Differences in Kynurenine Metabolism During Depressive, Manic, and Euthymic Phases of Bipolar Affective Disorder

Author(s): Alexander Maget, Martina Platzer*, Susanne A. Bengesser, Frederike T. Fellendorf, Armin Birner, Robert Queissner, Carlo Hamm, Bernd Reininghaus, Andrzej Hecker, Lukas Tomberger, Renè Pilz, Nina Dalkner, Natalie Moll, Gregor Schütze, Markus Schwarz, Hans P. Kapfhammer, Eva Z. Reininghaus

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 15 , 2020

DOI : 10.2174/1568026619666190802145128

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Abstract:

Background & Objective: The kynurenine pathway is involved in inflammatory diseases. Alterations of this pathway were shown in psychiatric entities as well. The aim of this study was to determine whether specific changes in kynurenine metabolism are associated with current mood symptoms in bipolar disorder.

Methods: Sum scores of the Hamilton Depression Scale, Beck Depression Inventory, and Young Mania Rating Scale were collected from 156 bipolar individuals to build groups of depressive, manic and euthymic subjects according to predefined cut-off scores. Severity of current mood symptoms was correlated with activities of the enzymes kynurenine 3-monooxygenase (ratio of 3-hydroxykynurenine/ kynurenine), kynurenine aminotransferase (ratio of kynurenic acid/ kynurenine) and kynureninase (ratio of 3-hydroxyanthranilic acid/ 3-hydroxykynurenine), proxied by ratios of serum concentrations.

Results: Individuals with manic symptoms showed a shift towards higher kynurenine 3-monooxygenase activity (χ2 = 7.14, Df = 2, p = .028), compared to euthymic as well as depressed individuals. There were no differences between groups regarding activity of kynurenine aminotransferase and kynureninase. Within the group of depressed patients, Hamilton Depression Scale and kynurenine aminotransferase showed a significant negative correlation (r = -0.41, p = .036), displaying lower metabolism in the direction of kynurenic acid.

Discussion: Depression severity in bipolar disorder seems to be associated with a decreased synthesis of putative neuroprotective kynurenic acid. Furthermore, higher kynurenine 3-monooxygenase activity in currently manic individuals indicates an increased inflammatory state within bipolar disorder with more severe inflammation during manic episodes. The underlying pathophysiological mechanisms of the different affective episodes could represent parallel mechanisms rather than opposed processes.

Keywords: Bipolar disorder, Kynurenine, Pteridines, Inflammation, Mood, Depression, Mania.

