{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:03:54Z","timestamp":1781647434424,"version":"3.54.5"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"BBSRC","doi-asserted-by":"crossref","award":["BB\/E527098\/1"],"award-info":[{"award-number":["BB\/E527098\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["080268"],"award-info":[{"award-number":["080268"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Nitric oxide synthases (NOS) synthesize nitric oxide (NO) from L-arginine in endothelial and neuronal cells. Asymmetric dimethylarginine (ADMA) is a homologue of arginine and an endogenous inhibitor of NOS. As NO is a critical signalling molecule and influences physiological pathways in health and disease, the transfer of arginine and ADMA across the blood-CNS barriers is of interest. Our research group have previously demonstrated the presence of saturable transporters for [\n                    <jats:sup>3<\/jats:sup>\n                    H]-\n                    <jats:italic\/>\n                    arginine and [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA at the blood-brain and blood-CSF barriers using\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in situ<\/jats:italic>\n                    methods. In this study, we determine the identity and kinetic characteristics of these transporters by means of the\n                    <jats:italic>in situ<\/jats:italic>\n                    brain\/choroid plexus perfusion technique in anaesthetised mice. Results indicated that [\n                    <jats:sup>3<\/jats:sup>\n                    H]-arginine and [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA could be transported across blood-brain and blood-CSF barriers by the cationic amino acid transporter, system-y\n                    <jats:sup>+<\/jats:sup>\n                    . In contrast to the results obtained with arginine where transport was predominately by a single transport system (system-y\n                    <jats:sup>+<\/jats:sup>\n                    ), ADMA delivery to the CNS was more complex and involved multiple transport systems (system y\n                    <jats:sup>+<\/jats:sup>\n                    , B\n                    <jats:sup>0,+<\/jats:sup>\n                    , y\n                    <jats:sup>+<\/jats:sup>\n                    L and b\n                    <jats:sup>0,+<\/jats:sup>\n                    ) suggesting its concentration is tightly regulated\n                    <jats:italic>.<\/jats:italic>\n                    System y\n                    <jats:sup>+<\/jats:sup>\n                    and system y\n                    <jats:sup>+<\/jats:sup>\n                    L transporters could be involved in the CNS to blood efflux of ADMA that we have previously observed. The half-saturation constant (K\n                    <jats:sub>m<\/jats:sub>\n                    ) and maximal influx rate of the saturable component (V\n                    <jats:sub>max<\/jats:sub>\n                    ) for [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA transport into the frontal cortex was 29.07\u2009\u00b1\u20097.19 \u03bcM and 0.307\u2009\u00b1\u20090.017 nmol.min\n                    <jats:sup>-1<\/jats:sup>\n                    .g\n                    <jats:sup>-1<\/jats:sup>\n                    , respectively, and into the CSF was 30.59\u2009\u00b1\u200925.41 \u03bcM and 2.07\u2009\u00b1\u20090.38 nmol.min\n                    <jats:sup>-1<\/jats:sup>\n                    .g\n                    <jats:sup>-1<\/jats:sup>\n                    , respectively. This information could help explain the arginine paradox providing evidence that ADMA interacts with transporters that can remove ADMA from cells. These removal mechanisms could be stimulated by excess arginine in the plasma resulting in increased NO production. It remains to be seen if arginine supplementation could be used to increase NO production and improve hypoperfusion observed in disease states such as Alzheimer\u2019s and stroke.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0320034","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T13:29:57Z","timestamp":1749648597000},"page":"e0320034","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Saturation kinetics and specificity of transporters for L-arginine and asymmetric dimethylarginine (ADMA) at the blood-brain and blood-CSF barriers"],"prefix":"10.1371","volume":"20","author":[{"given":"Mehmet","family":"Fidanboylu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-0154","authenticated-orcid":true,"given":"Sarah Ann","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"issue":"3","key":"pone.0320034.ref001","doi-asserted-by":"crossref","first-page":"100052","DOI":"10.1016\/j.pharmr.2025.100052","article-title":"The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player","volume":"77","author":"YA Divecha","year":"2025","journal-title":"Pharmacol