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Medicine Nov 2022Atrial fibrillation (AF) is associated with oxidative stress and inflammation. Paraoxonase-1 (PON1), circulates in blood bound to high-density lipoproteins and reduces...
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.
Topics: Humans; Aryldialkylphosphatase; Atrial Fibrillation; Lipoproteins, HDL; Oxidative Stress; Body Mass Index
PubMed: 36401436
DOI: 10.1097/MD.0000000000031553 -
Minerva Medica Jun 2019At present, the etiopathogenesis of Alzheimer's disease (AD), the most common form of dementia, remains far to be fully deciphered. In the recent years, also the... (Review)
Review
At present, the etiopathogenesis of Alzheimer's disease (AD), the most common form of dementia, remains far to be fully deciphered. In the recent years, also the centrality of amyloid-β peptide in the pathogenesis of the neurodegenerative disease has been questioned and other hypotheses have been advanced. Notably, a common denominator of many of these theoretical models is represented by oxidative stress, which is widely proposed to play a role in the disease initiation and/or progression. Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that endows its carrier with multiple biological functions, including the ability to contrast oxidative damage to lipid components of lipoproteins and cells and protect from toxicity of specific organophosphorus pesticides. The peculiar multi-functionality nature of PON1 might be the key for explaining the vast epidemiological data showing a close association between low serum PON1 activity and risk of several diseases, including cardiovascular and neurodegenerative diseases, in particular AD. In this review, we discuss the possible link between PON1 with AD pathogenesis and we hypothesize eventual mechanistic pathways that could account from epidemiological observations. We also highlight the methodological issue limitation in PON1 studies that still impede to give a definitive and certain picture of its effective biological impact on human health including AD.
Topics: Alzheimer Disease; Aryldialkylphosphatase; Humans
PubMed: 30334443
DOI: 10.23736/S0026-4806.18.05875-5 -
International Journal of Molecular... Feb 2021Organophosphorus compounds (OPCs) are able to interact with various biological targets in living organisms, including enzymes. The binding of OPCs to enzymes does not... (Review)
Review
Organophosphorus compounds (OPCs) are able to interact with various biological targets in living organisms, including enzymes. The binding of OPCs to enzymes does not always lead to negative consequences for the body itself, since there are a lot of natural biocatalysts that can catalyze the chemical transformations of the OPCs via hydrolysis or oxidation/reduction and thereby provide their detoxification. Some of these enzymes, their structural differences and identity, mechanisms, and specificity of catalytic action are discussed in this work, including results of computational modeling. Phylogenetic analysis of these diverse enzymes was specially realized for this review to emphasize a great area for future development(s) and applications.
Topics: Animals; Aryldialkylphosphatase; Bacteria; Biocatalysis; Cholinesterases; Humans; Hydrolases; Hydrolysis; Organophosphorus Compounds; Oxidation-Reduction; Phosphoric Monoester Hydrolases; Phylogeny
PubMed: 33578824
DOI: 10.3390/ijms22041761 -
Naunyn-Schmiedeberg's Archives of... Jan 2004The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, aligned next to each other on chromosome 7. By far the most-studied member of... (Review)
Review
The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, aligned next to each other on chromosome 7. By far the most-studied member of the family is the serum paraoxonase 1 (PON1), a high-density lipoprotein-associated esterase/lactonase. Early research focused on its capability to hydrolyze toxic organophosphates, and its name derives from one of its most commonly used in vitro substrates, paraoxon. Studies in the last 2 decades have demonstrated PON1's ability to protect against atherosclerosis by hydrolyzing specific derivatives of oxidized cholesterol and/or phospholipids in oxidized low-density lipoprotein and in atherosclerotic lesions. Levels and genetic variability of PON1 influence sensitivity to specific insecticides and nerve agents, as well as the risk of cardiovascular disease. More recently, the other two members of the PON family, PON2 and PON3, have also been shown to have antioxidant properties. A major goal in present research on the paraoxonases is to identify their natural substrates and to elucidate the mechanism(s) of their catalytic activities.
