A Critical Review on Human Serum

Total Page:16

File Type:pdf, Size:1020Kb

A Critical Review on Human Serum Turk J Biochem 2021; 46(1): 3–8 Review Article Michael Mackness* and Eser Yildirim Sozmen A critical review on human serum Paraoxonase-1 in the literature: truths and misconceptions İnsan serum Paraoksonaz-1 enzimi ile ilgili yayınların eleştirel olarak gözden geçirilmesi: gerçekler ve kavram yanılgıları https://doi.org/10.1515/tjb-2020-0186 yanlış anlamaların literatürde yaygınlaşması gibi bir takım Received April 17, 2020; accepted April 21, 2020; published online sorunlara yol açmıştır. June 24, 2020 Bu eleştirel inceleme, PON1’in temel özelliklerini ve yayınlarda gözlenen sorunları ve yanılgıları açıklamayı Abstract: Human serum paraoxonase 1 (PON1) appears to amaçlamaktadır. play an important role in the development of a large variety Anahtar kelimeler: hastalık; laktonaz; paraoksonaz; poli- of diseases with an inflammatory component including morfizmler. heart disease, diabetes, rheumatic diseases, neurological diseases and cancer. As such PON1 research is rapidly expanding into new biomedical fields. Unfortunately, this Introduction rapid expansion has resulted in a number of problems due to poor experimental design and the spreading of mis- The paraoxonase (PON) multi-gene family consists of three conceptions in the literature. This review seeks to describe enzymes: PON1, PON2 and PON3. The genes for which are the basic properties of PON1 and the problems and mis- located adjacent to each other on human chromosome 7 conceptions that have arisen. (q21.22). All share the considerable similarity in the amino- acid sequence. All three members of the PON family are Keywords: hastalık; lactonase; paraoxonase; poly- able to retard lipid (per)oxidation in lipoproteins and cell morphisms. membranes and are believed to be important in the development of diseases with an inflammatory component Öz: İnsan serum paraoksonaz -1 (PON1) enzimi, kalp such as cardiovascular diseases, rheumatic diseases and hastalığı, diyabetes mellitus, romatizmal hastalıklar, nör- cancer [1]. Since PON1 has the capability to hydrolyse olojik hastalıklar ve kanser dahil olmak üzere inflamatuvar various substrates (including lactones, thiolactones, bileşeni olan çok çeşitli hastalıkların gelişiminde önemli organophosphorus triester pesticides and nerve gases, bir rol oynamaktadır. Bu nedenle PON1 araştırmaları hızla arylesters, oestrogen-esters, cyclic carbamates and glucu- yeni biyomedikal alanlara doğru genişlemektedir. Maalesef ronide drugs) [1–3], it may have varied physiological roles bu hızlı genişleme, deneysel tasarımın zayıf olması ve in many diseases (inflammation, organophosphate intox- ication, drug metabolism, cardiovascular disease, etc.,). *Corresponding author: Dr Michael Mackness, PhD, Avenida Princip So, PON1 activity has been extensively studied in many D’Espanya, Miami Playa, 43892, Tarragona, Spain, diseases since 1986. In this review, we searched the liter- E-mail: [email protected] ature in PubMed between 1982 and 2020, with the search Eser Yildirim Sozmen: Ege Universıty Faculty of Medicine, Department term “paraoxonase + arylesterase” and limiting the search of Medical Biochemistry, Bornova Izmir, Turkey, E-mail: [email protected]. https://orcid.org/0000-0002- to clinical trials, randomised controlled trials and clinical 6383-6724 studies. A total of 775 results were found and evaluated. Open Access. © 2021 Michael Mackness and Eser Yildirim Sozmen, published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. 4 Mackness and Sozmen: Truths and misconceptions on Paraoxonase-1 With the number of investigations in the literature rapidly thiolactones, organophosphorus triester pesticides and increasing, some misconceptions have arisen. This review nerve gases (paraoxon, diazoxon, sarin and soman to name seeks to point out potential problems and pitfalls in the a few), arylesters, oestrogen-esters, cyclic carbamates and hope that they will be addressed and avoided. glucuronide drugs [1, 14]. Due to these various enzymatic activities, the role of PON1 in detoxifying organophosphate compounds, drug metabolism, cardiovascular disease, and PON1: Structure, genetics and other diseases, has been extensively studied. These activ- ities possibly explain the varied physiological roles of this substrate specificity enzyme. PON1 has been closely linked to the reduction of oxidative stress and inflammation, which are important Human serum paraoxonase1 (PON1) is the best-known features that can markedly affect the development of member of the paraoxonase multi-gene family which also atherosclerotic plaques and cardiovascular events [1, 15]. 