trace elements and the prescription of Zn supplements are easy measures to implement and that can improve the treatment of patients with LEAD.

Paraoxonases: metabolic role and pharmacological projection.

Atherosclerosis is one of the leading causes of death in Western countries, with high-density lipoproteins (HDL) playing an important protective role due to their ability to inhibit oxidation of low-density lipoproteins (LDL), thus relieving vascular subendothelial damage. One of the proteins constituting HDL particles is paraoxonase-1 (PON1), an enzyme able to hydrolyze aryl esters, lactones, and organophosphates. Other closely related paraoxonases are designated as PON2, which is a protein localized inside many different kinds of cells, and PON3, not only present in HDL but also in mitochondria and endoplasmic reticulum, as well. Given that the amount and the activity of PON1 in human serum are significantly lower in people suffering from cardiovascular diseases, enhancing both parameters might contribute to their treatment and prevention. One of the physiologically interesting substrates for the abovementioned hydrolytic cleavage is homocysteine thiolactone (HTL), an atherothrombotic active form of homocysteine. Although it was therefore postulated that PON1 would participate in preventing the HTL-mediated lipid peroxidation, some attention is recently paid to other enzymes, like biphenyl hydrolase-like protein, that seem to more selectively involved in lowering this risk factor. The aim of this paper is to elucidate the role of paraoxonases, especially PON1, by reviewing the latest studies in order to understand both its physiological role and modulation by drugs, nutrients, and plant extracts.

Effects of propolis, caffeic acid phenethyl ester, and pollen on renal injury in hypertensive rat: An experimental and theoretical approach.

The objective of this study was to evaluate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE; active compound in propolis), and pollen on biochemical oxidative stress biomarkers in rat kidney tissue inhibited by Nω -nitro-L-arginine methyl ester (L-NAME). The biomarkers evaluated were paraoxonase (PON1), oxidative stress index (OSI), total antioxidant status (TAS), total oxidant status (TOS), asymmetric dimethylarginine (ADMA), and nuclear factor kappa B (NF-κB). TAS levels and PON1 activity were significantly decreased in kidney tissue samples in the L-NAME-treated group (P < 0.05). The levels of TAS and PONI were higher in the L-NAME plus propolis, CAPE, and pollen groups compared with the L-NAME-treated group. TOS, ADMA, and NF-κB levels were significantly increased in the kidney tissue samples of the L-NAME-treated group (P < 0.05). However, these parameters were significantly lower in the L-NAME plus propolis, CAPE, and pollen groups (P < 0.05) compared with rats administered L-NAME alone (P < 0.05). Furthermore, the binding energy of CAPE within catalytic domain of glutathione reductase (GR) enzyme as well as its inhibitory mechanism was determined using molecular modeling approaches. In conclusion, experimental and theoretical data suggested that oxidative alterations occurring in the kidney tissue of chronic hypertensive rats may be prevented via active compound of propolis, CAPE administration.

The Search for Dietary Supplements to Elevate or Activate Circulating Paraoxonases.

Low levels of paraoxonase 1 (PON1) have been associated with the development of several pathological conditions, whereas high levels have been shown to be anti-atherosclerotic in mouse models. These findings suggest that PON1 could be a good surrogate biomarker. The other members of the family, namely PON2 and PON3, the role of which has been much less studied, deserve more attention. This paper provides a systematic review of current evidence concerning dietary supplements in that regard. Preliminary studies indicate that the response to dietary supplements may have a nutrigenetic aspect that will need to be considered in large population studies or in clinical trials. A wide range of plant preparations have been found to have a positive action, with pomegranate and some of its components being the best characterized and Aronia melanocarpa one of the most active. Flavonoids are found in the composition of all active extracts, with catechins and genistein being the most promising agents for increasing PON1 activity. However, some caveats regarding the dose, length of treatment, bioavailability, and stability of these compounds in formulations still need to be addressed. Once these issues have been resolved, these compounds could be included as nutraceuticals and functional foods capable of increasing PON1 activity, thereby helping with the long-term prevention of atherosclerosis and other chronic ailments.

Açai (Euterpe oleracea Mart.) Upregulates Paraoxonase 1 Gene Expression and Activity with Concomitant Reduction of Hepatic Steatosis in High-Fat Diet-Fed Rats.

Açai (Euterpe oleracea Mart.), a fruit from the Amazon region, has emerged as a promising source of polyphenols. Açai consumption has been increasing owing to ascribed health benefits and antioxidant properties; however, its effects on hepatic injury are limited. In this study, we evaluated the antioxidant effect of filtered açai pulp on the expression of paraoxonase (PON) isoforms and PON1 activity in rats with nonalcoholic fatty liver disease (NAFLD). The rats were fed a standard AIN-93M (control) diet or a high-fat (HF) diet containing 25% soy oil and 1% cholesterol with or without açai pulp (2 g/day) for 6 weeks. Our results show that açai pulp prevented low-density lipoprotein (LDL) oxidation, increased serum and hepatic PON1 activity, and upregulated the expression of PON1 and ApoA-I in the liver. In HF diet-fed rats, treatment with açai pulp attenuated liver damage, reducing fat infiltration and triglyceride (TG) content. In rats receiving açai, increased serum PON1 activity was correlated with a reduction in hepatic steatosis and hepatic injury. These findings suggest the use of açai as a potential therapy for liver injuries, supporting the idea that dietary antioxidants are a promising approach to enhance the defensive systems against oxidative stress.

Effects of vitamin A, C and E, or omega-3 fatty acid supplementation on the level of paraoxonase and arylesterase activity in streptozotocin-induced diabetic rats: an investigation of activities in plasma, and heart and liver homogenates.

INTRODUCTION: This study was designed and conducted to evaluate the effects of vitamin A, C and E supplementation, and omega-3 fatty acid supplementation on the activity of paraoxonase and arylesterase in an experimental model of diabetes mellitus. METHODS: A total of 64 male Sprague Dawley® rats, each weighing 250 g, were randomly distributed into four groups: (a) normal control; (b) diabetic control; (c) diabetic with vitamin A, C and E supplementation; and (d) diabetic with omega-3 fatty acid supplementation. The animals were anaesthetised after four weeks of intervention, and paraoxonase and arylesterase activity in blood plasma, and liver and heart homogenates were measured. RESULTS: Arylesterase activity in the heart and liver homogenates was significantly lower in the diabetic control group than in the normal control group (p < 0.01). Vitamin A, C and E supplementation, and omega-3 fatty acid supplementation significantly increased liver arylesterase activity (p < 0.05). No significant change was observed in paraoxonase activity and other investigated factors. CONCLUSION: Vitamin A, C and E, or omega-3 fatty acid supplementation were found to increase liver arylesterase activity in streptozotocin-induced diabetic rats. These supplements may be potential agents for the treatment of diabetes mellitus complications.