Rev"},{"key":"pone.0320034.ref002","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1152\/physrev.1998.78.2.487","article-title":"Transporters for cationic amino acids in animal cells: discovery, structure, and function","author":"R Deves","year":"1998","journal-title":"Physiol Rev"},{"issue":"1","key":"pone.0320034.ref003","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1152\/physrev.00022.2002","article-title":"Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells","volume":"83","author":"GE Mann","year":"2003","journal-title":"Physiol Rev"},{"issue":"1","key":"pone.0320034.ref004","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1177\/0271678X211039593","article-title":"Analysis of L-leucine amino acid transporter species activity and gene expression by human blood brain barrier hCMEC\/D3 model reveal potential LAT1, LAT4, B0AT2 and y+LAT1 functional cooperation","volume":"42","author":"M Taslimifar","year":"2022","journal-title":"J Cereb Blood Flow Metab"},{"issue":"8793","key":"pone.0320034.ref005","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/0140-6736(92)90865-Z","article-title":"Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure","volume":"339","author":"P Vallance","year":"1992","journal-title":"Lancet"},{"key":"pone.0320034.ref006","doi-asserted-by":"crossref","first-page":"1545044","DOI":"10.3389\/fphys.2025.1545044","article-title":"Promotion of nitric oxide production: mechanisms, strategies, and possibilities","volume":"16","author":"M Gonzalez","year":"2025","journal-title":"Front Physiol"},{"issue":"5","key":"pone.0320034.ref007","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.3390\/nu12051300","article-title":"Effects of Arginine Supplementation on Athletic Performance Based on Energy Metabolism: A Systematic Review and Meta-Analysis","volume":"12","author":"A Viribay","year":"2020","journal-title":"Nutrients"},{"issue":"9","key":"pone.0320034.ref008","doi-asserted-by":"crossref","first-page":"8205","DOI":"10.3390\/ijms24098205","article-title":"The Effectiveness of L-arginine in Clinical Conditions Associated with Hypoxia","volume":"24","author":"N Kurhaluk","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0320034.ref009","doi-asserted-by":"crossref","first-page":"15957","DOI":"10.1038\/s41598-018-34249-2","article-title":"Reversal of cerebrovascular constriction in experimental cerebral malaria by L-arginine","volume":"8","author":"PK Ong","year":"2018","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0320034.ref010","doi-asserted-by":"crossref","first-page":"13621","DOI":"10.1038\/s41598-019-49855-x","article-title":"L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria","volume":"9","author":"AS Moreira","year":"2019","journal-title":"Sci Rep"},{"issue":"7","key":"pone.0320034.ref011","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1038\/jcbfm.2012.12","article-title":"Nitric oxide: considerations for the treatment of ischemic stroke","volume":"32","author":"NA Terpolilli","year":"2012","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0320034.ref012","doi-asserted-by":"crossref","first-page":"176030","DOI":"10.1016\/j.ejphar.2023.176030","article-title":"Protective effects of L-arginine on Alzheimer\u2019s disease: Modulating hippocampal nitric oxide levels and memory deficits in aluminum chloride-induced rat model","volume":"958","author":"S Geravand","year":"2023","journal-title":"Eur J Pharmacol"},{"key":"pone.0320034.ref013","doi-asserted-by":"crossref","first-page":"102572","DOI":"10.1016\/j.tice.2024.102572","article-title":"L-arginine mitigates choroid plexus changes in Alzheimer\u2019s disease rat model via oxidative\/inflammatory burden and behavioral modulation","volume":"91","author":"WA Nasr El-Din","year":"2024","journal-title":"Tissue Cell"},{"issue":"4","key":"pone.0320034.ref014","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1212\/01.WNL.0000151976.60624.01","article-title":"L-arginine improves the symptoms of strokelike episodes in MELAS","volume":"64","author":"Y Koga","year":"2005","journal-title":"Neurology"},{"issue":"2","key":"pone.0320034.ref015","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.apsb.2024.12.042","article-title":"A novel anti-ischemic stroke candidate drug AAPB with dual effects of neuroprotection and cerebral blood flow improvement","volume":"15","author":"J Wu","year":"2025","journal-title":"Acta Pharm Sin B"},{"key":"pone.0320034.ref016","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.brainres.2016.07.026","article-title":"The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) and L-arginine with the human blood-brain barrier in vitro","volume":"1648","author":"CP Watson","year":"2016","journal-title":"Brain Res"},{"issue":"10","key":"pone.0320034.ref017","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0305318","article-title":"L-Arginine and asymmetric dimethylarginine (ADMA) transport