{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T17:50:56Z","timestamp":1783705856897,"version":"3.55.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T00:00:00Z","timestamp":1502409600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T00:00:00Z","timestamp":1502409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>. Cellular NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup> uptake is accomplished mainly by the Na<jats:sup>+<\/jats:sup>,K<jats:sup>+<\/jats:sup>,2Cl<jats:sup>\u2212<\/jats:sup> cotransporter. Here we show that hepatic clearance of NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup> is impaired in TNF\u03b1 deficient as well as TNFR1&amp;TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>, TNF\u03b1 deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup> load, virtually all TNF\u03b1 deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNF\u03b1 treatment of wild type mice sensitized the animals to the toxic effects of an NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup> load. The protection of TNF\u03b1-deficient mice against an NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup> load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNF\u03b1 formation and\/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.<\/jats:p>","DOI":"10.1038\/s41598-017-07640-8","type":"journal-article","created":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T14:16:34Z","timestamp":1502115394000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["TNF\u03b1 induced up-regulation of Na+,K+,2Cl\u2212 cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity"],"prefix":"10.1038","volume":"7","author":[{"given":"Vitaly I.","family":"Pozdeev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"G\u00f6rg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J.","family":"Bidmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant V.","family":"Shinde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Kircheis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diran","family":"Herebian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Pfeffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2962-1540","authenticated-orcid":false,"given":"Florian","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"H\u00e4ussinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl S.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp A.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,11]]},"reference":[{"key":"7640_CR1","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/nrgastro.2013.99","volume":"10","author":"RF Butterworth","year":"2013","unstructured":"Butterworth, R. F. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat. Rev. Gastroenterol. Hepatol. \n                           10, 522\u20138 (2013).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"7640_CR2","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1042\/bj2670281","volume":"267","author":"D H\u00e4ussinger","year":"1990","unstructured":"H\u00e4ussinger, D. Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem. J. \n                           267, 281\u2013290 (1990).","journal-title":"Biochem. J."},{"key":"7640_CR3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1159\/000468779","volume":"46","author":"D H\u00e4ussinger","year":"1992","unstructured":"H\u00e4ussinger, D., Lamers, W. H. & Moorman, A. F. Hepatocyte heterogeneity in the metabolism of amino acids and ammonia. Enzyme \n                           46, 72\u201393 (1992).","journal-title":"Enzyme"},{"key":"7640_CR4","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1111\/j.1432-1033.1983.tb07458.x","volume":"133","author":"D H\u00e4ussinger","year":"1983","unstructured":"H\u00e4ussinger, D. Hepatocyte Heterogeneity in Glutamine and Ammonia Metabolism and the Role of an Intercellular Glutamine Cycle during Ureogenesis in Perfused Rat Liver. Eur. J. Biochem. \n                           133, 269\u2013275 (1983).","journal-title":"Eur. J. Biochem."},{"key":"7640_CR5","doi-asserted-by":"publisher","first-page":"371","DOI":"10.2741\/2070","volume":"12","author":"D H\u00e4ussinger","year":"2007","unstructured":"H\u00e4ussinger, D. & Schliess, F. Glutamine metabolism and signaling in the liver. Front. Biosci. \n                           12, 371\u201391 (2007).","journal-title":"Front. Biosci."},{"key":"7640_CR6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/j.1460-2075.1983.tb01464.x","volume":"2","author":"R Gebhardt","year":"1983","unstructured":"Gebhardt, R. & Mecke, D. Heterogeneous distribution of glutamine synthetase among rat liver parenchymal cells in situ and in primary culture. EMBO J. \n                           2, 567\u201370 (1983).","journal-title":"EMBO J."