Topics: Animals; Aryldialkylphosphatase; Cardiovascular Diseases; Genetic Predisposition to Disease; Humans; Inactivation, Metabolic; Pharmacogenetics; Polymorphism, Genetic; Substrate Specificity; Xenobiotics
PubMed: 14579013
DOI: 10.1007/s00210-003-0833-1 -
Pharmacogenomics Sep 2013PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also... (Review)
Review
PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also associated with numerous human diseases, including cardiovascular disease, Parkinson's disease and cancer. In addition, PON1 metabolizes a broad variety of substrates, including toxic organophosphorous compounds, statin adducts, glucocorticoids, the likely atherogenic L-homocysteine thiolactone and the quorum-sensing factor of Pseudomonas aeruginosa. Numerous cardiovascular and antidiabetic pharmacologic agents, dietary macronutrients, lifestyle factors and antioxidant supplements affect PON1 expression and enzyme activity levels. Owing to the importance of PON1 to HDL function and its individual association with diverse human diseases, pharmacogenomic interactions between PON1 and the various factors that alter its expression and activity may represent an important therapeutic target for future investigation.
Topics: Antioxidants; Aryldialkylphosphatase; Atherosclerosis; Cardiovascular Diseases; Humans; Lipoproteins, HDL; Neoplasms; Parkinson Disease; Pharmacogenetics; Polymorphism, Genetic
PubMed: 24024900
DOI: 10.2217/pgs.13.147 -
The Journal of Nutritional Biochemistry Oct 2017Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme involved in the protection of low-density lipoprotein and HDLs against lipid peroxidation.... (Review)
Review
Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme involved in the protection of low-density lipoprotein and HDLs against lipid peroxidation. Several studies documented the capacity of polyphenols to stimulate PON1 transcription activation. The objective of the present review is to provide the main evidence about the role and the potential mechanism of action of polyphenols and polyphenol-rich foods in the modulation of PON1 gene expression and activity. A total of 76 in vitro and in vivo studies were included in the review. Overall, while evidence obtained in vitro is limited to quercetin and resveratrol, those deriving from animal models seem more convincing for a wide range of polyphenols but only at pharmacological doses. Evidence from human studies is promising but deserves more substantiation about the role of polyphenol-rich foods in the regulation of PON1 activity and expression. Research focused on the understanding of the structure-activity relationship of polyphenols with PON1 and on the mechanisms at the base of PON1 modulation is warranted. Well-designed human intervention studies are encouraged to corroborate the findings of polyphenols also at physiological doses.
Topics: Animals; Aryldialkylphosphatase; Food; Humans; Polyphenols; Structure-Activity Relationship
PubMed: 28623808
DOI: 10.1016/j.jnutbio.2017.06.002 -
Antioxidants & Redox Signaling Mar 2012The paraoxonase (PON) gene cluster contains three adjacent gene members, PON1, PON2, and PON3. Originating from the same fungus lactonase precursor, all of the three PON... (Review)
Review
The paraoxonase (PON) gene cluster contains three adjacent gene members, PON1, PON2, and PON3. Originating from the same fungus lactonase precursor, all of the three PON genes share high sequence identity and a similar β propeller protein structure. PON1 and PON3 are primarily expressed in the liver and secreted into the serum upon expression, whereas PON2 is ubiquitously expressed and remains inside the cell. Each PON member has high catalytic activity toward corresponding artificial organophosphate, and all exhibit activities to lactones. Therefore, all three members of the family are regarded as lactonases. Under physiological conditions, they act to degrade metabolites of polyunsaturated fatty acids and homocysteine (Hcy) thiolactone, among other compounds. By detoxifying both oxidized low-density lipoprotein and Hcy thiolactone, PONs protect against atherosclerosis and coronary artery diseases, as has been illustrated by many types of in vitro and in vivo experimental evidence. Clinical observations focusing on gene polymorphisms also indicate that PON1, PON2, and PON3 are protective against coronary artery disease. Many other conditions, such as diabetes, metabolic syndrome, and aging, have been shown to relate to PONs. The abundance and/or activity of PONs can be regulated by lipoproteins and their metabolites, biological macromolecules, pharmacological treatments, dietary factors, and lifestyle. In conclusion, both previous results and ongoing studies provide evidence, making the PON cluster a prospective target for the treatment of atherosclerosis.
Topics: Aryldialkylphosphatase; Atherosclerosis; Humans; Molecular Targeted Therapy
PubMed: 21867409
DOI: 10.1089/ars.2010.3774 -
Arquivos Brasileiros de Cardiologia Oct 2022
Topics: Humans; Coronary Artery Disease; Gene Frequency; Polymorphism, Genetic; Aryldialkylphosphatase; Genotype
PubMed: 36287414
DOI: 10.36660/abc.20220645 -
Journal of Healthcare Engineering 2022This paper aims to investigate the correlation between high mobility group protein-1 (HMG-b1), antioxidant enzyme-1 (paraoxon-1, PON-1), monocyte chemoattractant...
