{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman paraoxonase‐2 (PON2) is an intracellular lactonase that plays a central role in innate immunity by hydrolyzing bacterial quorum‐sensing molecules – notably N‑acyl‐homoserine lactones – thereby inactivating signals used by pathogens such as Pseudomonas aeruginosa. In addition to this antimicrobial activity, PON2 exhibits substrate specificity distinct from its family members by efficiently metabolizing aromatic and oxidized lactones, suggesting that its enzymatic properties contribute to the detoxification of endogenous oxidation products."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its lactonase function, PON2 is pivotal in modulating cellular oxidative stress. It reduces the formation of mitochondrial superoxide and curtails lipid peroxidation, thereby protecting cells from endoplasmic reticulum stress–induced apoptosis and foam cell formation in macrophages. PON2 expression is upregulated during monocyte‐to‐macrophage differentiation, reflecting a compensatory response to heightened oxidative activity. Its widespread intracellular distribution – including in vascular, intestinal, and immune cells – and even dynamic translocation to the plasma membrane in response to calcium signals underscore its critical role in maintaining redox balance and mitigating inflammatory damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, PON2 influences cellular metabolism and disease progression. In certain cancers, for example, altered PON2 levels modulate glucose transport and redox signaling pathways that can affect cell survival and chemoresistance. In parallel, genetic variants impairing its lactonase activity have been linked to atherosclerosis and neurodegenerative disorders such as amyotrophic lateral sclerosis, while dietary molecules like quercetin have been shown to regulate its expression in experimental settings. Collectively, these findings illuminate the dual role of PON2 – as an enzyme mediating lactone hydrolysis and as a potent antioxidant – underscoring its potential as a target for therapeutic strategies aimed at mitigating oxidative stress–related pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "23"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dragomir I Draganov, John F Teiber, Audrey Speelman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Lipid Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1194/jlr.M400511-JLR200"}], "href": "https://doi.org/10.1194/jlr.M400511-JLR200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15772423"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15772423"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "John F Teiber, Sven Horke, Donovan C Haines, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dominant role of paraoxonases in inactivation of the Pseudomonas aeruginosa quorum-sensing signal N-(3-oxododecanoyl)-L-homoserine lactone."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Infect Immun (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/IAI.01606-07"}], "href": "https://doi.org/10.1128/IAI.01606-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18347034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18347034"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sebastian Altenhöfer, Ines Witte, John F Teiber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "One enzyme, two functions: PON2 prevents mitochondrial superoxide formation and apoptosis independent from its lactonase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.118604"}], "href": "https://doi.org/10.1074/jbc.M110.118604"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20530481"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20530481"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sven Horke, Ines Witte, Petra Wilgenbus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.106.681700"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.106.681700"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17404154"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17404154"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Dimitry A Chistiakov, Alexandra A Melnichenko, Alexander N Orekhov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase and atherosclerosis-related cardiovascular diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochimie (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biochi.2016.10.010"}], "href": "https://doi.org/10.1016/j.biochi.2016.10.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27771368"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27771368"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Maayan Shiner, Bianca Fuhrman, Michael Aviram "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2004.09.003"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2004.09.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15544923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15544923"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sven Horke, Ines Witte, Petra Wilgenbus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protective effect of paraoxonase-2 against endoplasmic reticulum stress-induced apoptosis is lost upon disturbance of calcium homoeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20080775"}], "href": "https://doi.org/10.1042/BJ20080775"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18691157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18691157"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mira Rosenblat, Raymond Coleman, Srinivasa T Reddy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Lipid Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1194/jlr.M800550-JLR200"}], "href": "https://doi.org/10.1194/jlr.M800550-JLR200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19091699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19091699"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Julia Ebert, Petra Wilgenbus, John F Teiber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase-2 regulates coagulation activation through endothelial tissue factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2017-09-807040"}], "href": "https://doi.org/10.1182/blood-2017-09-807040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29439952"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29439952"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Emile Levy, Karine Trudel, Moise Bendayan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biological role, protein expression, subcellular localization, and oxidative stress response of paraoxonase 2 in the intestine of humans and rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Gastrointest Liver Physiol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpgi.00369.2007"}], "href": "https://doi.org/10.1152/ajpgi.00369.2007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17916643"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17916643"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Lilah Rothem, Corina Hartman, Aviva Dahan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonases are associated with intestinal inflammatory diseases and intracellularly localized to the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2007.05.003"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2007.05.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17664137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17664137"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Henning Hagmann, Alexander Kuczkowski, Michael Ruehl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Breaking the chain at the membrane: paraoxonase 2 counteracts lipid peroxidation at the plasma membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.13-240309"}], "href": "https://doi.org/10.1096/fj.13-240309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24421402"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24421402"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Carey J Ng, Noam Bourquard, Victor Grijalva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M605379200"}], "href": "https://doi.org/10.1074/jbc.M605379200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16891303"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16891303"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Asokan Devarajan, Diana Shih, Srinivasa T Reddy "}, {"type": "b", "children": [{"type": "t", "text": "Inflammation, infection, cancer and all that…the role of paraoxonases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Exp Med Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-3-319-07320-0_5"}], "href": "https://doi.org/10.1007/978-3-319-07320-0_5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25038992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25038992"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Bharti Mackness, Paul N Durrington, Michael I Mackness "}, {"type": "b", "children": [{"type": "t", "text": "The paraoxonase gene family and coronary heart disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Opin Lipidol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/00041433-200208000-00002"}], "href": "https://doi.org/10.1097/00041433-200208000-00002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12151850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12151850"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Giuliana Fortunato, Elio Marciano, Federica Zarrilli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1373/clinchem.2004.037788"}], "href": "https://doi.org/10.1373/clinchem.2004.037788"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15345661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15345661"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Bharti Mackness, Raul Beltran-Debon, Gerard Aragones, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human tissue distribution of paraoxonases 1 and 2 mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "IUBMB Life (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/iub.347"}], "href": "https://doi.org/10.1002/iub.347"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20503442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20503442"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Arvindhan Nagarajan, Shaillay Kumar Dogra, Lisha Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2017.07.014"}], "href": "https://doi.org/10.1016/j.molcel.2017.07.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28803777"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28803777"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Jen-Ho Tseng, Cheng-Yi Chen, Pei-Chun Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.14716"}], "href": "https://doi.org/10.18632/oncotarget.14716"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28108734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28108734"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "David A Stoltz, Egon A Ozer, Thomas J Recker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common mutation in paraoxonase-2 results in impaired lactonase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.051706"}], "href": "https://doi.org/10.1074/jbc.M109.051706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19840942"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19840942"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "P N Valdmanis, E Kabashi, A Dyck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/01.wnl.0000324997.21272.0c"}], "href": "https://doi.org/10.1212/01.wnl.0000324997.21272.0c"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18695162"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18695162"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Louis-Philippe Précourt, Devendra Amre, Marie-Claude Denis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The three-gene paraoxonase family: physiologic roles, actions and regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.atherosclerosis.2010.08.076"}], "href": "https://doi.org/10.1016/j.atherosclerosis.2010.08.076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20934178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20934178"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Christine Boesch-Saadatmandi, Renata Toedter Pospissil, Anne-Christin Graeser, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of quercetin on paraoxonase 2 levels in RAW264.7 macrophages and in human monocytes--role of quercetin metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms10094168"}], "href": "https://doi.org/10.3390/ijms10094168"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19865538"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19865538"}]}]}]}