across the mouse blood-brain and blood-CSF barriers: Evidence of saturable transport at both interfaces and CNS to blood efflux","volume":"19","author":"M Fidanboylu","year":"2024","journal-title":"PLoS One"},{"issue":"4","key":"pone.0320034.ref018","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbrc.2011.09.112","article-title":"Intracellular L-arginine concentration does not determine NO production in endothelial cells: implications on the \u201cL-arginine paradox\u201d","volume":"414","author":"S Shin","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"issue":"9","key":"pone.0320034.ref019","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1128\/AAC.00372-07","article-title":"Distribution of suramin, an antitrypanosomal drug, across the blood-brain and blood-cerebrospinal fluid interfaces in wild-type and P-glycoprotein transporter-deficient mice","volume":"51","author":"L Sanderson","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"issue":"11","key":"pone.0320034.ref020","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/jms.684","article-title":"Determination of arginine and asymmetric dimethylarginine (ADMA) in human plasma by liquid chromatography\/mass spectrometry with the isotope dilution technique","volume":"39","author":"J Martens-Lobenhoffer","year":"2004","journal-title":"J Mass Spectrom"},{"issue":"4","key":"pone.0320034.ref021","doi-asserted-by":"crossref","first-page":"747","DOI":"10.2337\/dc07-1762","article-title":"Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy","volume":"31","author":"M Lajer","year":"2008","journal-title":"Diabetes Care"},{"issue":"2","key":"pone.0320034.ref022","doi-asserted-by":"crossref","DOI":"10.1152\/ajpregu.90506.2008","article-title":"Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension","volume":"296","author":"D Wang","year":"2009","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"2","key":"pone.0320034.ref023","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1053\/j.ajkd.2007.09.020","article-title":"Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease","volume":"51","author":"D Wang","year":"2008","journal-title":"Am J Kidney Dis"},{"issue":"3","key":"pone.0320034.ref024","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1210\/jc.2004-2045","article-title":"Elevated plasma concentration of asymmetric dimethylarginine that is reduced by single dose testosterone administration in idiopathic hypogonadotropic hypogonadism patients","volume":"90","author":"E Cakir","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"pone.0320034.ref025","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.pharmthera.2007.03.002","article-title":"The L-arginine paradox: Importance of the L-arginine\/asymmetrical dimethylarginine ratio","volume":"114","author":"SM Bode-B\u00f6ger","year":"2007","journal-title":"Pharmacol Ther"},{"issue":"3","key":"pone.0320034.ref026","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1046\/j.1471-4159.1996.66031289.x","article-title":"Passage of a delta-opioid receptor selective enkephalin, [D-penicillamine2,5] enkephalin, across the blood-brain and the blood-cerebrospinal fluid barriers","volume":"66","author":"SA Williams","year":"1996","journal-title":"J Neurochem"},{"issue":"4","key":"pone.0320034.ref027","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1021\/mp2004127","article-title":"The involvement of a Na\u207a- and Cl\u207b-dependent transporter in the brain uptake of amantadine and rimantadine","volume":"9","author":"SAA Kooijmans","year":"2012","journal-title":"Mol Pharm"},{"issue":"5","key":"pone.0320034.ref028","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1111\/j.1471-4159.1993.tb13428.x","article-title":"Identification of the cationic amino acid transporter (System y+) of the rat blood-brain barrier","volume":"60","author":"J Stoll","year":"1993","journal-title":"J Neurochem"},{"issue":"25","key":"pone.0320034.ref029","doi-asserted-by":"crossref","first-page":"14913","DOI":"10.1074\/jbc.270.25.14913","article-title":"Neutral amino acid transport characterization of isolated luminal and abluminal membranes of the blood-brain barrier","volume":"270","author":"MM S\u00e1nchez del Pino","year":"1995","journal-title":"J Biol Chem"},{"issue":"2","key":"pone.0320034.ref030","doi-asserted-by":"crossref","DOI":"10.1152\/ajpendo.00007.2006","article-title":"Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+","volume":"291","author":"RL O\u2019Kane","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"pone.0320034.ref031","doi-asserted-by":"crossref","first-page":"1113493","DOI":"10.3389\/fddev.2023.1113493","article-title":"Identification of transport systems involved in eflornithine delivery across the blood-brain barrier","volume":"3","author":"CP Watson","year":"2023","journal-title":"Front Drug