{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:12:16Z","timestamp":1760173936360,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T00:00:00Z","timestamp":1580256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Gintonin is a newly discovered ingredient of ginseng and plays an exogenous ligand for G protein-coupled lysophosphatidic acid receptors. We previously showed that gintonin exhibits diverse effects from neurotransmitter release to improvement of Alzheimer\u2019s disease-related cognitive dysfunctions. However, previous studies did not show whether gintonin has protective effects against environmental heavy metal. We investigated the effects of gintonin-enriched fraction (GEF) on methylmercury (MeHg)-induced neurotoxicity and learning and memory dysfunction and on organ MeHg elimination. Using hippocampal neural progenitor cells (hNPCs) and mice we examined the effects of GEF on MeHg-induced hippocampal NPC neurotoxicity, on formation of reactive oxygen species (ROS), and on in vivo learning and memory functions after acute MeHg exposure. Treatment of GEF to hNPCs attenuated MeHg-induced neurotoxicity with concentration- and time-dependent manner. GEF treatment inhibited MeHg- and ROS inducer-induced ROS formations. Long-term treatment of GEF also improved MeHg-induced learning and memory dysfunctions. Oral administration of GEF decreased the concentrations of MeHg in blood, brain, liver, and kidney. This is the first report that GEF attenuated MeHg-induced in vitro and in vivo neurotoxicities through LPA (lysophosphatidic acids) receptor-independent manner and increased organ MeHg elimination. GEF-mediated neuroprotection might achieve via inhibition of ROS formation and facilitation of MeHg elimination from body.<\/jats:p>","DOI":"10.3390\/ijerph17030838","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T10:51:07Z","timestamp":1580295067000},"page":"838","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effects of Gintonin-Enriched Fraction on Methylmercury-Induced Neurotoxicity and Organ Methylmercury Elimination"],"prefix":"10.3390","volume":"17","author":[{"given":"Hyeon-Joong","family":"Kim","sequence":"first","affiliation":[{"name":"Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea"},{"name":"Biomedical Research Imaging Center, University of North Caroline at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun-Hye","family":"Choi","sequence":"additional","affiliation":[{"name":"Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na-Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2898-0464","authenticated-orcid":false,"given":"Hee-Jung","family":"Cho","sequence":"additional","affiliation":[{"name":"Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyewhon","family":"Rhim","sequence":"additional","affiliation":[{"name":"Center for Neuroscience, Korea Institute of Science and Technology, Seoul 02792, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyoung-Chun","family":"Kim","sequence":"additional","affiliation":[{"name":"Neuropsychopharmacology and Toxicology program, College of Pharmacy, Kangwon National University, Chunchon 24341, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung-Hee","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, College of Health Sciences, Sangji University, Wonju 26339, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung-Yeol","family":"Nah","sequence":"additional","affiliation":[{"name":"Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1126\/science.1185198","article-title":"The growing human footprint on coastal and open-ocean biogeochemistry","volume":"328","author":"Doney","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1080\/10408440600845619","article-title":"The toxicology of mercury and its chemical compounds","volume":"36","author":"Clarkson","year":"2006","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tox.2007.11.002","article-title":"Molecular mechanisms triggered by mercury","volume":"244","author":"Guzzi","year":"2008","journal-title":"Toxicology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1056\/NEJMra022471","article-title":"The toxicology of mercury \u2014 current exposures and clinical manifestations","volume":"349","author":"Clarkson","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1111\/j.1471-4159.1975.tb04405.x","article-title":"Organic mercurial encephalopathy: In vivo and in vitro effects of methyl mercury on synaptosomal respiration","volume":"25","author":"Verity","year":"1975","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/S0006-8993(01)02375-7","article-title":"Methylmercury-mediated inhibition of 3H-D-aspartate transport in cultured astrocytes is reversed by the antioxidant catalase","volume":"902","author":"Allen","year":"2001","journal-title":"Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1039\/C5MT00090D","article-title":"Unravelling