2+ includes PON2 and PON3. PON1 is a circulating Ca - Experiments with PON1 knockout mice have indicated that dependent enzyme with a molecular mass of 43 kDa and PON1 absence leads to an increase in endothelial adhesion – fi containing 354 amino acids [1 3], which is classi ed as an molecules and oxidative stress, confirming the role of this aryldialkylphosphatase (EC 3.1.8.1) [1]. PON1 is mainly enzyme in preventing the onset of atherosclerosis [16, 17]. synthesized by the liver and then secreted into the blood- Detailed structure/function studies have concluded stream, where it is tightly bound to high-density lipopro- that the natural substrates for PON1 are lactones and lip- tein (HDL) particles [4]. PON2 appears to be the ancestral ophylic lactones form the primary substrates [7, 18, 19]. The family member [5, 6]. The term paraoxonase is originally aromatic nature of amino acids in the active site of PON1 ’ derived from the enzyme s ability to hydrolyse paraoxon could explain why the enzyme prefers lipophilic substrates (diethyl p-nitrophenyl phosphate), which is the active [20]. PON1 is able to hydrolyse a wide range of lactones. All metabolite of the insecticide parathion [1, 7]. three members of the PON family (PON1, PON2 and PON3) The structure of PON1 is a six-bladed beta-propeller with share this property of being lactonases, albeit with distinct a central tunnel containing two calcium ions. One of these substrate specificities [7]. calcium ions is structural and therefore essential for the N-acylhomoserine γ-lactones (AHL) are produced by conformational stability of the enzyme while the second ion gram negative bacteria and regulate bacterial virulence is catalytic [8, 9]. The removal of calcium from PON1 by the and biofilm formation. All three PONs hydrolyse AHL (a + addition of EDTA results in the inactivation of Ca2 -dependent process known as quorum quenching) with PON2 having activities, including paraoxon and phenyl acetate hydrolysis, the greatest efficacy, the resulting metabolites are inactive however,itdoesnotaffecttheabilityofPON1toprotectlow- therefore the PON family could be important in preventing density lipoprotein (LDL) from oxidation. Different active bacterial infections [21]. + sites may therefore exist on PON1 for Ca2 - dependent activ- In recent years attention has turned to δ-lactone ei- ities and for protecting LDL from oxidation [10]. The amino cosanoids as PON substrates. These compounds are me- terminal end of the protein contains hydrophobic amino acid tabolites of arachidonic acid and mediate a number of residues that play a role in its binding to HDL and to other metabolic processes in vivo. 5-hydroxy-eicosatetraenoic proteins such as apoA1 and also in its self-aggregation [11]. acid 1,5 lactone (5-HL) is a substrate for all three PONs. According to recent findings, modulating the active site PON1 has the greatest hydrolytic efficacy followed by PON3 hydrophobicity of PON1 is a key factor that could affect the with PON2 having little activity towards this substrate [22]. organophosphatase activity of the enzyme [9]. PON3 has by far the highest activity towards two other A histidine–histidine (His) catalytic dyad is proposed eicosanoids, cycloepoxycyclopentenone (cyclo-EC) and to be involved in the catalytic mechanism of PON1 in which 5,6 dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) fol- His-115 acts as a general base to deprotonate a single water lowed by PON1 again with PON2 having little or no activity molecule while His-134 increases His-115 basicity via a towards these substrates [22, 23]. Interestingly, this order of proton shuttle mechanism [12]. However, Grunkemeyer hydrolytic efficacy also applies to the hydrolysis of oes- et al. based on His-dyad mutagenesis data recently re- trogen esters by the PON family indicating a preference of ported that the dyad likely does not participate directly in PON3 for bulky cyclic groups. Lactonase activity in the catalysis, but may play an important role in substrate endothelium can influence vascular dilation. In this binding or orientation [13]. context, Gilad et al. [24] recently showed that PON1 pene- PON1 is a highly promiscuous enzyme and will hydro- trates endothelial cells and is able to reduce 5,6-DHTL- lyse a large variety of substrates including lactones, dependent vasodilation through its lactonase activity. Mackness and Sozmen: Truths and misconceptions on Paraoxonase-1 5 PON1 inhibits lipid oxidation in LDL, thereby reducing Study design levels of oxidized lipids that are critical for the initiation and propagation of atherosclerosis and is believed to play a Because of the over 40 fold variation in PON1 activity be- central role in the antioxidant activity of HDL [1]. PON1 is tween individuals which has a large genetic (and epige- also an important determinant of HDL dysfunctionality netic) component due, as far as is currently understood, [15].
