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Rychel M, Suchanecka A, Chmielowiec J, Chmielowiec K, Różański J, Masiak J, Grzywacz A, Boroń A. Molecular Effect of Variants in Serotonin Transporter Gene in Women with Alcohol Use Disorder. Cells 2025; 14:699. [PMID: 40422201 DOI: 10.3390/cells14100699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Revised: 05/01/2025] [Accepted: 05/06/2025] [Indexed: 05/28/2025] Open
Abstract
The dysregulation of the serotonin system has been implicated in the pathophysiology of alcohol use disorders. Meta-analytic evidence suggests a significant correlation between genetic variation in the serotonin transporter gene and the risk of alcohol dependence. Hence, we aimed to analyse the association between 5-HTTLPR polymorphism and alcohol use disorder in a group of women and to perform an interaction analysis of 5-HTTLPR variants, personality traits, and AUD. The study group comprised 213 female volunteers; 101 were diagnosed with alcohol addiction, and 112 were not dependent on any substance or behaviour. The 5-HTTLPR variants were identified by PCR, and the resulting products were separated electrophoretically. When comparing the AUD group with the controls, we observed significant differences in the distribution of 5-HTTLPR genotypes (p = 0.0230) and alleles (p = 0.0046). We also observed a significant impact of the 5-HTTLPR genotype (p = 0.0001) on the Neuroticism and Extraversion (p = 0.0037) scales. Additionally, there was a statistically significant impact of 5-HTTLPR genotype interaction and alcohol dependency or lack of it on the Neuroticism scale (p < 0.0001). The observed interaction suggests that the effect of the 5-HTTLPR on neuroticism may be exacerbated or attenuated in the presence of alcohol addiction. Further investigation is needed to elucidate the precise nature of this interaction. Still, it potentially indicates a gene-environment interaction where the genetic predisposition conferred by the 5-HTTLPR polymorphism interacts with the environmental stressor of alcohol dependence to influence neuroticism.
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Affiliation(s)
- Monika Rychel
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland
| | - Aleksandra Suchanecka
- Independent Laboratory of Behavioral Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland
| | - Jolanta Chmielowiec
- Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland
| | - Krzysztof Chmielowiec
- Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland
| | - Jacek Różański
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland
| | - Jolanta Masiak
- Second Department of Psychiatry and Psychiatric Rehabilitation, Medical University of Lublin, Głuska 1 St., 20-059 Lublin, Poland
| | - Anna Grzywacz
- Department of Molecular Biology, Gdansk University of Physical Education and Sport, Kazimierza Górskiego 1 St., 80-336 Gdansk, Poland
| | - Agnieszka Boroń
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland
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Shu Y, Tian L, Wang X, Meng T, Yu S, Li Y. Decoding serotonin: the molecular symphony behind depression. Front Cell Neurosci 2025; 19:1572462. [PMID: 40342516 PMCID: PMC12058683 DOI: 10.3389/fncel.2025.1572462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 04/03/2025] [Indexed: 05/11/2025] Open
Abstract
The serotonin (5-hydroxytryptamine) system represents a crucial neurotransmitter network that regulates mood, behavior, and cognitive functions, playing a significant role in the pathogenesis and progression of depression. Although this perspective faces significant challenges, the serotonin system continues to exert substantial modulatory effects on specific aspects of psychological functioning and actively contributes to multiple pathological processes in depression development. Therefore, this review systematically integrates interdisciplinary research advances regarding the relationship between the 5-hydroxytryptamine (5-HT) system and depression. By focusing on core biological processes including serotonin biosynthesis and metabolism, SERT gene regulatory networks, and protein molecular modifications, it aims to elucidate how 5-HT system dysregulation contributes to the development of depression, while providing novel research perspectives and therapeutic targets for innovative antidepressant drug development.
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Affiliation(s)
- Yue Shu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Lei Tian
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xing Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Tinyang Meng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Shouyang Yu
- Key Laboratory of Brain Science, Key Laboratory of Anesthesia and Organ Protection of Ministry of Education (In Cultivation), Zunyi Medical University, Zunyi, China
| | - Yulan Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
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3
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Lachowicz M, Suchanecka A, Chmielowiec K, Boroń A, Chmielowiec J, Prabucka K, Rychel M, Pedrycz A, Recław R, Rahnama-Hezavah M, Grywalska E, Grzywacz A. Analysis of Serotonin Transporter Gene 5-HTTLPR Polymorphism and Its Impact on Personality Traits in a Sample Without Neuropsychiatric or Substance Use Disorders. Int J Mol Sci 2025; 26:3718. [PMID: 40332353 PMCID: PMC12028234 DOI: 10.3390/ijms26083718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
Variations within the serotonin transporter gene, SLC6A4 (solute carrier family 6 member 4), particularly the 5-HTTLPR (serotonin-transporter-linked promoter region), have been extensively studied in relation to behavioral and psychological traits. The aim of our study is to examine the relationship between the 5-HTTLPR polymorphism located in the SLC6A4 gene and personality traits, as assessed using the NEO-FFI (NEO Five Factor Inventory). The MANOVA model demonstrated a significant overall association, accounting for approximately 8% of the variance in the data (Wilk's λ = 0.847, F10,342 = 2.979, p = 0.0013, η2 = 0.08). Subsequent ANOVAs revealed statistically significant 5-HTTLPR polymorphism associations with the Neuroticism (p = 0.0018, R2 = 0.070), Openness (p = 0.0364, R2 = 0.037), and Conscientiousness (p = 0.0020, R2 = 0.068) dimensions. The post-hoc analysis revealed that individuals with the LL genotype obtained significantly lower Neuroticism scores compared to the S/S (p = 0.0011) and SL genotype (p = 0.0086) carriers. Similarly, individuals with the L/L genotype had lower Openness scores compared to those with SS genotype (p = 0.0107). LL and SL genotype carriers had higher Conscientiousness scores compared to those with the SS genotype (p = 0.0004 and p = 0.0109, respectively). In conclusion, our study provides further data regarding the implications of 5-HTTLPR polymorphism in the complex genetic architecture of human personality. The observed associations with Neuroticism, Openness, and Conscientiousness, while modest in effect size, contribute to our understanding of how genetic variation at the SLC6A4 locus may subtly shape individual personality differences.