the mechanisms of mercury hepatotoxicity in wild fish (Liza aurata) through a triad approach: Bioaccumulation, metabolomic profiles and oxidative stress","volume":"7","author":"Cappello","year":"2015","journal-title":"Metallomics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.scitotenv.2016.01.008","article-title":"Insights into the mechanisms underlying mercury-induced oxidative stress in gills of wild fish (Liza aurata) combining (1)H NMR metabolomics and conventional biochemical assays","volume":"548","author":"Cappello","year":"2016","journal-title":"Sci. Total Environ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.envpol.2016.10.033","article-title":"Advances in understanding the mechanisms of mercury toxicity in wild golden grey mullet (Liza aurata) by 1H NMR-based metabolomics","volume":"219","author":"Cappello","year":"2016","journal-title":"Environ. Pollut."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0149-7634(05)80217-9","article-title":"Mercury neurotoxicity: Mechanisms of blood\u2013brain barrier transport","volume":"14","author":"Aschner","year":"1990","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/0301-0082(89)90018-X","article-title":"The effects of methylmercury on the developing brain","volume":"32","author":"Choi","year":"1989","journal-title":"Prog. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1146\/annurev.pa.09.040169.002223","article-title":"New substances of plant origin which increase nonspecific resistance","volume":"9","author":"Brekhman","year":"1969","journal-title":"Annu. Rev. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/S10059-012-2216-z","article-title":"Gintonin, newly identified compounds from ginseng is novel lysophosphatidic acids-protein complexes and activates G protein-coupled lysophosphatidic acid receptors with high affinity","volume":"33","author":"Hwang","year":"2012","journal-title":"Mol. Cells"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jgr.2017.11.006","article-title":"Bioactive lipids in gintonin-enriched fraction from ginseng","volume":"43","author":"Cho","year":"2019","journal-title":"J. Ginseng Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jgr.2017.12.008","article-title":"Panax ginseng as an adjuvant treatment for Alzheimer\u2019s disease","volume":"42","author":"Kim","year":"2018","journal-title":"J. Ginseng Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s00204-009-0437-8","article-title":"Low level and sub-chronic exposure to methylmercury induces hypertension in rats: Nitric oxide depletion and oxidative damage as possible mechanisms","volume":"83","author":"Grotto","year":"2009","journal-title":"Arch. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s00204-007-0208-3","article-title":"Mercuric dichloride induces DNA damage in human salivary gland tissue cells and lymphocytes","volume":"81","author":"Schmid","year":"2007","journal-title":"Arch. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1590\/S0100-879X2007000300001","article-title":"Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity","volume":"40","author":"Aschner","year":"2007","journal-title":"Brazilian J. Med. Biol. Res. Rev. Bras. Pesqui. Medicas E Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.jgr.2015.05.002","article-title":"A brief method for preparation of gintonin-enriched fraction from ginseng","volume":"39","author":"Choi","year":"2015","journal-title":"J. Ginseng Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Garg, T.K., and Chang, J.Y. (2004). 15-deoxy-delta 12, 14-Prostaglandin J2 prevents reactive oxygen species generation and mitochondrial membrane depolarization induced by oxidative stress. BMC Pharmacol., 4.","DOI":"10.1186\/1471-2210-4-6"},{"key":"ref_21","unstructured":"Agency, U.S.E.P (2007). Mercury in Solids and Solutions by Thermal Decomposition, Amalgamation, and Atomic Absorption Spectrophotometry."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.brainres.2003.10.017","article-title":"Effects of naloxone on the long-term potentiation of EPSPs from the pathway of Schaffer collateral to CA1 region of hippocampus in aged rats with declined memory","volume":"996","author":"Zhao","year":"2004","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0165-0270(84)90007-4","article-title":"Developments of a water-maze procedure for studying spatial learning in the rat","volume":"11","author":"Morris","year":"1984","journal-title":"J. Neurosci. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neuint.2016.10.006","article-title":"Effects of gintonin-enriched fraction on hippocampal cell proliferation in wild-type mice and an APPswe\/PSEN-1 double Tg mouse model of Alzheimer\u2019s disease","volume":"101","author":"Kim","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s12011-015-0609-8","article-title":"MeHg suppressed neuronal potency of hippocampal NSCs contributing to the puberal spatial memory deficits","volume":"172","author":"Tian","year":"2016","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.chemosphere.2013.02.016","article-title":"Neurobehavioral effects, c-Fos\/Jun expression and tissue distribution in rat offspring prenatally co-exposed to MeHg and PFOA: PFOA impairs Hg retention","volume":"91","author":"Cheng","year":"2013","journal-title":"Chemosphere"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2013.10.884","article-title":"Blood mercury concentrations in pregnant and nonpregnant women in the United States: National Health and Nutrition Examination Survey 1999\u20132006","volume":"210","author":"Razzaghi","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.envres.2014.08.029","article-title":"Mercury levels in pregnant women, children, and seafood from Mexico City","volume":"135","author":"Basu","year":"2014","journal-title":"Environ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.3389\/fnins.2015.00150","article-title":"Hippocampal developmental vulnerability to methylmercury extends into prepubescence","volume":"9","author":"Obiorah","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/toxsci\/kfi227","article-title":"Effects of Methylmercury on Primary Brain Cells in Mono- and Co-culture","volume":"87","author":"Morken","year":"2005","journal-title":"Toxicol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.lfs.2011.05.019","article-title":"Mechanisms of methylmercury-induced neurotoxicity: Evidence from experimental studies","volume":"89","author":"Farina","year":"2011","journal-title":"Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0041-008X(92)90124-B","article-title":"Effects of charge and lipophilicity on mercurial-induced reduction of 45Ca2+ uptake in isolated nerve terminals of the rat","volume":"113","author":"Hewett","year":"1992","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/AAP.0b013e31827a3cbe","article-title":"Local Anesthetic\u2013induced Inhibition of Human Neutrophil Priming: The Influence of Structure, Lipophilicity, and Charge","volume":"38","author":"Picardi","year":"2013","journal-title":"Reg. Anesth. Pain Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.biochi.2014.07.026","article-title":"Phosphatidic acid in neuronal development: A node for membrane and cytoskeleton rearrangements","volume":"107","author":"Ammar","year":"2014","journal-title":"Biochimie"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0278-5846(00)00181-0","article-title":"Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia","volume":"25","author":"Mahadik","year":"2001","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Nguyen, T.M.D., Seigneurin, F., Froment, P., Combarnous, Y., and Blesbois, E. (2015). The 5\u2032-AMP-Activated Protein Kinase (AMPK) Is Involved in the Augmentation of Antioxidant Defenses in Cryopreserved Chicken Sperm. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134420"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.neuint.2013.02.013","article-title":"Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration","volume":"62","author":"Smith","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_38","first-page":"396","article-title":"Methylmercury: A new look at the risks","volume":"114","author":"Mahaffey","year":"1999","journal-title":"Public Health Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3233\/JAD-2012-120439","article-title":"Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates alzheimer\u2019s disease-related neuropathies: involvement of non-amyloidogenic processing","volume":"31","author":"Hwang","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s12035-018-1020-1","article-title":"Gintonin Mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of \u03b1-Synuclein via the Nrf2\/HO-1 pathway","volume":"56","author":"Jo","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3389\/fphar.2018.00515","article-title":"Multi-target protective effects of gintonin in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-mediated model of parkinson\u2019s disease via lysophosphatidic acid receptors","volume":"9","author":"Choi","year":"2018","journal-title":"Front. Pharmacol."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/3\/838\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:52:54Z","timestamp":1760172774000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/3\/838"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,29]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijerph17030838"],"URL":"https:\/\/doi.org\/10.3390\/ijerph17030838","relation":{},"ISSN":["1660-4601"],"issn-type":[{"type":"electronic","value":"1660-4601"}],"subject":[],"published":{"date-parts":[[2020,1,29]]}}}