Deliv"},{"issue":"9","key":"pone.0320034.ref032","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1038\/jcbfm.2009.72","article-title":"Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo","volume":"29","author":"R Lyck","year":"2009","journal-title":"J Cereb Blood Flow Metab"},{"issue":"2","key":"pone.0320034.ref033","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1124\/jpet.108.149831","article-title":"Expression profiling of the solute carrier gene family in the mouse brain","volume":"329","author":"A Dahlin","year":"2009","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0320034.ref034","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0304-4157(85)90015-2","article-title":"The transport of cationic amino acids across the plasma membrane of mammalian cells","volume":"822","author":"MF White","year":"1985","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"pone.0320034.ref035","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1038\/s41598-017-04965-2","article-title":"The prognostic biomarker L-homoarginine is a substrate of the cationic amino acid transporters CAT1, CAT2A and CAT2B","volume":"7","author":"A Chafai","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0320034.ref036","doi-asserted-by":"crossref","DOI":"10.1093\/jn\/130.4.1016S","article-title":"Transport of glutamate and other amino acids at the blood-brain barrier","volume":"130","author":"QR Smith","year":"2000","journal-title":"J Nutr"},{"issue":"6220","key":"pone.0320034.ref037","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"M Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"pone.0320034.ref038","volume-title":"The Human Protein Atlas - SLC7A1. In: Protein Atlas version 23.0. [Internet]","year":"2024"},{"issue":"1","key":"pone.0320034.ref039","doi-asserted-by":"crossref","first-page":"5282","DOI":"10.1038\/s41467-021-25563-x","article-title":"Quantitative modelling of amino acid transport and homeostasis in mammalian cells","volume":"12","author":"G Gauthier-Coles","year":"2021","journal-title":"Nat Commun"},{"issue":"1","key":"pone.0320034.ref040","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1006\/niox.1996.0106","article-title":"Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B","volume":"1","author":"EI Closs","year":"1997","journal-title":"Nitric Oxide"},{"issue":"5","key":"pone.0320034.ref041","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0178710","article-title":"Cellular interactions between L-arginine and asymmetric dimethylarginine: Transport and metabolism","volume":"12","author":"S Shin","year":"2017","journal-title":"PLoS One"},{"issue":"34","key":"pone.0320034.ref042","doi-asserted-by":"crossref","first-page":"23740","DOI":"10.1074\/jbc.274.34.23740","article-title":"Cloning and functional expression of a human Na(+) and Cl(-)-dependent neutral and cationic amino acid transporter B(0+)","volume":"274","author":"JL Sloan","year":"1999","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0320034.ref043","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1042\/BJ20080622","article-title":"Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy","volume":"414","author":"S Karunakaran","year":"2008","journal-title":"Biochem J"},{"issue":"36","key":"pone.0320034.ref044","doi-asserted-by":"crossref","first-page":"31830","DOI":"10.1074\/jbc.M111.229518","article-title":"SLC6A14 (ATB0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer","volume":"286","author":"S Karunakaran","year":"2011","journal-title":"J Biol Chem"},{"key":"pone.0320034.ref045","doi-asserted-by":"crossref","first-page":"646574","DOI":"10.3389\/fmolb.2021.646574","article-title":"A GC-MS\/Single-Cell Method to Evaluate Membrane Transporter Substrate Specificity and Signaling","volume":"8","author":"SJ Fairweather","year":"2021","journal-title":"Front Mol Biosci"},{"issue":"2","key":"pone.0320034.ref046","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0006-8993(92)90731-N","article-title":"The uptake of anionic and cationic amino acids by the isolated perfused sheep choroid plexus","volume":"581","author":"JE Preston","year":"1992","journal-title":"Brain Res"},{"issue":"4","key":"pone.0320034.ref047","article-title":"Transport of extracellular l-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production","volume":"289","author":"BG Zani","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"6","key":"pone.0320034.ref048","doi-asserted-by":"crossref","DOI":"10.1152\/ajpcell.00323.2006","article-title":"Activation of classical protein kinase C decreases transport via systems y+ and y+L","volume":"292","author":"A Rotmann","year":"2007","journal-title":"Am J Physiol Cell Physiol"},{"issue":"8","key":"pone.0320034.ref049","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1172\/JCI12060","article-title":"Na+ - and Cl- -coupled active transport of nitric oxide synthase inhibitors via amino acid transport system B(0,+)","volume":"107","author":"T Hatanaka","year":"2001","journal-title":"J Clin Invest"},{"key":"pone.0320034.ref050","volume-title":"The