Increased Paraoxonase Activity Research Articles

Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer's Disease.

Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer's disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian currant paste-supplemented diet (CurD), provided to 1-month-old 5xFAD mice for 1, 3, and 6 months, on PON1 activity and levels of oxidation markers in serum and the brain of mice as compared to a control diet (ConD) or glucose/fructose-matched diet (GFD). Administration of CurD for 1 month increased PON1 activity and decreased oxidized lipid levels in serum compared to ConD and GFD. Longer-term administration of CurD did not, however, affect serum PON1 activity and oxidized lipid levels. Furthermore, CurD administered for 1 and 3 months, but not for 6 months, increased PON1 activity and decreased free radical levels in the cortex of mice compared to ConD and GFD. To probe the mechanism for the increased PON1 activity in mice, we studied the effect of Corinthian currant polar phenolic extract on PON1 activity secreted by Huh-7 hepatocytes or HEK293 cells transfected with a PON1-expressing plasmid. Incubation of cells with the extract led to a dose-dependent increase of secreted PON1 activity, which was attributed to increased cellular PON1 expression. Collectively, our findings suggest that phenolics in Corinthian currants can increase the hepatic expression and activity of antioxidant enzyme PON1 and that a Corinthian currant-supplemented diet during the early stages of AD in mice reduces brain oxidative stress.

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.

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.

Paraoxonase-1, a novel link between periodontitis and ischemic heart disease: A case-control study.

Periodontitis is a chronic inflammatory disease and might be a potential risk factor for ischemic heart disease (IHD). However, the link between periodontitis and atherosclerosis is not yet fully understood. Paraoxonase-1 (PON-1) is a new biomarker representing both anti-atherosclerotic and antioxidant activity, which also acts against dental biofilm formation and periodontitis. The possible contributing role of PON-1 in the relationship between periodontitis and atherosclerosis has not been studied to date. The aim of the present study was to investigate the serum level of PON-1 with regard to the periodontal status in IHD patients. In this case-control study, 67 patients with IHD underwent a periodontal examination and were accordingly allocated to one of the 2 study groups: the case group with chronic periodontitis (n = 36); or the control group with a healthy periodontium (n = 31). Serum PON-1 activity was measured by means of colorimetric analysis. There were no significant differences between the groups in terms of demographic data, cardiac risk factors, initial biochemical test results, cardiac pump function, and the number of grafted vessels. The activity of PON-1 in cardiac patients suffering from periodontitis was significantly lower than in cardiac patients with a healthy periodontal status (53.01 ±7.53 U/mL and 59.11 ±9.95 U/mL, respectively; p = 0.007). This finding suggests that the combination of IHD and periodontitis is associated with lower PON-1 activity. Further studies might be required to assess the possible role of periodontal treatment in increasing PON-1 activity and reducing IHD severity.

Effect of Lactoferrin on Paraoxonase Activity, Some Acute Phase Proteins and Oxidant/Antioxidant System

Lactoferrin is a member of the high affinity to glycoprotein family of transferrin for iron and plays a role in natural immunity as well as antibacterial, antifungal, antiviral, antiparasitic, antioxidant, anticancer, antiinflammatory, bone health and immunomodulation. The aim this study was to investigate of the acute effect of lactoferrin on paraoxonase activity, oxidant/antioxidant system and total protein, albumin and globulin. This study was carried out on 6-month Sprague Dawley rats in a total number of 20 subjects. Paraoxonase activity, total antioxidant capacity (TAC), total oxidant capacity (TOC), total protein, albumin and globulin levels were measured through the spectrophotometer. When the lactoferrin group was compared with the control group, it was found that TAC levels were statistically higher (P&lt;0.05), TOC levels were statistically lower (P&lt;0.01) and paraoxonase activity was statistically higher (P&lt;0.05). There was no difference in total protein and globulin levels in the lactoferrin group compared to the control group. As a result, acute lactoferrin administration may play an important role in the regulation of antioxidant balance by increasing paraoxonase activity and decreasing the level of reactive oxygen species.

