{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:09:08Z","timestamp":1792804148773,"version":"4.5.0"},"reference-count":84,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,7]],"date-time":"2022-05-07T00:00:00Z","timestamp":1651881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AMERI-ASIA MED CO, Ltd","id":[{"id":"https:\/\/ror.org\/04663jx74","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Islamic University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Adverse childhood experiences (ACEs) enhance pro-inflammatory and pro-oxidant responses. In affective disorders, recent precision nomothetic psychiatry studies disclosed new pathway phenotypes, including an ROI\u2014reoccurrence of illness (ROI)\u2014oxidative stress latent construct. The aim of the present study is to delineate a) whether ACEs sensitize the M1 macrophage, the T helper cells (Th)1, Th2, and Th17, the IRS (immune-inflammatory-responses system), the CIRS (compensatory immunoregulatory system), and the neuroimmunotoxic and growth factor (GF) profiles and whether they are associated with ROI and the phenome of affective disorders and b) the molecular pathways underpinning the effects of the ACEs. We collected supernatants of stimulated (5 \u03bcg\/mL of PHA and 25 \u03bcg\/mL of LPS) and unstimulated diluted whole blood in 20 healthy controls and 30 depressed patients and measured a panel of 27 cytokines\/GF using a Luminex method. ACEs (comprising mental and physical trauma, mental neglect, domestic violence, family history of mental disease, and parent loss) are accompanied by the increased stimulated, but not unstimulated, production of M1, Th1, Th2, Th17, IRS, neuroimmunotoxic, and GF profiles and are strongly correlated with ROI and the phenome. A latent vector extracted from the ROI features (recurrent episodes and suicidal behaviors) and the IRS\/neuroimmunotoxic\/GF profiles explains 66.8% of the variance in the phenome and completely mediates the effects of ACEs on the phenome. Enrichment analysis showed that the ACE-associated sensitization of immune\/GF profiles involves JAK-STAT, nuclear factor-\u03baB, tumor necrosis factor-\u03b1, G-protein coupled receptor, PI3K\/Akt\/RAS\/MAPK, and hypoxia signaling. In summary, the ACE-induced sensitization of immune pathways and secondary immune hits predicts the phenome of affective disorders.<\/jats:p>","DOI":"10.3390\/cells11091564","type":"journal-article","created":{"date-parts":[[2022,5,7]],"date-time":"2022-05-07T03:04:10Z","timestamp":1651892650000},"page":"1564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Adverse Childhood Experiences Predict the Phenome of Affective Disorders and These Effects Are Mediated by Staging, Neuroimmunotoxic and Growth Factor Profiles"],"prefix":"10.3390","volume":"11","author":[{"given":"Michael","family":"Maes","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University and The Thai Red Cross Society, Bangkok 10330, Thailand"},{"name":"IMPACT Strategic Research Center, Barwon Health, Geelong 3220, Australia"},{"name":"Department of Psychiatry, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muanpetch","family":"Rachayon","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University and The Thai Red Cross Society, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ketsupar","family":"Jirakran","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University and The Thai Red Cross Society, Bangkok 10330, Thailand"},{"name":"Maximizing Thai Children\u2019s Developmental Potential Research Unit, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pimpayao","family":"Sodsai","sequence":"additional","affiliation":[{"name":"Center of Excellence in Immunology and Immune-Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Division of Immunology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siriwan","family":"Klinchanhom","sequence":"additional","affiliation":[{"name":"Center of Excellence in Immunology and Immune-Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Division of Immunology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5843-072X","authenticated-orcid":false,"given":"Monojit","family":"Debnath","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore 560 029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3109-0040","authenticated-orcid":false,"given":"Agnieska","family":"Basta-Kaim","sequence":"additional","affiliation":[{"name":"Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4401-5055","authenticated-orcid":false,"given":"Marta","family":"Kubera","sequence":"additional","affiliation":[{"name":"Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-6731","authenticated-orcid":false,"given":"Abbas F.","family":"Almulla","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University and The Thai Red Cross Society, Bangkok 10330, Thailand"},{"name":"Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf 54001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atapol","family":"Sughondhabirom","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University and The Thai Red Cross Society, Bangkok 10330, 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Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s11011-020-00656-6","article-title":"Towards a new model and classification of mood disorders based on risk resilience, neuro-affective toxicity, staging, and phenome features using the nomothetic network psychiatry approach","volume":"36","author":"Maes","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Maes, M. (2022). Precision Nomothetic Medicine in