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Terczynska M, Bargiel W, Grabarczyk M, Kozlowski T, Zakowicz P, Bojarski D, Wasicka-Przewozna K, Kapelski P, Rajewska-Rager A, Skibinska M. Circulating Growth Factors and Cytokines Correlate with Temperament and Character Dimensions in Adolescents with Mood Disorders. Brain Sci 2025; 15:121. [PMID: 40002454 PMCID: PMC11852978 DOI: 10.3390/brainsci15020121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: The incidence of mood disorders in adolescents is increasing. Bipolar disorder is often misdiagnosed in the early stages of the disease due to the prevalence of depressive symptoms, while manic episodes occur later. Identifying predictors of diagnosis conversion could facilitate timely and appropriate treatment. Our study aimed to find correlations of selected peripheral protein levels with temperament and character traits in adolescents diagnosed with major depressive disorder and bipolar disorder. Methods: A group of adolescents and young adults diagnosed with major depressive disorder (MDD, n = 50) or bipolar disorder (BD, n = 24) was enrolled in the study during the exacerbation of symptoms and followed up over two years. Diagnosis conversion from MDD to BD was monitored. The Temperament and Character Inventory was applied, and BDNF, proBDNF, EGF, MIF, SCF, S100B, TNF-alpha, and IL-8 serum levels were measured. Spearman's rank correlation analysis was conducted. Results: We found different patterns of correlations in MDD (TNF-alpha, IL-8, EGF, S100B with reward-dependence, self-directedness, and empathy) and BD (BDNF and EGF with persistence novelty-seeking and self-transcendence). Significant correlations were found in a group with diagnosis conversion. Conclusions: The findings of our study have the potential to significantly impact our understanding and treatment of mood disorders. Correlations obtained in the subgroup with diagnosis conversion may contribute to the development of prognostic markers in the future. Evaluating temperament and character traits alongside established biomarkers may offer a valuable method for predicting the conversion of mood disorders in adolescents, facilitating early and effective pharmacotherapy.
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Affiliation(s)
- Maria Terczynska
- The Student Scientific Society of Poznan University of Medical Sciences, Student’s Research Group “Biological Psychiatry”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Weronika Bargiel
- The Student Scientific Society of Poznan University of Medical Sciences, Student’s Research Group “Biological Psychiatry”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Maksymilian Grabarczyk
- The Student Scientific Society of Poznan University of Medical Sciences, Student’s Research Group “Biological Psychiatry”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Tomasz Kozlowski
- The Student Scientific Society of Poznan University of Medical Sciences, Student’s Research Group “Biological Psychiatry”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Przemyslaw Zakowicz
- Collegium Medicum, University of Zielona Gora, 65-417 Zielona Gora, Poland;
- Center for Children and Adolescent Treatment in Zabor, 66-003 Zabor, Poland
| | | | - Karolina Wasicka-Przewozna
- The Student Scientific Society of Poznan University of Medical Sciences, Student’s Research Group “Biological Psychiatry”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland (A.R.-R.)
| | - Pawel Kapelski
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland (A.R.-R.)
| | - Aleksandra Rajewska-Rager
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland (A.R.-R.)
| | - Maria Skibinska
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland (A.R.-R.)
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Cao YN, Feng LJ, Wang BM, Jiang K, Li S, Xu X, Wang WQ, Zhao JW, Wang YM. Lactobacillus acidophilus and Bifidobacterium longum supernatants upregulate the serotonin transporter expression in intestinal epithelial cells. Saudi J Gastroenterol 2018; 24:59-66. [PMID: 29451186 PMCID: PMC5848327 DOI: 10.4103/sjg.sjg_333_17] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Probiotics play a role in relieving irritable bowel syndrome (IBS); however, the underlying mechanism is yet unclear. The aim of the study was to investigate the effects of the supernatants of Lactobacillus acidophilus and Bifidobacterium longum on the expression of serotonin transporter (SERT) messenger ribonucleic acid (mRNA) and protein. MATERIALS AND METHODS HT-29 and Caco-2 cells were treated with different concentrations of L. acidophilus and B. longum supernatants for 12 h and 24 h, respectively. SERT mRNA and proteins levels were detected by real-time polymerase chain reaction (real-time PCR) and Western-blotting. RESULTS The mRNA levels of SERT in HT-29 and Caco-2 cells treated with different concentrations of L. acidophilus or B. longum supernatants for 12 h and 24 h, each, were higher than that in the control groups. In addition, the expression of the protein in both cells was also upregulated, which was approximately similar to that of the corresponding mRNA. CONCLUSIONS L. acidophilus and B. longum supernatants can upregulate SERT mRNA and protein levels in intestinal epithelial cells.