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.

Effect of Carotenoids on Paraoxonase-1 Activity and Gene Expression.

Paraoxonase 1 (PON1) is an antioxidant enzyme attached to HDL with an anti-atherogenic potential. It protects LDL and HDL from lipid peroxidation. The enzyme is sensitive to various modulating factors, such as genetic polymorphisms as well as pharmacological, dietary (including carotenoids), and lifestyle interventions. Carotenoids are nutritional pigments with antioxidant activity. The aim of this review was to gather evidence on their effect on the modulation of PON1 activity and gene expression. Carotenoids administered as naturally occurring nutritional mixtures may present a synergistic beneficial effect on PON1 status. The effect of carotenoids on the enzyme depends on age, ethnicity, gender, diet, and PON1 genetic variation. Carotenoids, especially astaxanthin, β-carotene, and lycopene, increase PON1 activity. This effect may be explained by their ability to quench singlet oxygen and scavenge free radicals. β-carotene and lycopene were additionally shown to upregulate PON1 gene expression. The putative mechanisms of such regulation involve PON1 CpG-rich region methylation, Ca(2+)/calmodulin-dependent kinase II (CaMKKII) pathway induction, and upregulation via steroid regulatory element-binding protein-2 (SREBP-2). More detailed and extensive research on the mechanisms of PON1 modulation by carotenoids may lead to the development of new targeted therapies for cardiovascular diseases.

Paraoxonase 1 activity in the sperm-rich portion of boar ejaculates is positively associated with sperm quality

Associations of the activity of the paraoxonase 1 (PON1) enzyme with boar sperm quality still needs to be characterized, since boar ejaculates present distinct portions with differences in sperm concentration and quality. This study evaluated PON1 activity in the serum, in the distinct portions of boar ejaculates and estimated correlations with sperm quality parameters. Ejaculates and blood samples were collected from six boars for three weeks (two per week per boar; n = 36). Serum and post-spermatic portion PON1 activities were positively correlated (P = 0.01) but were both uncorrelated with the PON1 activity in the sperm-rich portion and in the whole ejaculate (P > 0.05). Differences in PON1 activity among boars were only observed in the sperm-rich portion of the ejaculate (P < 0.05). The PON1 activity in the serum and in the post-spermatic portion was generally negatively correlated with parameters of spermatozoa kinetics (P < 0.05). In the sperm-rich portion, PON1 activity was positively correlated with sperm concentration (P < 0.0001), curvilinear distance and velocity (both P < 0.05) and DNA integrity (P < 0.05), but negatively correlated with straightness and linearity (P < 0.05). Thus, boar ejaculates with increased PON1 activity in the sperm-rich portion may present increased concentration and spermatozoa with acceptable curvilinear velocity and distance and DNA integrity, which suggests that PON1 activity may be a biomarker for potential fertility.

How effective is the obesity treatment on improving oxidative stress? Is there any difference between drugs?

Aim: Obesity shortens the life period and decreases its quality, causing several complications. Recently, oxidative stress produced by lipid peroxydation is considered a cardiovascular risk factor. In this study, we aimed to investigate the relationship between weight loss with lipid profile, insulin resistance, and lipid peroxidation products malondialdehyde (MDA, oxidant) and paraoxonase-1 (PON1, antioxidant) levels which is protective in atherosclerosis, and to evaluate alteration on oxidative stress.Methods: Patients diagnosed as obese at the Endocrinology and Metabolic Diseases Outpatient Clinics of Inonu University Faculty of Medicine between December 2005 and February 2008 were studied. 103 patients were included in the study. Study population was divided into two treatment groups. In the first group, 120 mg of orlistat, three times daily, and in the second group, sibutramine 15 mg per day were given in addition to appropriate diet therapy. The patients were evaluated at the end of three months treatment period.Results: Dramatic changes in body weight, Body Mass Index (BMI), and waist and hip circumference were observed during the three-month evaluation in patients receiving orlistat or sibutramine. Additionally, significant improvements were measured in systolic-diastolic blood pressure levels, lipid levels, and insulin resistance. The decrease in the MDA level and the increase in the PON level were similar and significant in both patient groups.Conclusion: The treatment of obesity, aimed at reducing body weight, acts to reduce oxidative stress by increasing paraoxonase-1 activity (antioxidant) and reducing the amount of the peroxidation product malondialdehyde (oxidant), regardless of the type of medication administered.