Depression Research: A New Depression Model, and New Endophenotype Classes and Pathway Phenotypes, and A Digital Self. J. Pers. Med., 12.","DOI":"10.3390\/jpm12030403"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S2215-0366(15)00544-1","article-title":"Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: A systematic review and meta-analysis","volume":"3","author":"Danese","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/acps.12551","article-title":"Childhood trauma, family history, and their association with mood disorders in early adulthood","volume":"134","author":"Jansen","year":"2016","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.comppsych.2012.06.009","article-title":"High prevalence of childhood trauma in patients with schizophrenia spectrum and affective disorder","volume":"54","author":"Larsson","year":"2013","journal-title":"Compr. Psychiatry."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jad.2011.11.019","article-title":"Suicide and history of childhood trauma among street youth","volume":"136","author":"Hadland","year":"2012","journal-title":"J. Affect Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/j.1600-0447.2005.00647.x","article-title":"Family history of suicide, female sex, and childhood trauma: Separate or interacting risk factors for attempts at suicide?","volume":"112","author":"Roy","year":"2005","journal-title":"Acta. Psychiatr. Scand."},{"key":"ref_9","unstructured":"Krug, E.G., Dahlberg, L.L., Mercy, J., Zwi, A., and Lozano, R. (2002). Child abuse and neglect by parents and other caregivers. World Report on Violence and Health, World Health Organization. Available online: https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/42495\/9241545615_eng.pdf;jsessionid=785F7033A37D18F473DDA7ABE0DC0F9C?sequence=1."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/NMD.0b013e31820c751c","article-title":"Prevalence and clinical impact of childhood trauma in patients with severe mental disorders","volume":"199","author":"Alvarez","year":"2011","journal-title":"J. Nerv. Ment. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1017\/S0033291716003081","article-title":"Affective lability mediates the association between childhood trauma and suicide attempts, mixed episodes and co-morbid anxiety disorders in bipolar disorders","volume":"47","author":"Aas","year":"2017","journal-title":"Psychol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"514","DOI":"10.2174\/1871527316666170407151514","article-title":"Elevated C-reactive Protein Levels in Women with Bipolar Disorder may be Explained by a History of Childhood Trauma, Especially Sexual Abuse, Body Mass Index and Age","volume":"16","author":"Moraes","year":"2017","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jad.2014.12.055","article-title":"Childhood traumatic experiences of patients with bipolar disorder type I and type II","volume":"175","author":"Janiri","year":"2015","journal-title":"J. Affect Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1080\/10538711003615038","article-title":"The clinical correlates of reported childhood sexual abuse: An association between age at trauma onset and severity of depression and PTSD in adults","volume":"19","author":"Schoedl","year":"2010","journal-title":"J. Child Sex Abus"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jad.2015.12.055","article-title":"The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies","volume":"193","author":"Marangoni","year":"2016","journal-title":"J. Affect Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/S2215-0366(15)00055-3","article-title":"Bullying victimisation and risk of psychotic phenomena: Analyses of British national survey data","volume":"2","author":"Catone","year":"2015","journal-title":"Lancet Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jad.2021.12.103","article-title":"Childhood trauma history is linked to abnormal brain metabolism of non-medicated adult patients with major depressive disorder","volume":"302","author":"Miao","year":"2022","journal-title":"J. Affect Disord."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Whitaker, R.C., Dearth-Wesley, T., Herman, A.N., Block, A.E., Holderness, M.H., Waring, N.A., and Oakes, J.M. (2021). The interaction of adverse childhood experiences and gender as risk factors for depression and anxiety disorders in US adults: A cross-sectional study. BMC Public Health, 21.","DOI":"10.1186\/s12889-021-12058-z"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00213-010-2009-2","article-title":"Effects of early life stress on cognitive and affective function: An integrated review of human literature","volume":"214","author":"Pechtel","year":"2011","journal-title":"Psychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/ije\/30.2.256","article-title":"Childhood socioeconomic position and cognitive function in adulthood","volume":"30","author":"Kaplan","year":"2001","journal-title":"Int. J. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1192\/bjp.186.2.121","article-title":"Impact of childhood abuse on the clinical course of bipolar disorder","volume":"186","author":"Garno","year":"2005","journal-title":"Br. J. Psychiatry."},{"key":"ref_22","first-page":"445","article-title":"Which factors determine our quality of life, health and ability? Results from a Danish population sample and the Copenhagen perinatal cohort","volume":"18","author":"Ventegodt","year":"2008","journal-title":"J. Coll. Physicians Surg Pak."