},{"key":"7640_CR7","doi-asserted-by":"publisher","first-page":"1892","DOI":"10.1002\/hep.25819","volume":"56","author":"EL Clinkenbeard","year":"2012","unstructured":"Clinkenbeard, E. L., Butler, J. E. & Spear, B. T. Pericentral activity of alpha-fetoprotein enhancer 3 and glutamine synthetase upstream enhancer in the adult liver are regulated by \u03b2-catenin in mice. Hepatology \n                           56, 1892\u20131901 (2012).","journal-title":"Hepatology"},{"key":"7640_CR8","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1002\/hep.20662","volume":"41","author":"B G\u00f6rg","year":"2005","unstructured":"G\u00f6rg, B., Wettstein, M., Metzger, S., Schliess, F. & H\u00e4ussinger, D. Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat. Hepatology \n                           41, 1065\u20131073 (2005).","journal-title":"Hepatology"},{"key":"7640_CR9","doi-asserted-by":"publisher","first-page":"201423968","DOI":"10.1073\/pnas.1423968112","volume":"112","author":"N Qvartskhava","year":"2015","unstructured":"Qvartskhava, N. et al. Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase. Proc. Natl. Acad. Sci. \n                           112, 201423968 (2015).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"7640_CR10","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1002\/hep.22345","volume":"48","author":"B G\u00f6rg","year":"2008","unstructured":"G\u00f6rg, B. et al. Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo. Hepatology \n                           48, 567\u2013579 (2008).","journal-title":"Hepatology"},{"key":"7640_CR11","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/S0002-9343(02)01477-8","volume":"114","author":"JP Ong","year":"2003","unstructured":"Ong, J. P. et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am. J. Med. \n                           114, 188\u2013193 (2003).","journal-title":"Am. J. Med."},{"key":"7640_CR12","first-page":"110","volume":"24","author":"M Odeh","year":"2004","unstructured":"Odeh, M., Sabo, E. & Srugo, I. & Oliven, A. Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Int. \n                           24, 110\u20136 (2004).","journal-title":"Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Int."},{"key":"7640_CR13","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1080\/07853890500317414","volume":"37","author":"M Odeh","year":"2005","unstructured":"Odeh, M., Sabo, E., Srugo, I. & Oliven, A. Relationship between tumor necrosis factor-alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann. Med. \n                           37, 603\u201312 (2005).","journal-title":"Ann. Med."},{"key":"7640_CR14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/glia.22731","volume":"63","author":"B G\u00f6rg","year":"2015","unstructured":"G\u00f6rg, B., Karababa, A., Shafigullina, A., Bidmon, H. J. & H\u00e4ussinger, D. Ammonia-induced senescence in cultured rat astrocytes and in human cerebral cortex in hepatic encephalopathy. Glia \n                           63, 37\u201350 (2015).","journal-title":"Glia"},{"key":"7640_CR15","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1038\/nm.3400","volume":"19","author":"V Rangroo Thrane","year":"2013","unstructured":"Rangroo Thrane, V. et al. Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nat. Med. \n                           19, 1643\u20138 (2013).","journal-title":"Nat. Med."},{"key":"7640_CR16","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1113\/jphysiol.2002.030205","volume":"549","author":"O Bachmann","year":"2003","unstructured":"Bachmann, O. et al. Expression and regulation of the Na\u2009+\u2009-K\u2009+\u2009-2Cl\u2212 cotransporter NKCC1 in the normal and CFTR-deficient murine colon. J. Physiol. \n                           549, 525\u2013536 (2003).","journal-title":"J. Physiol."},{"key":"7640_CR17","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/1742-2094-11-102","volume":"11","author":"L-Q Huang","year":"2014","unstructured":"Huang, L.-Q. et al. Hypertonic saline alleviates cerebral edema by inhibiting microglia-derived TNF-\u03b1 and IL-1\u03b2-induced Na-K-Cl Cotransporter up-regulation. J. Neuroinflammation \n                           11, 102 (2014).","journal-title":"J. Neuroinflammation"},{"key":"7640_CR18","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.neuint.2009.11.010","volume":"56","author":"C B\u00e9meur","year":"2010","unstructured":"B\u00e9meur, C., Qu, H., Desjardins, P. & Butterworth, R. F. IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem. Int. \n                           56, 213\u2013215 (2010).","journal-title":"Neurochem. Int."