Arylesterase activity of paraoxonase 1 in patients with primary hypertension

Abstract Introduction Paraoxonase 1 is an enzyme associated with high-density lipoprotein fraction and is considered to present antioxidant activity. Objectives The aim of the study was to assess the arylesterase activity of paraoxonase 1 (PON1) in the serum of patients with hypertension, due to effect of therapy and before treatment. Patients and Methods. The study was conducted in 76 patients with primary hypertension and 28 volunteers for the control group. Hypertensive subjects were assigned to one of three groups: well controlled (n=25), poorly controlled (n=26), and newly diagnosed before therapy (n=25) hypertension. We evaluated metabolic parameters in all participants using routine laboratory methods, as well as arylesterase activity of PON1. Results The four study groups differed with arylesterase activity of PON1 and the highest levels were found in patients with well controlled hypertension and the lowest in newly diagnosed. All patients diagnosed with hypertension presented negative correlations between PON1 and systolic and diastolic blood pressure. Conclusions Effective treatment of hypertension could result in increased PON1 activity, despite unfavorable homocysteine concentrations in blood. Untreated hypertension might decrease activity of PON.

Evaluation of the relationship between serum paraoxonase-1 activity and superovulation response/embryo yield in Holstein cows.

In this study, the effect of serum paraoxonase-1 (PON-1) activity on superovulation response and embryo yield was evaluated. The study material comprised 50 Holstein cows aged 3–4 years on postpartum day 90–120 with a body condition score of 3–3.25. A progesterone-based estrus synchronization protocol was initially administered to the selected donors. For this purpose, progesterone source was inserted intravaginally (day 0) and gonadotropin-releasing hormone injection was performed (day 6). Seven days after the insertion of progesterone device, follicle-stimulating hormone injections (total dose of 500 µg in decreasing doses for 4 days) were administered for superovulation. On the morning of the ninth day, prostaglandin (PG) F2α was administered, and the progesterone device was removed from the vagina in the evening on the same day. Two days after PGF2α administration, fixed-time artificial insemination was performed in the morning and in the evening. On the day of artificial insemination, blood samples were taken from the donors to determine the serum PON-1 activity. Uterine flushing was performed seven days after insemination. The results revealed that the serum PON-1 activity (mean ± SD, 562.71 ± 140.23 U/l) of the cows that responded to superovulation (donors with total corpus luteum count of ≥3 in both ovaries) was higher than those (389.91 ± 80.51 U/l) that did not (P<0.05). On the day of insemination, a positive correlation was determined between serum PON-1 activity and the counts of total corpus luteum (r=0.398), total oocyte/embryo (r=0.468), transferable embryo (r=0.453), and Code I embryos (r=0.315, P<0.05). Unlike the Code I embryos, there was no significant correlation between serum PON-1 activity and the number of Code III embryos. Moreover, no significant difference in the number of Code III embryos between the two PON-1 groups was observed. However, embryo yield and quality were found to have increased with increased PON-1 activity. Therefore, it was concluded that serum PON-1 activity may be associated with superovulation response, embryo yield and quality in donor cows.

Curcumin exerts hepatoprotection via overexpression of Paraoxonase-1 and its regulatory genes in rats undergone bile duct ligation.