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jad.2014.03.046","article-title":"Effects of childhood trauma and clinical features on determining quality of life in patients with bipolar I disorder","volume":"162","author":"Erten","year":"2014","journal-title":"J. Affect Disord."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"417","DOI":"10.2190\/PM.39.4.f","article-title":"Relationship between child abuse and adult smoking","volume":"39","author":"Spratt","year":"2009","journal-title":"Int. J. Psychiatry Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1515\/bmc-2018-0010","article-title":"Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences","volume":"9","author":"Maes","year":"2018","journal-title":"Biomol. Concepts."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jpsychires.2017.07.013","article-title":"FACE-BD Clinical Coordinating Center (FondaMental Foundation); FACE-BD Data Coordinating Center (FondaMental Foundation); FACE-BD Clinical Sites and Principal Collaborators in France. Childhood trauma, dimensions of psychopathology and the clinical expression of bipolar disorders: A pathway analysis","volume":"95","author":"Etain","year":"2017","journal-title":"J. Psychiatr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1007\/s11011-018-0209-3","article-title":"In major affective disorders, early life trauma predict increased nitro-oxidative stress, lipid peroxidation and protein oxidation and recurrence of major affective disorders, suicidal behaviors and a lowered quality of life","volume":"33","author":"Moraes","year":"2018","journal-title":"Metab. Brain Dis."},{"key":"ref_28","unstructured":"Maes, M. (2022). False dogmas in affective disorders research. World J. Psychiatry, in press."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5498\/wjp.v11.i1.1","article-title":"How to construct neuroscience-informed psychiatric classification? Towards nomothetic networks psychiatry","volume":"11","author":"Stoyanov","year":"2021","journal-title":"World J. Psychiatry."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neubiorev.2014.05.007","article-title":"Oxidative & nitrosative stress in depression: Why so much stress?","volume":"45","author":"Moylan","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.pnpbp.2010.05.004","article-title":"A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness","volume":"35","author":"Maes","year":"2011","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8885","DOI":"10.1007\/s12035-018-1016-x","article-title":"The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder","volume":"55","author":"Maes","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rachayon, M., Jirakran, K., Sodsai, P., Klinchanhom, S., Sughondhabirom, A., Plaimas, K., Suratanee, A., and Maes, M. (2022). In Vitro Effects of Cannabidiol on Activated Immune\u2013Inflammatory Pathways in Major Depressive Patients and Healthy Controls. Pharmaceuticals, 15.","DOI":"10.1101\/2022.02.04.22270489"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Maes, M., Rachayon, M., Jirakran, K., Sodsai, P., Klinchanhom, S., Ga\u0142ecki, P., Sughondhabirom, A., and Basta-Kaim, A. (2022). The immune profile of Major Dysmood Disorder: Proof of concept and mechanism using the precision nomothetic psychiatry approach. Cells, in press.","DOI":"10.1101\/2022.02.22.22271319"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbi.2021.06.018","article-title":"Linking stressful life events and chronic inflammation using suPAR (soluble urokinase plasminogen activator receptor)","volume":"97","author":"Bourassa","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100006","DOI":"10.1016\/j.bbih.2019.100006","article-title":"Adverse childhood experiences and biomarkers of inflammation in a diverse cohort of early school-aged children","volume":"1","author":"Davis","year":"2020","journal-title":"Brain Behav. Immunity-Health."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1007\/s00406-021-01245-z","article-title":"Assessing the links between childhood trauma, C-reactive protein and response to antidepressant treatment in patients with affective disorders","volume":"271","author":"Fischer","year":"2021","journal-title":"Eur. Arch. Psychiatry Clin Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.neubiorev.2019.10.013","article-title":"Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood","volume":"117","author":"Desplats","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.jad.2019.09.024","article-title":"Prenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence","volume":"260","author":"Flouri","year":"2020","journal-title":"J. Affect Disord."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1001\/jamapediatrics.2019.3875","article-title":"Association of Adverse Experiences and Exposure to Violence in Childhood and Adolescence With Inflammatory Burden in Young People","volume":"174","author":"Rasmussen","year":"2020","journal-title":"JAMA Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jpsychires.2019.05.011","article-title":"Anxiety disorders in childhood are associated with youth IL-6 levels: A mediation study including metabolic stress and childhood traumatic events","volume":"115","author":"Bortoluzzi","year":"2019","journal-title":"J. Psychiatr. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/smi.2871","article-title":"Adverse childhood experiences and neuroinflammatory biomarkers-The role of sex","volume":"35","author":"Kim","year":"2019","journal-title":"Stress Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.jad.2020.07.034","article-title":"Dissecting major depression: The role of blood biomarkers and adverse childhood experiences in distinguishing clinical subgroups","volume":"276","author":"Bussone","year":"2020","journal-title":"J. Affect Disord."