Recommended publications
  • Screening and Functional Pathway Analysis of Pulmonary Genes
    Hindawi Stem Cells International Volume 2020, Article ID 5684250, 11 pages https://doi.org/10.1155/2020/5684250 Research Article Screening and Functional Pathway Analysis of Pulmonary Genes Associated with Suppression of Allergic Airway Inflammation by Adipose Stem Cell-Derived Extracellular Vesicles Sung-Dong Kim,1 Shin Ae Kang,2 Yong-Wan Kim,3 Hak Sun Yu,2 Kyu-Sup Cho ,1 and Hwan-Jung Roh 4 1Department of Otorhinolaryngology and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea 2Department of Parasitology and Tropical Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea 3Department of Otorhinolaryngology, Inje University Haeundae Paik Hospital, Republic of Korea 4Department of Otorhinolaryngology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea Correspondence should be addressed to Hwan-Jung Roh; [email protected] Received 5 February 2020; Revised 19 May 2020; Accepted 2 June 2020; Published 27 June 2020 Academic Editor: Kar Wey Yong Copyright © 2020 Sung-Dong Kim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Although mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) are as effective as MSCs in the suppression of allergic airway inflammation, few studies have explored the molecular mechanisms of MSC-derived EVs in allergic airway diseases. The objective of this study was to evaluate differentially expressed genes (DEGs) in the lung associated with the suppression of allergic airway inflammation using adipose stem cell- (ASC-) derived EVs.
    [Show full text]
  • PON1) Polymorphisms with Osteoporotic Fracture Risk in Postmenopausal Korean Women
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 2, 71-81, February 2011 Association of Paraoxonase 1 (PON1) polymorphisms with osteoporotic fracture risk in postmenopausal Korean women Beom-Jun Kim1,2*, Shin-Yoon Kim2,6*, PON1 to ascertain its contribution to osteoporotic frac- Yoon Shin Cho3, Bon-Jo Kim3, Bok-Ghee Han3, tures (OFs) and bone mineral density (BMD). We di- Eui Kyun Park2,4, Seung Hun Lee1,2, Ha Young Kim5, rectly sequenced the PON1 gene in 24 Korean in- Ghi Su Kim1,2, Jong-Young Lee3,7 dividuals and identified 26 sequence variants. A large population of Korean postmenopausal women (n = and Jung-Min Koh1,2,7 1,329) was then genotyped for eight selected PON1 polymorphisms. BMD at the lumbar spine and femoral 1Division of Endocrinology and Metabolism neck was measured using dual-energy X-ray ab- Asan Medical Center, University of Ulsan College of Medicine sorptiometry. Lateral thoracolumbar (T4-L4) radio- Seoul 138-736, Korea 2 graphs were obtained for vertebral fracture assess- Skeletal Diseases Genome Research Center Kyungpook National University Hospital ment, and the occurrence of non-vertebral fractures Daegu 700-412, Korea (i.e., wrist, hip, forearm, humerus, rib, and pelvis) was 3The Center for Genome Science examined using self-reported data. Multivariate analy- National Institute of Health ses showed that none of the polymorphisms was asso- Seoul 122-701, Korea ciated with BMD at either site. However, +5989A>G 4Department of Pathology and Regenerative Medicine and +26080T>C polymorphisms were significantly School of Dentistry, Kyungpook National University associated with non-vertebral and vertebral fractures, Daegu 700-412, Korea respectively, after adjustment for covariates.