Human Protein Atlas-SLC6A14 [Internet]. In: Protein Atlas version 23.0 [Internet]","year":"2024"},{"issue":"7","key":"pone.0320034.ref051","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1016\/S0021-9258(18)69048-9","article-title":"Na+-independent transport of basic and zwitterionic amino acids in mouse blastocysts by a shared system and by processes which distinguish between these substrates","volume":"263","author":"LJ Van Winkle","year":"1988","journal-title":"J Biol Chem"},{"key":"pone.0320034.ref052","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1113\/jphysiol.1989.sp017444","article-title":"Neutral amino acid uptake by the isolated perfused sheep choroid plexus","volume":"408","author":"JE Preston","year":"1989","journal-title":"J Physiol"},{"issue":"4364","key":"pone.0320034.ref053","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1126\/science.211586","article-title":"Polarity of the blood-brain barrier: neutral amino acid transport into isolated brain capillaries","volume":"202","author":"AL Betz","year":"1978","journal-title":"Science"},{"issue":"4","key":"pone.0320034.ref054","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/neu.480130402","article-title":"Ventriculo-cisternal perfusion of twelve amino acids in the rabbit","volume":"13","author":"H Davson","year":"1982","journal-title":"J Neurobiol"},{"issue":"4","key":"pone.0320034.ref055","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1211\/0022357011775794","article-title":"Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier","volume":"53","author":"Y Kido","year":"2001","journal-title":"J Pharm Pharmacol"},{"key":"pone.0320034.ref056","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1113\/jphysiol.1992.sp019275","article-title":"Identification of a new transport system (y+L) in human erythrocytes that recognizes lysine and leucine with high affinity","volume":"454","author":"R Dev\u00e9s","year":"1992","journal-title":"J Physiol"},{"key":"pone.0320034.ref057","volume-title":"The Human Protein Atlas\u2014SLC7A7 [Internet]. In: Protein Atlas version 23.0 [Internet]","year":"2024"},{"key":"pone.0320034.ref058","volume-title":"The Human Protein Atlas-SLC3A2 [Internet]. In: Protein Atlas version 23.0 [Internet]","year":"2024"},{"key":"pone.0320034.ref059","volume-title":"The Human Protein Atlas-SLC7A6 [Internet]. In: Protein Atlas version 23.0 [Internet]","year":"2024"},{"key":"pone.0320034.ref060","volume-title":"The Human Protein Atlas-SLC7A9 [Internet]. In: Protein Atlas version 23.0 [Internet]","year":"2024"},{"issue":"2","key":"pone.0320034.ref061","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1074\/jbc.M603606200","article-title":"Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function","volume":"282","author":"AJ Cardounel","year":"2007","journal-title":"J Biol Chem"},{"issue":"18","key":"pone.0320034.ref062","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1161\/01.CIR.98.18.1842","article-title":"Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia","volume":"98","author":"RH B\u00f6ger","year":"1998","journal-title":"Circulation"},{"issue":"1","key":"pone.0320034.ref063","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1159\/000144026","article-title":"Asymmetrical dimethylarginine is increased in plasma and decreased in cerebrospinal fluid of patients with Alzheimer\u2019s disease","volume":"26","author":"S Arlt","year":"2008","journal-title":"Dement Geriatr Cogn Disord"},{"key":"pone.0320034.ref064","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jns.2009.12.020","article-title":"Asymmetric dimethylarginine (ADMA) as a possible risk marker for ischemic stroke","volume":"290","author":"Y Nishiyama","year":"2010","journal-title":"J Neurol Sci"},{"issue":"10","key":"pone.0320034.ref065","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S0002-9149(01)02063-X","article-title":"Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus","volume":"88","author":"F Abbasi","year":"2001","journal-title":"Am J Cardiol"},{"issue":"8","key":"pone.0320034.ref066","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1097\/00004872-199715080-00015","article-title":"Nitric oxide synthase inhibitors and hypertension in children and adolescents","volume":"15","author":"CD Goonasekera","year":"1997","journal-title":"J Hypertens"},{"issue":"9","key":"pone.0320034.ref067","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3390\/sports9090120","article-title":"Reduced L-Arginine and L-Arginine-ADMA-Ratio, and Increased SDMA after Norseman Xtreme Triathlon","volume":"9","author":"C Nyborg","year":"2021","journal-title":"Sports (Basel)"},{"issue":"6","key":"pone.0320034.ref068","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.phrs.2009.08.002","article-title":"Cellular ADMA: regulation and action","volume":"60","author":"T Teerlink","year":"2009","journal-title":"Pharmacol