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/jnnp.23.1.56","article-title":"A rating scale for depression","volume":"23","author":"Hamilton","year":"1960","journal-title":"J. Neurol. Neurosurg. Psychiatry."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pettersson, A., Modin, S., Wahlstr\u00f6m, R., Hammarberg, S.A.W., and Krakau, I. (2018). The Mini-International Neuropsychiatric Interview is useful and well accepted as part of the clinical assessment for depression and anxiety in primary care: A mixed-methods study. BMC Fam. Pract., 19.","DOI":"10.1186\/s12875-017-0674-5"},{"key":"ref_46","first-page":"251","article-title":"Development of the adverse childhood experiences (ACE) questionnaire Thai version","volume":"1","author":"Rungmueanporn","year":"2019","journal-title":"Chula Med. Bull."},{"key":"ref_47","unstructured":"Spielberger, C., Gorsuch, R., Lushene, R., Vagg, P.R., and Jacobs, G. (1983). Manual for the State-Trait Anxiety Inventory (Form Y1\u2013Y2), Consulting Psychologists Press."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","article-title":"The Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults","volume":"168","author":"Posner","year":"2011","journal-title":"Am. J. Psychiatry."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/1043-4666(92)90021-I","article-title":"Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation","volume":"4","author":"Zangerle","year":"1992","journal-title":"Cytokine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/S0893-133X(98)00088-8","article-title":"Negative immunoregulatory effects of antidepressants: Inhibition of interferon-gamma and stimulation of interleukin-10 secretion","volume":"20","author":"Maes","year":"1999","journal-title":"Neuropsychopharmacol"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/00004714-200104000-00012","article-title":"Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma\/interleukin-10 production ratio","volume":"21","author":"Kubera","year":"2001","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.cyto.2014.10.030","article-title":"Bead-based multiplex immuno-assays for cytokines, chemokines, growth factors and other analytes: Median fluorescence intensities versus their derived absolute concentration values for statistical analysis","volume":"71","author":"Breen","year":"2015","journal-title":"Cytokine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. Royal Statist. Soc. Series B"},{"key":"ref_54","first-page":"56","article-title":"Structural equation modeling with the SmartPLS","volume":"13","author":"Ringle","year":"2015","journal-title":"Braz J. Market."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/0005-7967(93)90052-V","article-title":"Negative recall bias and neuroticism: State vs. trait effects","volume":"31","author":"Bradley","year":"1993","journal-title":"Behav. Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jad.2020.03.145","article-title":"The Association Between Adverse Childhood Experiences and Inflammation in Patients with Major Depressive Disorder: A Systematic Review","volume":"272","author":"Gill","year":"2020","journal-title":"J. Affect Disord."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.niox.2020.11.001","article-title":"Construction of a nitro-oxidative stress-driven, mechanistic model of mood disorders: A nomothetic network approach","volume":"106","author":"Simeonova","year":"2021","journal-title":"Nitric. Oxide."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e4563","DOI":"10.1097\/MD.0000000000004563","article-title":"Significantly higher peripheral fibroblast growth factor-2 levels in patients with major depressive disorder: A preliminary meta-analysis under MOOSE guidelines","volume":"95","author":"Wu","year":"2016","journal-title":"Medicine"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.neulet.2014.07.035","article-title":"Decreased serum fibroblast growth factor - 2 levels in pre- and post-treatment patients with major depressive disorder","volume":"579","author":"He","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.jpsychires.2013.04.008","article-title":"VEGF and depression: A comprehensive assessment of clinical data","volume":"47","author":"Halaris","year":"2013","journal-title":"J. Psychiatr. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.psyneuen.2008.09.016","article-title":"Angiogenic factors in patients with current major depressive disorder comorbid with borderline personality disorder","volume":"34","author":"Kahl","year":"2009","journal-title":"Psychoneuroendocrinol"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.pnpbp.2006.12.011","article-title":"Gene expression and association analysis of vascular endothelial growth factor in major depressive disorder","volume":"31","author":"Iga","year":"2007","journal-title":"Prog. Neuro.-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/ijnp\/pyx060","article-title":"Platelet-Derived Growth Factor as an Antidepressant Treatment Selection Biomarker: Higher Levels Selectively Predict Better Outcomes with Bupropion-SSRI Combination","volume":"20","author":"Jha","year":"2017","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_64","unstructured":"Thisayakorn, P., Thipakorn, Y., Tantavisut, S., Sirivichayakul, S., and Maes, M. Delirium due to hip fracture is associated with activated immune-inflammatory pathways and a reduction in negative immunoregulatory mechanisms. medRxiv, 22271663. Available online: https:\/\/www.medrxiv.org\/content\/10.1101\/2022.02.28.22271663v1.full."