Curcumin is described as an antioxidant, hepato-protective and antifibrotic in liver fibrosis, although its mechanism is still not known. One of the models of the chronic liver disease stemming from oxidative stress and the generation of free radical has been considered to be bile duct ligation (BDL). Paraoxonase 1 (PON1) is a prominent antioxidant enzyme. Therefore, the objective of the present research is to assess the effects of curcumin on upregulation of PON1 in BDL rats. As predicted, the rats have been divided into the four groups of Sham, Sham+Cur (curcumin), BDL and BDL+Cur. We evaluated the efficacy of curcumin (100mg/kg/day) on protein and gene expression of PON1 and regulatory genes contributed to the gene expression PON1 such as Sp1, PKCα, SREBP-2, AhR, JNK and regulation PON1 activity gene expression of Apo A1. Curcumin attenuated alterations in liver histology, hepatic enzymes and the mRNA expression of fibrotic markers (p<0.05). In addition, curcumin increased significantly mRNA, protein expression of PON1 and mRNA of the genes that are contributed to the expression of PON1 such as Sp1, PKCα, SREBP-2, AhR, JNK and increased PON1 activity through upregulation of Apo A1 (p<0.05). Cirrhosis progression may be inhibited by treatment with curcumin through the increased influence the expression and activity of PON1.

Do PON1–Q192R and PON1–L55M polymorphisms modify the effects of hypoxic training on paraoxonase and arylesterase activity?

BackgroundLow levels of antioxidant paraoxonase 1 (PON1) enzyme activity, PON1–Q192R polymorphism (a glutamine (Q) to arginine (R) substitution at position 192), PON1–L55M polymorphism (a leucine (L) to methionine (M) substitution at position 55), and oxidized low-density lipoprotein (oxLDL) are risk factors for coronary heart disease. Aerobic exercise improves PON1 activity, but the effects of hypoxic exercise are yet unclear. The aim of this study was to determine the effects of hypoxic underwater rugby training on PON1 activity and oxLDL levels and the role of the mentioned polymorphisms. MethodsSerum PON1 and arylesterase activities (ARE), PON1, PON3, and oxLDL protein levels (by using the enzyme-linked immunosorbent assays) were determined in an athletic group (42 trained male underwater rugby players; age = 21.7 ± 4.2 years, mean ± SD) and a control group (43 sedentary men; age = 23.9 ± 3.2 years). The polymorphisms were determined from genomic DNA samples. ResultsPON1 activity (25.1%, p = 0.052), PON3 (p < 0.001), and oxLDL (p < 0.001) of the athletic group, including most genotype groups, were higher than those of the control group. In comparison to the controls, PON1 activity levels (p = 0.005) of the PON1–Q192R homozygote QQ genotype group and PON1 activity levels (30%, p = 0.116) of the PON1–L55M homozygote LL genotype group were higher, whereas ARE activity values of athletic R allele carrier (Rc = QR + RR) (p = 0.005) and LL group (p = 0.002) were lower than the control genotype groups related to their polymorphisms. ConclusionHypoxic training can cause (1) significant oxidative stress, including oxLDL, and an antioxidant response (increase in PON1 activity and PON3), (2) differences in the activity of PON1 and ARE, which are modified by PON1–Q192R and PON1–L55M polymorphisms, respectively, and (3) improvements in PON1 activity of QQ and LL groups. However, hypoxic training can cause a disadvantage of LL and Rc groups for ARE.

Fisetin Alleviates Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice.

The present study aimed to investigate the protective role of the flavonoid fisetin (FI) on inflammation-mediated metabolic diseases, especially tissue fibrosis and insulin resistance (IR) in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed with normal-fat diet, HFD (40 kcal% fat), or HFD +0.02% (w/w) FI for 16 weeks. Dietary FI supplementation improved hepatic steatosis by restricting lipogenesis, while promoting lipolysis in the liver. FI also prevented adiposity via an increase in the expression of genes involved in FA oxidation and a decrease in the expression of genes involved in lipogenesis in white adipose tissue. In addition, FI increased brown adipose tissue (BAT) and skeletal muscle weights, thermogenic gene mRNA expression in BAT, and tricarboxylic acid cycle-related gene expression in skeletal muscle, which may be linked to the prevention of nonalcoholic fatty liver disease as well as adiposity. Moreover, FI supplementation decreased excessive reactive oxygen species production by increasing paraoxonase activity, adipokine dysregulation, proinflammatory cytokine production, and extracellular matrix amassment in the liver. FI supplementation ameliorated IR, in part, by normalizing pancreatic islet dysfunction, and it declined hepatic gluconeogenesis and proinflammatory responses. Taken together, the present findings indicate that FI can protect against HFD-induced inflammation-mediated disorders, including fibrosis and IR.

Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity.

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe−/− macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe−/− macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.

Renal Fibrosis Is Significantly Attenuated Following Targeted Disruption of Cd40 in Experimental Renal Ischemia.

BackgroundRenal artery stenosis is a common cause of renal ischemia, contributing to the development of chronic kidney disease. To investigate the role of local CD40 expression in renal artery stenosis, Goldblatt 2‐kidney 1‐clip surgery was performed on hypertensive Dahl salt‐sensitive rats (S rats) and genetically modified S rats in which CD40 function is abolished (Cd40 mutant).Methods and ResultsFour weeks following the 2‐kidney 1‐clip procedure, Cd40 mutant rats demonstrated significantly reduced blood pressure and renal fibrosis in the ischemic kidneys compared with S rat controls. Similarly, disruption of Cd40 resulted in reduced 24‐hour urinary protein excretion in Cd40 mutant rats versus S rat controls (46.2±1.9 versus 118.4±5.3 mg/24 h; P<0.01), as well as protection from oxidative stress, as indicated by increased paraoxonase activity in Cd40 mutant rats versus S rat controls (P<0.01). Ischemic kidneys from Cd40 mutant rats demonstrated a significant decrease in gene expression of the profibrotic mediator, plasminogen activator inhibitor‐1 (P<0.05), and the proinflammatory mediators, C‐C motif chemokine ligand 19 (P<0.01), C‐X‐C Motif Chemokine Ligand 9 (P<0.01), and interleukin‐6 receptor (P<0.001), compared with S rat ischemic kidneys, as assessed by quantitative PCR assay. Reciprocal renal transplantation documented that CD40 exclusively expressed in the kidney contributes to ischemia‐induced renal fibrosis. Furthermore, human CD40‐knockout proximal tubule epithelial cells suggested that suppression of CD40 signaling significantly inhibited expression of proinflammatory and ‐fibrotic genes.ConclusionsTaken together, our data suggest that activation of CD40 induces a significant proinflammatory and ‐fibrotic response and represents an attractive therapeutic target for treatment of ischemic renal disease.

The Effects of Anthocyanins and Their Microbial Metabolites on the Expression and Enzyme Activities of Paraoxonase 1, an Important Marker of HDL Function

High circulating HDL concentrations and measures of various HDL functions are inversely associated with cardiovascular disease (CVD) risk. Paraoxonase 1 (PON1) contributes to many of the athero-protective functions of HDL, such as promoting the reverse cholesterol transport process and reducing the levels of oxidized LDL. PON1 activities are influenced by several factors, the most important being diet and genetic polymorphisms. Reported data from randomized controlled trials have shown that anthocyanin consumption increased PON1 activity. However, the underlying molecular mechanisms by which anthocyanins increase PON1 activity are not understood. Therefore, the aim of this research was to investigate the ability of anthocyanins and their metabolites to increase PON1 gene expression and/or enzyme activities as potential mechanisms. The effect of the two predominant dietary anthocyanins and 18 of their recently identified microbial metabolites including their phase-II conjugates on PON1 gene expression was studied using a PON1-Huh7 stably-transfected cell line and reporter gene assay. The effects of these compounds on PON1 arylesterase and lactonase activities were investigated using two isoforms of the PON1 enzyme that are the phenotypes of the 192Q/R polymorphism. None of the compounds caused even modest changes in PON1 promoter activity (p ≥ 0.05). Further, none of the compounds at physiological concentrations caused any significant changes in the arylesterase or lactonase activity of either of the iso-enzymes. Cyanidin reduced the lactonase activity of the PON1-R192R enzyme at high concentrations (−22%, p < 0.001), but not at physiologically achievable concentrations. In conclusion, none of the data reported here support the notion that anthocyanins or their metabolites affect PON1 transactivation or enzyme activities.