Res"},{"issue":"3","key":"pone.0320034.ref069","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.yjmcc.2012.06.002","article-title":"Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1)","volume":"53","author":"J Strobel","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"pone.0320034.ref070","doi-asserted-by":"crossref","DOI":"10.1093\/jn\/134.10.2842S","article-title":"Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the \u201cL-arginine paradox\u201d and acts as a novel cardiovascular risk factor","volume":"134","author":"RH B\u00f6ger","year":"2004","journal-title":"J Nutr"},{"issue":"2","key":"pone.0320034.ref071","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/0006-8993(75)90053-0","article-title":"Differential permeability of cerebral capillary and choroid plexus to lanthanum ion","volume":"99","author":"TW Bouldin","year":"1975","journal-title":"Brain Res"},{"issue":"1","key":"pone.0320034.ref072","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0165-3806(90)90163-S","article-title":"A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat","volume":"56","author":"RF Keep","year":"1990","journal-title":"Brain Res Dev Brain Res"},{"issue":"2","key":"pone.0320034.ref073","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1023\/A:1007045605751","article-title":"The choroid plexuses and the barriers between the blood and the cerebrospinal fluid","volume":"20","author":"MB Segal","year":"2000","journal-title":"Cell Mol Neurobiol"},{"key":"pone.0320034.ref074","first-page":"165","volume-title":"The Choroid Plexus\u2014CSF Nexus. Neuroscience in Medicine","author":"CE Johanson","year":"2003"},{"issue":"1","key":"pone.0320034.ref075","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/1097-0029(20010101)52:1<31::AID-JEMT5>3.0.CO;2-T","article-title":"Ageing choroid plexus-cerebrospinal fluid system","volume":"52","author":"JE Preston","year":"2000","journal-title":"Microsc Res Tech"},{"issue":"7","key":"pone.0320034.ref076","doi-asserted-by":"crossref","DOI":"10.1002\/nbm.5029","article-title":"Cerebrospinal fluid turnover as a driver of brain clearance","volume":"37","author":"NG Smets","year":"2024","journal-title":"NMR Biomed"},{"issue":"3","key":"pone.0320034.ref077","article-title":"Distributed model for drug delivery to CSF and brain tissue","volume":"245","author":"JM Collins","year":"1983","journal-title":"Am J Physiol"},{"key":"pone.0320034.ref078","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.drudis.2012.11.008","article-title":"The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so","volume":"18","author":"DB Kell","year":"2013","journal-title":"Drug Discov Today"},{"issue":"18","key":"pone.0320034.ref079","doi-asserted-by":"crossref","first-page":"5629","DOI":"10.3390\/molecules26185629","article-title":"The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes","volume":"26","author":"DB Kell","year":"2021","journal-title":"Molecules"},{"issue":"24","key":"pone.0320034.ref080","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.1021\/acschemneuro.0c00564","article-title":"L-Type Amino Acid Transporter 1 Enables the Efficient Brain Delivery of Small-Sized Prodrug across the Blood-Brain Barrier and into Human and Mouse Brain Parenchymal Cells","volume":"11","author":"AB Montaser","year":"2020","journal-title":"ACS Chem Neurosci"},{"issue":"2","key":"pone.0320034.ref081","doi-asserted-by":"crossref","first-page":"151406","DOI":"10.1016\/j.ejcb.2024.151406","article-title":"The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier","volume":"103","author":"M Kurtyka","year":"2024","journal-title":"Eur J Cell Biol"},{"issue":"3","key":"pone.0320034.ref082","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1128\/jvi.67.3.1310-1314.1993","article-title":"Identification of amino acid residues critical for infection with ecotropic murine leukemia retrovirus","volume":"67","author":"T Yoshimoto","year":"1993","journal-title":"J Virol"},{"issue":"12","key":"pone.0320034.ref083","doi-asserted-by":"crossref","first-page":"14516","DOI":"10.1096\/fj.201901528R","article-title":"CAT1\/SLC7A1 acts as a cellular receptor for bovine leukemia virus infection","volume":"33","author":"L Bai","year":"2019","journal-title":"FASEB J"},{"key":"pone.0320034.ref084","volume-title":"Blood-CNS transport mechanisms in pathophysiology and drug delivery [PhD thesis]","author":"M Fidanboylu","year":"2013"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0320034","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T13:30:14Z","timestamp":1749648614000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0320034"}},"subtitle":[],"editor":[{"given":"Alexandra","family":"Chittka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,11]]},"references-count":84,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0320034","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.02.14.638257","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,11]]}}}