BACKGROUND
This paper aims to investigate the correlation between high mobility group protein-1 (HMG-b1), antioxidant enzyme-1 (paraoxon-1, PON-1), monocyte chemoattractant protein-1 (monocyte chemoattractant protein-1, MCP-1), , and MSAF.
MATERIALS AND METHODS
The total sample size comprised of 73 cases in both groups. These patients were further subdivided into 2 groups: the MSAF group and the control group. 38 women were in the MSAF group and 35 women with term amniotic fluid serum were in the control group. The MSAF group was selected as a full-term singleton amniotic fluid fecal infection group. Clinical data were collected, and specimens were collected. Fecal staining of amniotic fluid and full-term amniotic fluid removes the placenta and umbilical cord blood. The expression of HMGB1 in the placenta was observed by immune-histochemical staining of MSAF and control groups. The content of PON-1 in cord blood was determined by ELISA.
RESULTS
Correlation between maternal and neonatal clinical data and MSAF was done; MSAF group mean gestational age was 41.38 ± 1.40 weeks; control group mean gestational age was 39.20 ± 1.24 weeks. This study found no correlation between the birth weight, maternal age, sex, first/transmaternal, hyperthyroidism, hypothyroidism, and anemia between the MSAF and control group with nonsignificant value ( > 0.05). However, the fatal age, gestational diabetes, gestational hypertension, umbilical cord abnormalities, placental abnormalities, and neonatal asphyxia factors were statistically different with a significant value of <0.05 between both groups. HMGB1 and Periodontal are mostly expressed in placental trophoblast, vascular endothelial cells, and amniotic epithelial and interstitial cells. After HE staining of 72 placentas by HE in MSAF and control, 6 had acute chorioamnionitis (5.1 control), 32 had chronic (23.9), 35 had abnormal placentas, and three in MSAF had chorionic columnar metaplasia. In immune-histochemistry experiments, the HMGB1 expression intensity of placental tissue was higher in the MSAF group ( < 0.05); however, the level of PON-1 was lower in the MSAF group as compared to the controls ( < 0.05).
CONCLUSIONS
Gestational age and placental abnormalities are clinical high-risk factors for MSAF. HMGB1, PON-1, MCP-1, and Periodontal may be involved in the development of MSAF, suggesting an oxidative/antioxidant imbalance with inflammation, and may be one of the mechanisms for MSAF development.
Topics: Amniotic Fluid; Antioxidants; Aryldialkylphosphatase; Bacteroidaceae Infections; Chemokine CCL2; Endothelial Cells; Female; HMGB1 Protein; Humans; Infant; Infant, Newborn; Male; Meconium; Periodontium; Placenta; Porphyromonas gingivalis; Pregnancy
PubMed: 35242296
DOI: 10.1155/2022/3143102 -
TheScientificWorldJournal 2014Human PON1 (h-PON1) is a multifaceted enzyme and can hydrolyze (and inactivate) a wide range of substrates. The enzyme shows anti-inflammatory, antioxidative,... (Review)
Review
Human PON1 (h-PON1) is a multifaceted enzyme and can hydrolyze (and inactivate) a wide range of substrates. The enzyme shows anti-inflammatory, antioxidative, antiatherogenic, ant-diabetic, antimicrobial, and organophosphate (OP)-detoxifying properties. However, there are certain limitations regarding large-scale production and use of h-PON1 as a therapeutic candidate. These include difficulties in producing recombinant h-PON1 (rh-PON1) using microbial expression system, low hydrolytic activity of wild-type h-PON1 towards certain substrates, and low storage stability of the purified enzyme. This review summarizes the work done in our laboratory to address these limitations. Our results show that (a) optimized polynucleotide sequence encoding rh-PON1 can express the protein in an active form in E. coli and can be used to generate variant of the enzyme having enhanced hydrolytic activity, (b) in vitro refolding of rh-PON1 enzyme can dramatically increase the yield of an active enzyme, (c) common excipients can be used to stabilize purified rh-PON1 enzyme when stored under different storage conditions, and (d) variants of rh-PON1 enzyme impart significant protection against OP-poisoning in human blood (ex vivo) and mouse (in vivo) model of OP-poisoning. The rh-PON1 variants and their process of production discussed here will help to develop h-PON1 as a therapeutic candidate.
Topics: Animals; Aryldialkylphosphatase; Escherichia coli; Humans; Hydrolysis; Inflammation; Mice; Molecular Targeted Therapy; Organophosphate Poisoning; Recombinant Proteins
PubMed: 25386619
DOI: 10.1155/2014/854391