    [Show full text]
  • Comparative Genome Mapping in the Sequence-Based Era: Early Experience with Human Chromosome 7
    Downloaded from genome.cshlp.org on May 28, 2019 - Published by Cold Spring Harbor Laboratory Press First Glimpses/Report Comparative Genome Mapping in the Sequence-based Era: Early Experience with Human Chromosome 7 James W. Thomas,1 Tyrone J. Summers,1 Shih-Queen Lee-Lin,1 Valerie V. Braden Maduro,1 Jacquelyn R. Idol,1 Stephen D. Mastrian,1 Joseph F. Ryan,1 D. Curtis Jamison,1 and Eric D. Green1,2 1Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892 USA The success of the ongoing Human Genome Project has resulted in accelerated plans for completing the human genome sequence and the earlier-than-anticipated initiation of efforts to sequence the mouse genome. As a complement to these efforts, we are utilizing the available human sequence to refine human-mouse comparative maps and to assemble sequence-ready mouse physical maps. Here we describe how the first glimpses of genomic sequence from human chromosome 7 are directly facilitating these activities. Specifically, we are actively enhancing the available human-mouse comparative map by analyzing human chromosome 7 sequence for the presence of orthologs of mapped mouse genes. Such orthologs can then be precisely positioned relative to mapped human STSs and other genes. The chromosome 7 sequence generated to date has allowed us to more than double the number of genes that can be placed on the comparative map. The latter effort reveals that human chromosome 7 is represented by at least 20 orthologous segments of DNA in the mouse genome. A second component of our program involves systematically analyzing the evolving human chromosome 7 sequence for the presence of matching mouse genes and expressed-sequence tags (ESTs).
    [Show full text]
  • Serendipitous Discovery and X-Ray Structure of a Human Phosphate Binding Apolipoprotein
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure 14, 601–609, March 2006 ª2006 Elsevier Ltd All rights reserved DOI 10.1016/j.str.2005.12.012 Serendipitous Discovery and X-Ray Structure of a Human Phosphate Binding Apolipoprotein Renaud Morales,1 Anne Berna,2 Philippe Carpentier,1 is the only known transporter capable of binding phos- Carlos Contreras-Martel,1 Fre´de´rique Renault,3 phate ions in human plasma and may become a new Murielle Nicodeme,4 Marie-Laure Chesne-Seck,6 predictor of or a potential therapeutic agent for phos- Franc¸ois Bernier,2 Je´roˆ me Dupuy,1 phate-related diseases such as atherosclerosis. Christine Schaeffer,7 He´le`ne Diemer,7 Alain Van-Dorsselaer,7 Juan C. Fontecilla-Camps,1 Introduction Patrick Masson,3 Daniel Rochu,3 and Eric Chabriere3,5,* Both cholesterol and HDL (high-density lipoprotein) 1 Laboratoire de Cristallogene` se et Cristallographie levels are commonly used as risk predictors of cardio- des Prote´ ines vascular disease (Gordon and Rifkind, 1989; Amann Institut de Biologie Structurale JP EBEL et al., 2003). HDL protects against atherosclerosis 38027 Grenoble mainly through the reverse cholesterol transport pro- France cess in which excess cholesterol is transferred from 2 Institut de Biologie Mole´ culaire des Plantes du CNRS peripheral tissues to the liver by the ATP binding cas- Universite´ Louis Pasteur sette ABCA1 transporter, which is defective in Tangier 67083 Strasbourg Cedex disease (Brooks-Wilson et al., 1999). Although HDLs France have been extensively studied, their metabolic role 3 Unite´ d’Enzymologie has not been completely elucidated yet.