[1]
Pfennig, A.; Bschor, T.; Baghai, T.; Bräunig, P.; Brieger, P.; Falkai, P.; Geissler, D.; Gielen, R.; Giesler, H.; Gruber, O.; Kopp, I.; Meyer, T.D.; Möhrmann, K.H.; Muche-Borowski, C.; Padberg, F.; Scherk, H.; Strech, D.; Bauer, M. S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen: Entwicklungsprozess und wesentliche Empfehlungen. Nervenarzt, 2012, 83(5), 568-586.
[http://dx.doi.org/10.1007/s00115-011-3415-3] [PMID: 22576049]
[2]
Wittchen, H.U.; Hoyer, J., Eds.; Klinische Psychologie & Psychotherapie (Lehrbuch mit Online-Materialien), 2nd ed; Springer: Heidelberg, 2011. [http://10.1007/978-3-642-13018-2]
[3]
Panaccione, I.; Spalletta, G.; Sani, G. Neuroinflammation and excitatory symptoms in bipolar disorder. Neuroimmunol. Neuroinflamm., 2015, 2, 215-227. [http://10.4103/2347-8659.167304].
[4]
Munkholm, K.; Braüner, J.V.; Kessing, L.V.; Vinberg, M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J. Psychiatr. Res., 2013, 47(9), 1119-1133.
[http://dx.doi.org/10.1016/j.jpsychires.2013.05.018] [PMID: 23768870]
[5]
Ortiz-Domínguez, A.; Hernández, M.E.; Berlanga, C.; Gutiérrez-Mora, D.; Moreno, J.; Heinze, G.; Pavón, L. Immune variations in bipolar disorder: phasic differences. Bipolar Disord., 2007, 9(6), 596-602.
[http://dx.doi.org/10.1111/j.1399-5618.2007.00493.x] [PMID: 17845274]
[6]
Michelhaugh, S.K.; Guastella, A.R.; Mittal, S. Overview of the kynurenine pathway of tryptophan metabolism. In: Targeting the Broadly Pathogenic Kynurenine Pathway Cham; Mittal, S., Ed.; Springer, 2015, pp. 3-9. [http://10.1007/978-3-319-11870-3_1]
[7]
Badawy, A.A. Tryptophan metabolism in health and disease.Targeting the Broadly Pathogenic Kynurenine Pathway Cham; Mittal, S., Ed.; Springer, 2015, pp. 11-30. [http://10.1007/978-3-319-11870-3_2]
[8]
Dantzer, R.; O’Connor, J.C.; Lawson, M.A.; Kelley, K.W. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology, 2011, 36(3), 426-436.
[http://dx.doi.org/10.1016/j.psyneuen.2010.09.012] [PMID: 21041030]
[9]
Birner, A.; Platzer, M.; Bengesser, S.A.; Dalkner, N.; Fellendorf, F.T.; Queissner, R.; Pilz, R.; Rauch, P.; Maget, A.; Hamm, C.; Herzog-Eberhard, S.; Mangge, H.; Fuchs, D.; Moll, N.; Zelzer, S.; Schütze, G.; Schwarz, M.; Reininghaus, B.; Kapfhammer, H.; Reininghaus, E.Z. Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder. PLoS One, 2017, 12(2), e0172699
[10]
Campbell, B.M.; Charych, E.; Lee, A.W.; Möller, T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front. Neurosci., 2014, 8, 12.
[http://dx.doi.org/10.3389/fnins.2014.00012] [PMID: 24567701]
[11]
Campbell, B.; Pocivavsek, A.; Notarangelo, F.; Parachikova, A. The role of kynurenine pathway metabolites in neuropsychiatric disorders.Targeting the Broadly Pathogenic Kynurenine Pathway Cham; Mittal, S., Ed.; Springer, 2015, pp. 241-254. [http://10.1007/978-3-319-11870-3_19]
[12]
Lau, A.; Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch., 2010, 460(2), 525-542.
[http://dx.doi.org/10.1007/s00424-010-0809-1] [PMID: 20229265]
[13]
Zádori, D.; Nyiri, G.; Szonyi, A.; Szatmári, I.; Fülöp, F.; Toldi, J.; Freund, T.F.; Vécsei, L.; Klivényi, P. Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. J. Neural Transm. (Vienna), 2011, 118(6), 865-875.
[http://dx.doi.org/10.1007/s00702-010-0573-6] [PMID: 21194001]
[14]
Reininghaus, E.Z.; McIntyre, R.S.; Reininghaus, B.; Geisler, S.; Bengesser, S.A.; Lackner, N.; Hecht, K.; Birner, A.; Kattnig, F.; Unterweger, R.; Kapfhammer, H.P.; Zelzer, S.; Fuchs, D.; Mangge, H. Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report. Bipolar Disord., 2014, 16(4), 432-440.
[http://dx.doi.org/10.1111/bdi.12166] [PMID: 24330408]
[15]