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Affiliation(s)
- Ya-Nan Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Li-Juan Feng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shu Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xin Xu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei-Qiang Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Wen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yu-Ming Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China,Address for correspondence: Dr. Yu-Ming Wang, Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China. E-mail:
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Bermingham DP, Blakely RD. Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol Rev 2016; 68:888-953. [PMID: 27591044 PMCID: PMC5050440 DOI: 10.1124/pr.115.012260] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies.
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Affiliation(s)
- Daniel P Bermingham
- Department of Pharmacology (D.P.B., R.D.B.) and Psychiatry (R.D.B.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biomedical Sciences, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida (R.D.B.)
| | - Randy D Blakely
- Department of Pharmacology (D.P.B., R.D.B.) and Psychiatry (R.D.B.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biomedical Sciences, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida (R.D.B.)
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Cui XF, Zhou WM, Yang Y, Zhou J, Li XL, Lin L, Zhang HJ. Epidermal growth factor upregulates serotonin transporter and its association with visceral hypersensitivity in irritable bowel syndrome. World J Gastroenterol 2014; 20:13521-13529. [PMID: 25309082 PMCID: PMC4188903 DOI: 10.3748/wjg.v20.i37.13521] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/10/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of epidermal growth factor (EGF) in visceral hypersensitivity and its effect on the serotonin transporter (SERT).
METHODS: A rat model for visceral hypersensitivity was established by intra-colonic infusion of 0.5% acetic acid in 10-d-old Sprague-Dawley rats. The visceral sensitivity was assessed by observing the abdominal withdrawal reflex and recording electromyographic activity of the external oblique muscle in response to colorectal distension. An enzyme-linked immunosorbent assay was used to measure the EGF levels in plasma and colonic tissues. SERT mRNA expression was detected by real-time PCR while protein level was determined by Western blot. The correlation between EGF and SERT levels in colon tissues was analyzed by Pearson’s correlation analysis. SERT function was examined by tritiated serotonin (5-HT) uptake experiments. Rat intestinal epithelial cells (IEC-6) were used to examine the EGF regulatory effect on SERT expression and function via the EGF receptor (EGFR).
RESULTS: EGF levels were significantly lower in the rats with visceral hypersensitivity as measured in plasma (2.639 ± 0.107 ng/mL vs 4.066 ± 0.573 ng/mL, P < 0.01) and in colonic tissue (3.244 ± 0.135 ng/100 mg vs 3.582 ± 0.197 ng/100 mg colon tissue, P < 0.01) compared with controls. Moreover, the EGF levels were positively correlated with SERT levels (r = 0.820, P < 0.01). EGF displayed dose- and time-dependent increased SERT gene expressions in IEC-6 cells. An EGFR kinase inhibitor inhibited the effect of EGF on SERT gene upregulation. SERT activity was enhanced following treatment with EGF (592.908 ± 31.515 fmol/min per milligram vs 316.789 ± 85.652 fmol/min per milligram protein, P < 0.05) and blocked by the EGFR kinase inhibitor in IEC-6 cells (590.274 ± 25.954 fmol/min per milligram vs 367.834 ± 120.307 fmol/min per milligram protein, P < 0.05).
CONCLUSION: A decrease in EGF levels may contribute to the formation of visceral hypersensitivity through downregulation of SERT-mediated 5-HT uptake into enterocytes.
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Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK. Proc Natl Acad Sci U S A 2013; 110:11624-9. [PMID: 23798440 DOI: 10.1073/pnas.1301485110] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The serotonin transporter (SERT) is a major regulator of serotonergic neurotransmission and anxiety-related behaviors. SERT is expressed in two alternative polyadenylation forms that differ by an evolutionarily conserved element in the 3' untranslated region of its mRNA. Expression of SERT mRNA containing the distal polyadenylation element is associated with decreased anxiety-related behaviors in mice and humans, suggesting that this element has behaviorally relevant modulatory effects on SERT expression. We have identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a protein known to integrate multiple signal transduction pathways with gene expression, as a SERT distal polyadenylation element binding protein. This interaction is functionally meaningful because genetic manipulation of hnRNPK alters expression of the SERT protein. Furthermore, the trophic factor S100β induces Src-family kinase-mediated tyrosine phosphorylation of hnRNPK and increased SERT expression. These results identify a previously unknown mechanism of regulated SERT expression and provide a putative mechanism by which the SERT distal polyadenylation element modulates anxiety-related behaviors.