    [Show full text]
  • Paraoxonase Role in Human Neurodegenerative Diseases
    antioxidants Review Paraoxonase Role in Human Neurodegenerative Diseases Cadiele Oliana Reichert 1, Debora Levy 1 and Sergio P. Bydlowski 1,2,* 1 Lipids, Oxidation, and Cell Biology Group, Laboratory of Immunology (LIM19), Heart Institute (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403-900, Brazil; [email protected] (C.O.R.); [email protected] (D.L.) 2 Instituto Nacional de Ciencia e Tecnologia em Medicina Regenerativa (INCT-Regenera), CNPq, Rio de Janeiro 21941-902, Brazil * Correspondence: [email protected] Abstract: The human body has biological redox systems capable of preventing or mitigating the damage caused by increased oxidative stress throughout life. One of them are the paraoxonase (PON) enzymes. The PONs genetic cluster is made up of three members (PON1, PON2, PON3) that share a structural homology, located adjacent to chromosome seven. The most studied enzyme is PON1, which is associated with high density lipoprotein (HDL), having paraoxonase, arylesterase and lactonase activities. Due to these characteristics, the enzyme PON1 has been associated with the development of neurodegenerative diseases. Here we update the knowledge about the association of PON enzymes and their polymorphisms and the development of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Keywords: paraoxonases; oxidative stress; multiple sclerosis; amyotrophic lateral sclerosis; Alzhei- mer’s disease; Parkinson’s disease 1. Introduction Over the years, biotechnological changes and advances have guaranteed the popula- tion a significant increase in life expectancy that does not necessarily involve an increase in quality of life and/or having a healthy old age.
    [Show full text]
  • Mclean, Chelsea.Pdf
    COMPUTATIONAL PREDICTION AND EXPERIMENTAL VALIDATION OF NOVEL MOUSE IMPRINTED GENES A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Chelsea Marie McLean August 2009 © 2009 Chelsea Marie McLean COMPUTATIONAL PREDICTION AND EXPERIMENTAL VALIDATION OF NOVEL MOUSE IMPRINTED GENES Chelsea Marie McLean, Ph.D. Cornell University 2009 Epigenetic modifications, including DNA methylation and covalent modifications to histone tails, are major contributors to the regulation of gene expression. These changes are reversible, yet can be stably inherited, and may last for multiple generations without change to the underlying DNA sequence. Genomic imprinting results in expression from one of the two parental alleles and is one example of epigenetic control of gene expression. So far, 60 to 100 imprinted genes have been identified in the human and mouse genomes, respectively. Identification of additional imprinted genes has become increasingly important with the realization that imprinting defects are associated with complex disorders ranging from obesity to diabetes and behavioral disorders. Despite the importance imprinted genes play in human health, few studies have undertaken genome-wide searches for new imprinted genes. These have used empirical approaches, with some success. However, computational prediction of novel imprinted genes has recently come to the forefront. I have developed generalized linear models using data on a variety of sequence and epigenetic features within a training set of known imprinted genes. The resulting models were used to predict novel imprinted genes in the mouse genome. After imposing a stringency threshold, I compiled an initial candidate list of 155 genes.
    [Show full text]
  • Polymorphism of Paraoxonase-2 Gene Is Associated With
    Molecular Psychiatry (2002) 7, 110–112 2002 Nature Publishing Group All rights reserved 1359-4184/02 $15.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Codon 311 (Cys → Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer’s and vascular dementias Z Janka1, A Juha´sz1,A´ Rimano´czy1, K Boda2,JMa´rki-Zay3 and J Ka´lma´n1 1Department of Psychiatry; 2Medical Informatics, Albert Szent-Gyo¨rgyi Center for Medical and Pharmaceutical Sciences, Faculty of Medicine, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary; 3Central Laboratory, Be´ke´s County Hospital, PO Box 46, H-5701, Gyula, Hungary Keywords: paraoxonase; apolipoprotein E; genetic mark- Table 1 Frequency distribution of PON2 and apoE geno- ers; Alzheimer’s disease; vascular dementia; DNA polymor- types and alleles in the control, Alzheimer’s and vascular phism dementia populations The gene of an esterase enzyme, called paraoxonase (PON, EC.3.1.8.1.) is a member of a multigene family that Control Alzheimer’s Vascular comprises three related genes PON1, PON2, and PON3 dementia dementia with structural homology clustering on the chromosome 7.1,2 The PON1 activity and the polymorphism of the PON2 genotype PON1 and PON2 genes have been found to be associa- CC 4 (8%) 2 (4%) 3 (6%) ted with risk of cardiovascular diseases such as hyper- CS 20 (39%) 23 (43%) 19 (34%) cholesterolaemia, non-insulin-dependent diabetes, coron- SS 27 (53%) 28 (53%) 33 (60%) ary heart disease (CHD) and myocardial infaction.3–8 The PON2 allele importance of cardiovascular risk factors in the patho- C (cys) 28 (27%) 27 (25%) 25 (23%) mechanism of Alzheimer’s disease (AD) and vascular S (ser) 74 (73%) 79 (75%) 85 (77%) dementia (VD)9–13 prompted us to examine the genetic ApoE genotype effect of PON2 gene codon 311 (Cys→Ser; PON2*S) 22 – – – polymorphism and the relationship between the PON2*S 2 3 6 (12%) 3 (6%) 6 (11%) allele and the other dementia risk factor, the apoE poly- 2 4 – – 1 (2%) morphism in these dementias.