Platzer, M.; Dalkner, N.; Fellendorf, F.T.; Birner, A.; Bengesser, S.A.; Queissner, R.; Kainzbauer, N.; Pilz, R.; Herzog-Eberhard, S.; Hamm, C.; Hörmanseder, C.; Maget, A.; Rauch, P.; Mangge, H.; Fuchs, D.; Zelzer, S.; Schütze, G.; Moll, N.; Schwarz, M.J.; Mansur, R.B.; McIntyre, R.S.; Reininghaus, E.Z. Tryptophan breakdown and cognition in bipolar disorder. Psychoneuroendocrinology, 2017, 81, 144-150.
[http://dx.doi.org/10.1016/j.psyneuen.2017.04.015] [PMID: 28482311]
[16]
Majlath, Z.; Toldi, J.; Vecsei, L. The role of the kynurenine pathway in neurodegenerative diseases.Targeting the Broadly Pathogenic Kynurenine Pathway Cham; Mittal, S., Ed.; Springer, 2015, pp. 193-204.
[http://dx.doi.org/10.1007/978-3-319-11870-3_15]
[17]
Thomas, S.R.; Stocker, R. Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Rep., 1999, 4(5), 199-220.
[http://dx.doi.org/10.1179/135100099101534927] [PMID: 10731095]
[18]
Kim, J.P.; Choi, D.W. Quinolinate neurotoxicity in cortical cell culture. Neuroscience, 1987, 23(2), 423-432.
[http://dx.doi.org/10.1016/0306-4522(87)90066-2] [PMID: 2963969]
[19]
Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry, 2009, 65(9), 732-741.
[http://dx.doi.org/10.1016/j.biopsych.2008.11.029] [PMID: 19150053]
[20]
Reininghaus, E.Z.; Lackner, N.; Fellendorf, F.T.; Bengesser, S.; Birner, A.; Reininghaus, B.; Unterweger, R.; Platzer, M.; Wallner-Liebmann, S.J.; Zelzer, S.; Mangge, H.; Fuchs, D.; Kapfhammer, H.P.; McIntyre, R.S. Weight cycling in bipolar disorder. J. Affect. Disord., 2015, 171, 33-38.
[http://dx.doi.org/10.1016/j.jad.2014.09.006] [PMID: 25443762]
[21]
Lackner, N.; Bengesser, S.A.; Birner, A.; Painold, A.; Fellendorf, F.T.; Platzer, M.; Reininghaus, B.; Weiss, E.M.; Mangge, H.; McIntyre, R.S.; Fuchs, D.; Kapfhammer, H.P.; Wallner-Liebmann, S.; Reininghaus, E.Z. Abdominal obesity is associated with impaired cognitive function in euthymic bipolar individuals. J. Affect. Disord., 2016, 17(7), 535-546.
[http://dx.doi.org/10.3109/15622975.2015.1046917] [PMID: 26068130]
[22]
Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry, 1960, 23, 56-62.
[http://dx.doi.org/10.1136/jnnp.23.1.56] [PMID: 14399272]
[23]
Young, R.C.; Biggs, J.T.; Ziegler, V.E.; Meyer, D.A. A rating scale for mania: reliability, validity and sensitivity. Br. J. Psychiatry, 1978, 133, 429-435.
[http://dx.doi.org/10.1192/bjp.133.5.429] [PMID: 728692]
[24]
Beck, A.T.; Ward, C.H.; Mendelson, M.; Mock, J.; Erbaugh, J. An inventory for measuring depression. Arch. Gen. Psychiatry, 1961, 4, 561-571.
[http://dx.doi.org/10.1001/archpsyc.1961.01710120031004] [PMID: 13688369]
[25]
Connor, T.J.; Starr, N.; O’Sullivan, J.B.; Harkin, A. Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-gamma? Neurosci. Lett., 2008, 441(1), 29-34.
[http://dx.doi.org/10.1016/j.neulet.2008.06.007] [PMID: 18584961]
[26]
Molteni, R.; Macchi, F.; Zecchillo, C.; Dell’agli, M.; Colombo, E.; Calabrese, F.; Guidotti, G.; Racagni, G.; Riva, M.A. Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine. Eur. Neuropsychopharmacol., 2013, 23(11), 1645-1655.
[http://dx.doi.org/10.1016/j.euroneuro.2013.03.008] [PMID: 23622958]
[27]
Zunszain, P.A.; Anacker, C.; Cattaneo, A.; Choudhury, S.; Musaelyan, K.; Myint, A.M.; Thuret, S.; Price, J.; Pariante, C.M. Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology, 2012, 37(4), 939-949.
[http://dx.doi.org/10.1038/npp.2011.277] [PMID: 22071871]
[28]
Johansson, A; Owe-Larsson, B; Asp, L; Kocki, T; Adler, M; Hetta, J; Gardner, R; Lundkvist, GBS; Urbanska, EM; Karlsson, H Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: Cytokine challenge increases production of 3-hydroxykynurenine J. Psychiatr. Res., 2013, 47(11), 1815-1823.