},{"key":"7640_CR19","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/364798a0","volume":"364","author":"J Rothe","year":"1993","unstructured":"Rothe, J. et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature \n                           364, 798\u2013802 (1993).","journal-title":"Nature"},{"key":"7640_CR20","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/0092-8674(93)90134-C","volume":"73","author":"K Pfeffer","year":"1993","unstructured":"Pfeffer, K. et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell \n                           73, 457\u2013467 (1993).","journal-title":"Cell"},{"key":"7640_CR21","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/nri3834","volume":"15","author":"D Brenner","year":"2015","unstructured":"Brenner, D., Blaser, H. & Mak, T. W. Regulation of tumour necrosis factor signalling: live or let die. Nat. Rev. Immunol. \n                           15, 362\u201374 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"7640_CR22","doi-asserted-by":"publisher","first-page":"e49670","DOI":"10.1371\/journal.pone.0049670","volume":"7","author":"A Chastre","year":"2012","unstructured":"Chastre, A. et al. Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications. PLoS One \n                           7, e49670 (2012).","journal-title":"PLoS One"},{"key":"7640_CR23","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.1016\/j.cell.2015.11.023","volume":"163","author":"S Habbas","year":"2015","unstructured":"Habbas, S. et al. Neuroinflammatory TNF?? Impairs Memory via Astrocyte Signaling. Cell \n                           163, 1730\u20131741 (2015).","journal-title":"Cell"},{"key":"7640_CR24","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s00424-005-1399-1","volume":"450","author":"LM Holm","year":"2005","unstructured":"Holm, L. M. et al. NH3 and NH4\u2009+\u2009permeability in aquaporin-expressing Xenopus oocytes. Pflugers Arch. Eur. J. Physiol. \n                           450, 415\u2013428 (2005).","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"7640_CR25","doi-asserted-by":"publisher","first-page":"5296","DOI":"10.1074\/jbc.M609343200","volume":"282","author":"SM Saparov","year":"2007","unstructured":"Saparov, S. M., Liu, K., Agre, P. & Pohl, P. Fast and selective ammonia transport by aquaporin-8. J. Biol. Chem. \n                           282, 5296\u20135301 (2007).","journal-title":"J. Biol. Chem."},{"key":"7640_CR26","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1097\/00001756-200312190-00018","volume":"14","author":"KV Rama Rao","year":"2003","unstructured":"Rama Rao, K. V., Chen, M., Simard, J. M. & Norenberg, M. D. Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport \n                           14, 2379\u201382 (2003).","journal-title":"Neuroreport"},{"key":"7640_CR27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/72256","volume":"6","author":"GT Manley","year":"2000","unstructured":"Manley, G. T. et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat. Med. \n                           6, 159\u2013163 (2000).","journal-title":"Nat. Med."},{"key":"7640_CR28","doi-asserted-by":"crossref","unstructured":"Cooper, A. J. & Jeitner, T. M. Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain. Biomolecules \n                           6, (2016).","DOI":"10.3390\/biom6020016"},{"key":"7640_CR29","first-page":"31","volume":"7","author":"AR Jayakumar","year":"2012","unstructured":"Jayakumar, A. R. et al. The Na-K-Cl Co-transporter in astrocyte swelling. J. Neurochem. \n                           7, 31\u20138 (2012).","journal-title":"J. Neurochem."},{"key":"7640_CR30","doi-asserted-by":"crossref","first-page":"C883","DOI":"10.1152\/ajpcell.1998.274.4.C883","volume":"274","author":"TN Nagaraja","year":"1998","unstructured":"Nagaraja, T. N. & Brookes, N. Intracellular acidification induced by passive and active transport of ammonium ions in astrocytes. Am. J. Physiol. \n                           274, C883\u201391 (1998).","journal-title":"Am. J. Physiol."},{"key":"7640_CR31","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1002\/hep.20820","volume":"42","author":"B Gorg","year":"2005","unstructured":"Gorg, B., Wettstein, M., Metzger, S., Schliess, F. & Haussinger, D. LPS-induced tyrosine nitration of hepatic glutamine synthetase. Hepatology (Baltimore, Md.) \n                           42, 499 (2005).","journal-title":"Hepatology (Baltimore, Md.)"},{"key":"7640_CR32","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.jhep.2015.08.018","volume":"64","author":"FS Larsen","year":"2016","unstructured":"Larsen, F. S. et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J. Hepatol. \n                           64, 69\u201378 (2016).","journal-title":"J. Hepatol."