    [Show full text]
  • Comparative Genome Mapping in the Sequence-Based Era: Early Experience with Human Chromosome 7
    Downloaded from genome.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press First Glimpses/Report Comparative Genome Mapping in the Sequence-based Era: Early Experience with Human Chromosome 7 James W. Thomas,1 Tyrone J. Summers,1 Shih-Queen Lee-Lin,1 Valerie V. Braden Maduro,1 Jacquelyn R. Idol,1 Stephen D. Mastrian,1 Joseph F. Ryan,1 D. Curtis Jamison,1 and Eric D. Green1,2 1Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892 USA The success of the ongoing Human Genome Project has resulted in accelerated plans for completing the human genome sequence and the earlier-than-anticipated initiation of efforts to sequence the mouse genome. As a complement to these efforts, we are utilizing the available human sequence to refine human-mouse comparative maps and to assemble sequence-ready mouse physical maps. Here we describe how the first glimpses of genomic sequence from human chromosome 7 are directly facilitating these activities. Specifically, we are actively enhancing the available human-mouse comparative map by analyzing human chromosome 7 sequence for the presence of orthologs of mapped mouse genes. Such orthologs can then be precisely positioned relative to mapped human STSs and other genes. The chromosome 7 sequence generated to date has allowed us to more than double the number of genes that can be placed on the comparative map. The latter effort reveals that human chromosome 7 is represented by at least 20 orthologous segments of DNA in the mouse genome. A second component of our program involves systematically analyzing the evolving human chromosome 7 sequence for the presence of matching mouse genes and expressed-sequence tags (ESTs).
    [Show full text]
  • PON1 Status of Farmworker Mothers and Children As a Predictor of Organophosphate Sensitivity Clement E
    Original article 183 PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity Clement E. Furlonga,*, Nina Hollandb,*, Rebecca J. Richtera, Asa Bradmanb, Alan Hob and Brenda Eskenazib The objective was to determine PON1 status as a predictor the mothers in this cohort would be more susceptible for organophosphorus insecticide sensitivity in a cohort of to the adverse effects of specific organophosphorus Latina mothers and newborns from the Salinas Valley, pesticide exposure due to their PON1 status. Of particular California, an area with high levels of organophosphorus concern are exposures of pregnant mothers and newborns insecticide use. PON1 status was established for 130 with low PON1 status. Pharmacogenetics and Genomics pregnant Latina women and their newborns using a high- 16:183–190 c 2006 Lippincott Williams & Wilkins. throughput two substrate activity/analysis method which plots rates of diazoxon (DZO) hydrolysis against rates of Pharmacogenetics and Genomics 2006, 16:183–190 paraoxon (PO) hydrolysis. Arylesterase activity (AREase) Keywords: children, chlorpyrifos, diazinon, Latino cohort, paraoxonase 1 was determined using phenylacetate as a substrate, (PON1), PON1 status, pregnancy allowing comparison of PON1 levels across PON1192 genotypes in mothers and children. Phenylacetate hydro- aDepartments of Genome Sciences and Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington and bCenter for Children’s lysis is not affected by the Q192R polymorphism. Among Environmental Health, School of Public Health, University of California, Berkeley, newborns, levels of PON1 (AREase) varied by 26-fold California, USA (4.3–110.7 U/ml) and among mothers by 14-fold Correspondence and requests for reprints to Clement Furlong, University (19.8–281.4 U/ml).