[http://dx.doi.org/10.1016/j.jpsychires.2013.08.008] [PMID: 24012176]
[29]
Schwieler, L.; Erhardt, S.; Nilsson, L.; Linderholm, K.; Engberg, G. Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons--possible involvement of endogenous kynurenic acid. Synapse, 2006, 59(5), 290-298.
[http://dx.doi.org/10.1002/syn.20241] [PMID: 16416446]
[30]
Bender, D.A. Biochemistry of tryptophan in health and disease. Mol. Aspects Med., 1983, 6(2), 101-197.
[http://dx.doi.org/10.1016/0098-2997(83)90005-5] [PMID: 6371429]
[31]
Lavebratt, C.; Olsson, S.; Backlund, L.; Frisén, L.; Sellgren, C.; Priebe, L.; Nikamo, P.; Träskman-Bendz, L.; Cichon, S.; Vawter, M.P.; Osby, U.; Engberg, G.; Landén, M.; Erhardt, S.; Schalling, M. The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. Mol. Psychiatry, 2014, 19(3), 334-341.
[http://dx.doi.org/10.1038/mp.2013.11] [PMID: 23459468]
[32]
Brietzke, E.; Stertz, L.; Fernandes, B.S.; Kauer-Sant’anna, M.; Mascarenhas, M.; Escosteguy Vargas, A.; Chies, J.A.; Kapczinski, F. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J. Affect. Disord., 2009, 116(3), 214-217.
[http://dx.doi.org/10.1016/j.jad.2008.12.001] [PMID: 19251324]
[33]
Kim, Y.K.; Jung, H.G.; Myint, A.M.; Kim, H.; Park, S.H. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J. Affect. Disord., 2007, 104(1-3), 91-95.
[http://dx.doi.org/10.1016/j.jad.2007.02.018] [PMID: 17434599]
[34]
Wurfel, B.E.; Drevets, W.C.; Bliss, S.A.; McMillin, J.R.; Suzuki, H.; Ford, B.N.; Morris, H.M.; Teague, T.K.; Dantzer, R.; Savitz, J.B. Serum kynurenic acid is reduced in affective psychosis. Transl. Psychiatry, 2017, 7(5), e1115
[http://dx.doi.org/10.1038/tp.2017.88]
[35]
Linderholm, K.R.; Skogh, E.; Olsson, S.K.; Dahl, M.L.; Holtze, M.; Engberg, G.; Samuelsson, M.; Erhardt, S. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr. Bull., 2012, 38(3), 426-432.
[http://dx.doi.org/10.1093/schbul/sbq086] [PMID: 20729465]
[36]
Olsson, S.K.; Samuelsson, M.; Saetre, P.; Lindström, L.; Jönsson, E.G.; Nordin, C.; Engberg, G.; Erhardt, S.; Landén, M. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J. Psychiatry Neurosci., 2010, 35(3), 195-199.
[PMID: 20420770]
[37]
Smarr, K.L.; Keefer, A.L. Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care Res. (Hoboken), 2011, 63(S11)(Suppl. 11), S454-S466.
[http://dx.doi.org/10.1002/acr.20556] [PMID: 22588766]
[38]
Savitz, J.; Dantzer, R.; Wurfel, B.E.; Victor, T.A.; Ford, B.N.; Bodurka, J.; Bellgowan, P.S.F.; Teague, T.K.; Drevets, W.C. Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology, 2015, 52, 200-211.
[http://dx.doi.org/10.1016/j.psyneuen.2014.11.015]
[39]
Bay-Richter, C.; Linderholm, K.R.; Lim, C.K.; Samuelsson, M.; Träskman-Bendz, L.; Guillemin, G.J.; Erhardt, S.; Brundin, L. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav. Immun., 2015, 43, 110-117.
[http://dx.doi.org/10.1016/j.bbi.2014.07.012] [PMID: 25124710]
[40]
Guillemin, G.J.; Wang, L.; Brew, B.J. Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex. J. Neuroinflammation, 2005, 2, 16.
[http://dx.doi.org/10.1186/1742-2094-2-16] [PMID: 16042813]
[41]
Mahlknecht, P. Bipolare Störungen - Erkrankungen. Facharzt Neurologie/Psychiatrie, 2013, 2013(2+3), 8-10.
[42]
Gostner, J.; Becker, K.; Sperner-Unterweger, B.; Überall, F.; Fuchs, D.; Strasser, B. Role of tryptophan metabolism in mood, behavior, and cognition.Targeting the Broadly Pathogenic Kynurenine Pathway Cham; Mittal, S., Ed.; Springer: Berlin, 2015, pp. 75-89.
[http://dx.doi.org/10.1007/978-3-319-11870-3_6]
[43]
Pardridge, W.M. Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem. Res., 1998, 23(5), 635-644.
[http://dx.doi.org/10.1023/A:1022482604276] [PMID: 9566601]
[44]