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Popoff MR, Poulain B. Bacterial toxins and the nervous system: neurotoxins and multipotential toxins interacting with neuronal cells. Toxins (Basel) 2010; 2:683-737. [PMID: 22069606 PMCID: PMC3153206 DOI: 10.3390/toxins2040683] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2010] [Revised: 03/18/2010] [Accepted: 04/07/2010] [Indexed: 12/13/2022] Open
Abstract
Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons.
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Affiliation(s)
- Michel R. Popoff
- Neurotransmission et Sécrétion Neuroendocrine, CNRS UPR 2356 IFR 37 - Neurosciences, Centre de Neurochimie, 5, rue Blaise Pascal, F-67084 STRASBOURG cedex, France;
- Author to whom correspondence should be addressed;
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Hoover BR, Everett CV, Sorkin A, Zahniser NR. Rapid regulation of dopamine transporters by tyrosine kinases in rat neuronal preparations. J Neurochem 2007; 101:1258-71. [PMID: 17419806 DOI: 10.1111/j.1471-4159.2007.04522.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Termination of dopamine neurotransmission is primarily controlled by the plasma membrane-localized dopamine transporter. In this study, we investigated how this transporter is regulated by tyrosine kinases in neuronal preparations. In rat dorsal striatal synaptosomes, inhibition of tyrosine kinases by genistein or tyrphostin 23 resulted in a rapid (5-15 min), concentration-dependent decrease in [(3)H]dopamine uptake because of a reduction in maximal [(3)H]dopamine uptake velocity and dopamine transporter cell surface expression. The reduced transporter activity was associated with a decrease in phosphorylated p44/p42 mitogen-activated protein kinases. In primary rat mesencephalic neuronal cultures, the tyrosine kinase inhibitors similarly reduced [(3)H]dopamine uptake. When cultures were serum-deprived, acute activation of tyrosine kinase-coupled TrkB receptors by 100 ng/mL brain-derived neurotrophic factor significantly increased [(3)H]dopamine uptake; the effects were complex with increased maximal velocity but reduced affinity. The facilitatory effect of brain-derived neurotrophic factor on dopamine transporter activity depended on both the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. Taken together, our results suggest that striatal dopamine transporter function and cell surface expression is constitutively up-regulated by tyrosine kinase activation and that brain-derived neurotrophic factor can mediate this type of rapid regulation.
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Affiliation(s)
- B R Hoover
- Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA.
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Ramakrishnan R, Sheeladevi R, Suthanthirarajan N, Namasivayam A. An acute hyperglycemia or acidosis-induced changes of indolamines level correlates with PKC-alpha expression in rat brain. Brain Res Bull 2005; 67:46-52. [PMID: 16140162 DOI: 10.1016/j.brainresbull.2005.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2005] [Accepted: 05/24/2005] [Indexed: 11/18/2022]
Abstract
Hyperglycemia and ketoacidosis are the two most serious factors in acute metabolic complications of both type 1 and type 2 diabetes. Dysfunction of the central nervous system is a well-documented complication of diabetes. We and others have previously reported that acute or chronic diabetes in animal's results in altered brain neurotransmitter levels. In this study, we investigated the effects of acute (7 days) glucose-induced hyperglycemia and sodium acetoacetate (NaAcAc) or ammonium chloride (NH4Cl) induced acidosis on the level of indolamines (5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA)) as well as PKC-alpha expression/activity in discrete areas of rat brain. Glucose-induced (500 mg/kg, bw) hyperglycemic ( approximately 249 mg%) rats showed significant (p<0.05) increase in 5-HT levels in mid brain (MB), pons medulla (PM) and cerebellum (CB), respectively. 5-HIAA level increased in hippocampus (HC) (p<0.05) as compared to control. The rats treated with sodium acetoacetate (NaAcAc) for 7 days (60 mg/kg, bw) showed significant decrease (p<0.05) of 5-HT level in hypothalamus (HT). Whereas, the 5-HIAA level increased in MB (p<0.05). Similarly, the PKC-alpha expression as well as the enzyme activity showed significant increase in HC, MB, PM and CB under glucose-induced hyperglycemia and that changes correlated the changes of indolamines, suggesting that the hyperglycemia may be the major metabolic disorder in diabetic complications.
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Affiliation(s)
- R Ramakrishnan
- Department of Surgery, Drexel University College of Medicine, MS 413, 245 N, 15th Street, Philadelphia, PA 19102, USA.
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Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Association of EGF polymorphism with schizophrenia in Finnish men. Neuroreport 2004; 15:1215-8. [PMID: 15129177 DOI: 10.1097/00001756-200405190-00027] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.
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