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jad.2021.08.015","article-title":"Suicide attempts are associated with activated immune-inflammatory, nitro-oxidative, and neurotoxic pathways: A systematic review and meta-analysis","volume":"295","author":"Vasupanrajit","year":"2021","journal-title":"J. Affect Disord."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Vasupanrajit, A., Jirakran, K., Tunvirachaisakul, C., Solmi, M., and Maes, M. (2022). Inflammation and nitro-oxidative stress in current suicidal attempts and current suicidal ideation: A systematic review and meta-analysis. Mol. Psychiatry, 1\u201312.","DOI":"10.1101\/2021.09.09.21263363"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3242","DOI":"10.3390\/cancers3033242","article-title":"Aberrant signaling pathways in glioma","volume":"3","author":"Nakada","year":"2011","journal-title":"Cancers"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1002\/pro.3519","article-title":"The molecular details of cytokine signaling via the JAK\/STAT pathway","volume":"27","author":"Morris","year":"2018","journal-title":"Protein Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.4049\/jimmunol.178.5.2623","article-title":"The JAK-STAT Signaling Pathway: Input and Output Integration","volume":"178","author":"Murray","year":"2007","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"240","DOI":"10.12659\/MSMBR.904014","article-title":"STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis","volume":"23","author":"Gong","year":"2017","journal-title":"Med. Sci. Monit. Basic Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1159\/000450581","article-title":"Activated Phosphorylated STAT1 Levels as a Biologically Relevant Immune Signal in Schizophrenia","volume":"23","author":"Sharma","year":"2016","journal-title":"Neuroimmunomodulation"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3319","DOI":"10.1007\/s12035-021-02343-8","article-title":"Inflammatory and Oxidative Pathways Are New Drug Targets in Multiple Episode Schizophrenia and Leaky Gut, Klebsiella pneumoniae, and C1q Immune Complexes Are Additional Drug Targets in First Episode Schizophrenia","volume":"58","author":"Maes","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_73","unstructured":"UniProtB (2021, July 23). UniProtKB\u2014Q04206 (TF65_HUMAN). RELA\u2014Transcription Factor p65\u2014Homo Sapiens (Human)\u2014RELA Gene & Protein., Available online: https:\/\/www.uniprot.org."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0749-3797(98)00017-8","article-title":"Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study","volume":"14","author":"Felitti","year":"1998","journal-title":"Am. J. Prev. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1001\/archgenpsychiatry.2011.77","article-title":"Association of childhood adversities and early-onset mental disorders with adult-onset chronic physical conditions","volume":"68","author":"Scott","year":"2011","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Al-Hakeim, H.K., Al-Jassas, H.K., Morris, G., and Maes, M. (2022). Increased ACE2, sRAGE, and immune activation, but lowered calcium and magnesium in COVID-19. Recent Adv. Inflamm. Allergy Drug Discov., 16.","DOI":"10.2174\/2772270816666220318103929"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1081\/CBI-100106083","article-title":"Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer","volume":"18","author":"Haus","year":"2001","journal-title":"Chronobiol Int."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/nm.3249","article-title":"FGF21 regulates metabolism and circadian behavior by acting on the nervous system","volume":"19","author":"Bookout","year":"2013","journal-title":"Nat. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1515\/bmc-2014-0009","article-title":"Circadian angiogenesis","volume":"5","author":"Jensen","year":"2014","journal-title":"Biomol Concepts."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1073\/pnas.1607989114","article-title":"CRYPTOCHROME mediates behavioral executive choice in response to UV light","volume":"114","author":"Baik","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Bozek, K., Rel\u00f3gio, A., Kielbasa, S.M., Heine, M., Dame, C., Kramer, A., and Herzel, H. (2009). Regulation of clock-controlled genes in mammals. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004882"},{"key":"ref_82","first-page":"7","article-title":"Depression\u2019s multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways","volume":"32","author":"Maes","year":"2011","journal-title":"Neuro. Endocrinol. Lett."},{"key":"ref_83","first-page":"287","article-title":"The cytokine hypothesis of depression: Inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression","volume":"29","author":"Maes","year":"2008","journal-title":"Neuro. Endocrinol. Lett."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s12035-020-02110-1","article-title":"Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels","volume":"58","author":"Maes","year":"2021","journal-title":"Mol. Neurobiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/9\/1564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:07:21Z","timestamp":1760137641000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/9\/1564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,7]]},"references-count":84,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cells11091564"],"URL":"https:\/\/doi.org\/10.3390\/cells11091564","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,7]]}}}