Fukui, S.; Schwarcz, R.; Rapoport, S.I.; Takada, Y.; Smith, Q.R. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J. Neurochem., 1991, 56(6), 2007-2017.
[http://dx.doi.org/10.1111/j.1471-4159.1991.tb03460.x] [PMID: 1827495]
[45]
Anderson, G.; Maes, M. Bipolar disorder: role of immune-inflammatory cytokines, oxidative and nitrosative stress and tryptophan catabolites. Curr. Psychiatry Rep., 2015, 17(2)
[http://dx.doi.org/10.1007/s11920-014-0541-1]
[46]
Raison, C.L.; Dantzer, R.; Kelley, K.W.; Lawson, M.A.; Woolwine, B.J.; Vogt, G.; Spivey, J.R.; Saito, K.; Miller, A.H. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol. Psychiatry, 2010, 15(4), 393-403.
[http://dx.doi.org/10.1038/mp.2009.116] [PMID: 19918244]
[47]
Capuron, L.; Schroecksnadel, S.; Féart, C.; Aubert, A.; Higueret, D.; Barberger-Gateau, P.; Layé, S.; Fuchs, D. Chronic low grade immune activation in the elderly is associated with increased tryptophan catabolism and altered phenylalanine turnover: role in neuropsychiatric symptomatology. Biol Psych, 2011, 70, 175-182.
[http://dx.doi.org/10.1016/j.biopsych.2010.12.006]
[48]
Capuron, L.; Geisler, S.; Kurz, K.; Leblhuber, F.; Sperner-Unterweger, B.; Fuchs, D. Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism. Curr. Pharm. Des., 2014, 20(38), 6048-6057.
[http://dx.doi.org/10.2174/1381612820666140317110217] [PMID: 24641220]
[49]
Oxenkrug, G.F. Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism. Ann. N. Y. Acad. Sci., 2010, 1199(1), 1-14.
[http://dx.doi.org/10.1111/j.1749-6632.2009.05356.x] [PMID: 20633104]
[50]
Myint, A.M. Kynurenines: from the perspective of major psychiatric disorders. FEBS J., 2012, 279(8), 1375-1385.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08551.x] [PMID: 22404766]
[51]
Chen, Y.; Guillemin, G.J. Kynurenine pathway metabolites in humans: disease and healthy States. Int. J. Tryptophan Res., 2009, 2(2), 1-19.
[http://dx.doi.org/10.4137/IJTR.S2097] [PMID: 22084578]
[52]
Myint, A.M.; Schwarz, M.J.; Verkerk, R.; Mueller, H.H.; Zach, J.; Scharpé, S.; Steinbusch, H.W.M.; Leonard, B.E.; Kim, Y.K. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain Behav. Immun., 2011, 25(8), 1576-1581.
[http://dx.doi.org/10.1016/j.bbi.2011.05.005] [PMID: 21620952]
[53]
Huengsberg, M.; Winer, J.B.; Gompels, M.; Round, R.; Ross, J.; Shahmanesh, M. Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clin. Chem., 1998, 44(4), 858.
[PMID: 9554499]
[54]
Clarke, G.; Fitzgerald, P.; Cryan, J.F.; Cassidy, E.M.; Quigley, E.M.; Dinan, T.G. Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterol., 2009, 9(1), 6.
[http://dx.doi.org/10.1186/1471-230X-9-6]
[55]
McIntyre, R.S.; Danilewitz, M.; Liauw, S.S.; Kemp, D.E.; Nguyen, H.T.; Kahn, L.S.; Kucyi, A.; Soczynska, J.K.; Woldeyohannes, H.O.; Lachowski, A.; Kim, B.; Nathanson, J.; Alsuwaidan, M.; Taylor, V.H. Bipolar disorder and metabolic syndrome: an international perspective. J. Affect. Disord., 2010, 126(3), 366-387.
[http://dx.doi.org/10.1016/j.jad.2010.04.012] [PMID: 20541810]
[56]
Barbini, B.; Bertelli, S.; Colombo, C.; Smeraldi, E. Sleep loss, a possible factor in augmenting manic episode. Psychiatry Res., 1996, 65(2), 121-125.
[http://dx.doi.org/10.1016/S0165-1781(96)02909-5] [PMID: 9122286]
[57]
Anderson, G.; Jacob, A.; Bellivier, F.; Geoffroy, P.A. Bipolar disorder: The role of the kynurenine and melatonergic pathways. Curr. Pharm. Des., 2016, 22(8), 987-1012.
[http://dx.doi.org/10.2174/1381612822666151214105314] [PMID: 26654772]


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VOLUME: 20
ISSUE: 15
Year: 2020
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DOI: 10.2174/1568026619666190802145128
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