    [Show full text]
  • BRG1/SMARCA4 Inactivation Promotes Non–Small Cell Lung Cancer Aggressiveness by Altering Chromatin Organization
    Published OnlineFirst August 12, 2014; DOI: 10.1158/0008-5472.CAN-14-0061 Cancer Molecular and Cellular Pathobiology Research BRG1/SMARCA4 Inactivation Promotes Non–Small Cell Lung Cancer Aggressiveness by Altering Chromatin Organization Tess Orvis1, Austin Hepperla1,2, Vonn Walter1, Shujie Song1,3, Jeremy Simon1,4, Joel Parker1,5, Matthew D. Wilkerson1,5, Nisarg Desai1, Michael B. Major1,6, D. Neil Hayes1,7, Ian J. Davis1,5,8, and Bernard Weissman1,9 Abstract SWI/SNF chromatin remodeling complexes regulate critical cellular processes, including cell-cycle control, programmed cell death, differentiation, genomic instability, and DNA repair. Inactivation of this class of chromatin remodeling complex has been associated with a variety of malignancies, including lung, ovarian, renal, liver, and pediatric cancers. In particular, approximately 10% of primary human lung non–small cell lung cancers (NSCLC) display attenuations in the BRG1 ATPase, a core factor in SWI/SNF complexes. To evaluate the role of BRG1 attenuation in NSCLC development, we examined the effect of BRG1 silencing in primary and established human NSCLC cells. BRG1 loss altered cellular morphology and increased tumorigenic potential. Gene expression analyses showed reduced expression of genes known to be associated with progression of human NSCLC. We demonstrated that BRG1 losses in NSCLC cells were associated with variations in chromatin structure, including differences in nucleosome positioning and occupancy surrounding transcriptional start sites of disease-relevant genes. Our results offer direct evidence that BRG1 attenuation contributes to NSCLC aggressiveness by altering nucleosome positioning at a wide range of genes, including key cancer-associated genes. Cancer Res; 74(22); 1–13. Ó2014 AACR.
    [Show full text]
  • PON1 De Ciency Promotes TREM2 Pathway
    PON1 Deciency Promotes TREM2 Pathway- Mediated Microglial Phagocytosis and Inhibits Pro- Inammatory Cytokines Release in Vitro and in Vivo Li Zhang ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences Wei Dong ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences Yuanwu Ma CAMS ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences Lin Bai CAMS ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences Xu Zhang CAMS ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences Caixian Sun CAMS ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences Jingwen Li CAMS ILAS: Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences lianfeng zhang ( [email protected] ) Chinese Academy of Medical Sciences Institute of Laboratory Animal Sciences https://orcid.org/0000- 0002-5774-2924 Research Article Keywords: PON1, microglia, TREM2, interaction, knockout rats, phagocytosis, Aβ, LPS Posted Date: August 23rd, 2021 DOI: https://doi.org/10.21203/rs.3.rs-673247/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/28 Abstract Paraoxonase 1 (PON1) plays an anti-inammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD are not clear. To address this issue, we used PON1 knockout rats previously generated by our lab to investigate the role of PON1 in microglia. Knockout of PON1 in rat brain tissues protected against LPS-induced microglia activation.
    [Show full text]
  • Anti-PON3 Antibody (ARG57089)
    Product datasheet [email protected] ARG57089 Package: 100 μl anti-PON3 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes PON3 Tested Reactivity Hu Tested Application FACS, IHC-P, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name PON3 Antigen Species Human Immunogen KLH-conjugated synthetic peptide corresponding to aa. 10-38 (N-terminus) of Human PON3. Conjugation Un-conjugated Alternate Names EC 3.1.8.1; EC 3.1.1.2; Serum paraoxonase/lactonase 3; EC 3.1.1.81 Application Instructions Application table Application Dilution FACS 1:10 - 1:50 IHC-P 1:50 - 1:100 WB 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control HepG2 Calculated Mw 40 kDa Properties Form Liquid Purification Purification with Protein A and immunogen peptide. Buffer PBS and 0.09% (W/V) Sodium azide. Preservative 0.09% (W/V) Sodium azide. Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/3 Bioinformation Database links GeneID: 5446 Human Swiss-port # Q15166 Human Gene Symbol PON3 Gene Full Name paraoxonase 3 Background This gene is a member of the paraoxonase family and lies in a cluster on chromosome 7 with the other two family members.
    [Show full text]