},{"key":"7640_CR33","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.jhep.2016.03.003","volume":"65","author":"W Bernal","year":"2016","unstructured":"Bernal, W. et al. A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. J. Hepatol. \n                           65, 273\u2013279 (2016).","journal-title":"J. Hepatol."},{"key":"7640_CR34","doi-asserted-by":"publisher","first-page":"21362","DOI":"10.1074\/jbc.M600504200","volume":"281","author":"H Takeuchi","year":"2006","unstructured":"Takeuchi, H. et al. Tumor necrosis factor-a induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J. Biol. Chem. \n                           281, 21362\u201321368 (2006).","journal-title":"J. Biol. Chem."},{"key":"7640_CR35","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1186\/s12974-016-0708-2","volume":"13","author":"IA Clark","year":"2016","unstructured":"Clark, I. A. et al. Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents. J. Neuroinflammation \n                           13, 236 (2016).","journal-title":"J. Neuroinflammation"},{"key":"7640_CR36","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/0014-5793(92)80404-5","volume":"296","author":"G Marcaida","year":"1992","unstructured":"Marcaida, G., Felipo, V., Hermenegildo, C., Mi\u00f1ana, M. D. & Grisolia, S. Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett. \n                           296, 67\u201368 (1992).","journal-title":"FEBS Lett."},{"key":"7640_CR37","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1007\/BF02532401","volume":"21","author":"C Hermenegildo","year":"1996","unstructured":"Hermenegildo, C. et al. NMDA Receptor antagonists prevent acute ammonia toxicity in mice. Neurochem. Res. \n                           21, 1237\u20131244 (1996).","journal-title":"Neurochem. Res."},{"key":"7640_CR38","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/S0197-0186(00)00027-9","volume":"37","author":"P Monfort","year":"2000","unstructured":"Monfort, P., Montoliu, C., Hermenegildo, C., Munoz, M. & Felipo, V. Differential effects of acute and chronic hyperammonemia on signal transduction pathways associated to NMDA receptors. Neurochem. Int. \n                           37, 249\u2013253 (2000).","journal-title":"Neurochem. Int."},{"key":"7640_CR39","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1002\/hep.510310322","volume":"31","author":"C Hermenegildo","year":"2000","unstructured":"Hermenegildo, C., Monfort, P. & Felipo, V. Activation of N-methyl-D-aspartate receptors in rat brain in vivo following acute ammonia intoxication: characterization by in vivo brain microdialysis. Hepatology \n                           31, 709\u2013715 (2000).","journal-title":"Hepatology"},{"key":"7640_CR40","first-page":"675","volume":"19","author":"V Felipo","year":"1998","unstructured":"Felipo, V., Hermenegildo, C., Montoliu, C., Llansola, M. & Minana, M. D. Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. Neurotoxicology \n                           19, 675\u201381 (1998).","journal-title":"Neurotoxicology"},{"key":"7640_CR41","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1111\/j.1471-4159.2006.04330.x","volume":"100","author":"JH Jara","year":"2007","unstructured":"Jara, J. H., Singh, B. B., Floden, A. M. & Combs, C. K. Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death. J. Neurochem. \n                           100, 1407\u20131420 (2007).","journal-title":"J. Neurochem."},{"key":"7640_CR42","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1002\/hep.1840100310","volume":"10","author":"I Azorin","year":"1989","unstructured":"Azorin, I., Minana, M. \u202fD., Felipo, V. & Grisolia, S. A simple animal model of hyperammonemia. Hepatology \n                           10, 311\u2013314 (1989).","journal-title":"Hepatology"},{"key":"7640_CR43","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/S0006-291X(88)81324-X","volume":"153","author":"MD Minana","year":"1988","unstructured":"Minana, M. D., Felipo, V. & Grisolia, S. Protective effect of long term ammonium ingestion against acute ammonium intoxication. Biochem. Biophys. Res. Commun. \n                           153, 979\u2013983 (1988).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"7640_CR44","doi-asserted-by":"publisher","first-page":"3201","DOI":"10.1046\/j.1460-9568.1998.00329.x","volume":"10","author":"C Hermenegildo","year":"1998","unstructured":"Hermenegildo, C. Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur. J. Neurosci. \n                           10, 3201\u20133209 (1998).","journal-title":"Eur. J. Neurosci."},{"key":"7640_CR45","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1186\/s12974-016-0710-8","volume":"13","author":"S Dadsetan","year":"2016","unstructured":"Dadsetan, S. et al. Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy. J Neuroinflammation \n                           13, 245 (2016).","journal-title":"J Neuroinflammation"},{"key":"7640_CR46","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s12974-016-0549-z","volume":"13","author":"V Hernandez-Rabaza","year":"2016","unstructured":"Hernandez-Rabaza, V. et al. Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia. J. Neuroinflammation \n                           13, 83 (2016).","journal-title":"J. Neuroinflammation"},{"key":"7640_CR47","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s12974-016-0505-y","volume":"13","author":"V Hern\u00e1ndez-Rabaza","year":"2016","unstructured":"Hern\u00e1ndez-Rabaza, V. et al. Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane. J. Neuroinflammation \n                           13, 41 (2016).","journal-title":"J. Neuroinflammation"},{"key":"7640_CR48","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.bbi.2016.05.011","volume":"57","author":"A Cabrera-Pastor","year":"2016","unstructured":"Cabrera-Pastor, A. et al. In vivo administration of extracellular cGMP normalizes TNF-alpha and membrane expression of AMPA receptors in hippocampus and spatial reference memory but not IL-1beta, NMDA receptors in membrane and working memory in hyperammonemic rats. Brain. Behav. Immun. \n                           57, 360\u2013370 (2016).","journal-title":"Brain. Behav. Immun."},{"key":"7640_CR49","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/j.neuint.2011.07.014","volume":"59","author":"RF Butterworth","year":"2011","unstructured":"Butterworth, R. F. Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets. Neurochem. Int. \n                           59, 830\u2013836 (2011).","journal-title":"Neurochem. Int."},{"key":"7640_CR50","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1002\/hep.24326","volume":"54","author":"I Zemtsova","year":"2011","unstructured":"Zemtsova, I. et al. Microglia activation in hepatic encephalopathy in rats and humans. Hepatology \n                           54, 204\u201315 (2011).","journal-title":"Hepatology"},{"key":"7640_CR51","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1053\/j.gastro.2010.03.040","volume":"139","author":"R Rodrigo","year":"2010","unstructured":"Rodrigo, R. et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology \n                           139, 675\u2013684 (2010).","journal-title":"Gastroenterology"},{"key":"7640_CR52","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1002\/hep.26265","volume":"57","author":"B G\u00f6rg","year":"2013","unstructured":"G\u00f6rg, B., Bidmon, H.-J. & H\u00e4ussinger, D. Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy. Hepatology \n                           57, 2436\u201347 (2013).","journal-title":"Hepatology"},{"key":"7640_CR53","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1002\/hep.23367","volume":"51","author":"DL Shawcross","year":"2010","unstructured":"Shawcross, D. L., Shabbir, S. S., Taylor, N. J. & Hughes, R. D. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology \n                           51, 1062\u20131069 (2010).","journal-title":"Hepatology"},{"key":"7640_CR54","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1097\/CCM.0000000000001309","volume":"44","author":"GK Manakkat Vijay","year":"2016","unstructured":"Manakkat Vijay, G. K. et al. Neutrophil Toll-Like Receptor 9 Expression and the Systemic Inflammatory Response in Acetaminophen-Induced Acute Liver Failure. Crit. Care Med. \n                           44, 43\u201353 (2016).","journal-title":"Crit. Care Med."},{"key":"7640_CR55","doi-asserted-by":"publisher","first-page":"4748","DOI":"10.1128\/JVI.02976-14","volume":"89","author":"HC Xu","year":"2015","unstructured":"Xu, H. C. et al. Deficiency of the B cell-activating factor receptor results in limited CD169\u2009+\u2009macrophage function during viral infection. J. Virol. \n                           89, 4748\u20134759 (2015).","journal-title":"J. Virol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07640-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07640-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07640-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T08:23:53Z","timestamp":1671783833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-07640-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,11]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["7640"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-07640-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,11]]},"assertion":[{"value":"13 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 June 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7938"}}