Plasma paraoxonase1 activity in rats treated with monocrotophos: a study of the effect of duration of exposure.

We have earlier demonstrated the potential of monocrotophos (MCP), a highly toxic organophosphorus insecticide (OPI), to elicit insulin resistance in rats after chronic exposure. Given the understanding of role of paraoxonase1 (PON1) in OPI toxicity and diabetes pathology, this study was envisaged to understand the effect of duration of exposure to MCP on plasma PON1 activity in rats. Rats were administered MCP per os at 1/20 and 1/10th LD50 as daily doses for 180 days. Interim blood samples were collected at 15, 30, 45, 90 and 180 d for analysis of plasma parameters. Exposure to MCP for 45 resulted in persistent trend of hyperinsulinemia, while significant increase in fasting glucose levels was observed after 180 days. MCP caused suppression of plasma cholinesterase activity though the study period, albeit extent of inhibition was more severe during the early phase of the study. Exposure to MCP for 180 d resulted in hypertriglyceridemia and marginal decrease in HDL-C levels. MCP failed to modulate PON1 activity in plasma during the early phase of the study (up to 45 d). However, prolonged exposure resulted in significant increase in the plasma PON1 activity. This suggests that manifestation of insulin resistance in rats subjected to chronic exposure to MCP is associated with increase in PON1 activity. Our work provides rationale for studying whether the increase in PON1 activity observed in the present study serves to counter the deleterious effect of long term exposure to organophosphorus insecticides on metabolic homeostasis.

Why Should Psychiatrists and Neuroscientists Worry about Paraoxonase 1?

Background: Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms.Objectives: 1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities.Methods: The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity.Results: The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity.Conclusion: Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.

Microencapsulated Pomegranate Reverts High-Density Lipoprotein (HDL)-Induced Endothelial Dysfunction and Reduces Postprandial Triglyceridemia in Women with Acute Coronary Syndrome.

(1) Background: the composition of high-density lipoproteins (HDL) becomes altered during the postprandial state, probably affecting their functionality vis-à-vis the endothelium. Since acute coronary syndrome (ACS) in women is frequently associated with endothelial dysfunction, it is likely that HDL are unable to improve artery vasodilation in these patients. Therefore, we characterized HDL from women with ACS in fasting and postprandial conditions. We also determined whether microencapsulated pomegranate (MiPo) reverts the HDL abnormalities, since previous studies have suggested that this fruit improves HDL functionality. (2) Methods: Eleven women with a history of ACS were supplemented daily with 20 g of MiPo, for 30 days. Plasma samples were obtained during fasting and at different times, after a lipid load test to determine the lipid profile and paraoxonase–1 (PON1) activity. HDL were isolated by sequential ultracentrifugation to determine their size distribution and to assess their effect on endothelial function, by using an in vitro model of rat aorta rings. (3) Results: MiPo improved the lipid profile and increased PON1 activity, as previously reported, with fresh pomegranate juice. After supplementation with MiPo, the incremental area under the curve of triglycerides decreased to half of the initial values. The HDL distribution shifted from large HDL to intermediate and small-size particles during the postprandial period in the basal conditions, whereas such a shift was no longer observed after MiPo supplementation. Consistently, HDL isolated from postprandial plasma samples hindered the vasodilation of aorta rings, and this endothelial dysfunction was reverted after MiPo consumption. (4) Conclusions: MiPo exhibited the same beneficial effects on the lipid profile and PON1 activity as the previously reported fresh pomegranate. In addition, MiPo supplementation reverted the negative effects of HDL on endothelial function generated during the postprandial period in women with ACS.