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Affiliation(s)
- Milena Lachowicz
- Department and Clinic of Oncology and Radiotherapy, Medical University of Gdansk, ul. M. Skłodowskiej-Curie 3a, 80-210 Gdansk, Poland;
| | - Aleksandra Suchanecka
- Independent Laboratory of Behavioral Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.S.); (K.P.); (R.R.)
| | - Krzysztof Chmielowiec
- Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland; (K.C.); (J.C.)
| | - Agnieszka Boroń
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.B.); (M.R.)
| | - Jolanta Chmielowiec
- Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland; (K.C.); (J.C.)
| | - Katarzyna Prabucka
- Independent Laboratory of Behavioral Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.S.); (K.P.); (R.R.)
| | - Monika Rychel
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.B.); (M.R.)
| | - Agnieszka Pedrycz
- Faculty of Medicine and Health Sciences, University of Applied Sciences in Tarnow, Mickiewicza 8, 33-100 Tarnów, Poland;
| | - Remigiusz Recław
- Independent Laboratory of Behavioral Genetics and Epigenetics, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland; (A.S.); (K.P.); (R.R.)
| | - Mansur Rahnama-Hezavah
- Chair and Department of Oral Surgery, Medical University of Lublin, 6 Chodzki Street, 20-093 Lublin, Poland;
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland;
| | - Anna Grzywacz
- Department of Medical Sciences and Public Health, Gdansk University of Physical Education and Sport, Kazimierza Górskiego 1 St., 80-336 Gdansk, Poland
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Thorne BN, Ellenbroek BA, Day DJ. Reduced expression of the serotonin transporter impacts mitochondria in a sexually dimorphic manner. Biochem Biophys Rep 2025; 41:101895. [PMID: 39760099 PMCID: PMC11699461 DOI: 10.1016/j.bbrep.2024.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025] Open
Abstract
Neuropsychiatric and neurodevelopmental disorders are complex conditions that arise from a variety of interacting genetic and environmental factors. Among these factors, altered serotonergic signalling and mitochondrial dysfunction are strongly implicated, with a growing body of evidence to suggesting that serotonergic signalling is an important regulator of mitochondrial biogenesis. The serotonin transporter (SERT) functions to regulate synaptic 5-HT, and human allelic variants of the serotonin reuptake transporter-linked polymorphic region (5-HTTLPR) are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using the heterozygous (HET) variant of the SERT knockout rat to model reduced SERT expression, Western blotting was used to measure the abundance of TOMM20 and the complex I protein MT-CO1 as metrics for mitochondrial mass and abundance of respiratory complex IV. Mitochondrial activity was determined by dye reduction. We found sex-based and region-specific differences in mitochondrial mass and activity and that male and females show differing responses to reduced SERT expression. Our findings suggest that the sexually dimorphic differences in serotonergic signalling impact mitochondrial function and that these differences may be important for understanding sex differences in neuropsychiatric and neurodevelopmental disorders.
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Affiliation(s)
- Bryony N. Thorne
- School of Biological Sciences, Victoria University of Wellington Kelburn, Parade, 6012, Wellington, New Zealand
- Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS, Australia
| | - Bart A. Ellenbroek
- School of Psychology, Victoria University of Wellington Faculty of Science, 6012, Wellington, New Zealand
| | - Darren J. Day
- School of Biological Sciences, Victoria University of Wellington Kelburn, Parade, 6012, Wellington, New Zealand
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Petrovick M, Shcherbina A, Farina EK, Thompson LA, Niro PJ, McClung JP, Lieberman HR. The minor allele of the serotonin transporter gene variant rs4251417 is associated with increased resilience in soldiers experiencing acute stress during survival training: preliminary findings. ANXIETY, STRESS, AND COPING 2025; 38:161-180. [PMID: 39165169 DOI: 10.1080/10615806.2024.2388850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 07/26/2024] [Accepted: 07/30/2024] [Indexed: 08/22/2024]
Abstract
BACKGROUND Variation in cognitive, emotional and physical performance in response to stress is attributable to environmental and genetic factors. Ability to adapt to stress is resilience. OBJECTIVES This study investigated genetic factors associated with resilience in soldiers exposed to severe stress due to intense physical and mental demands at Survive, Evade, Resist and Escape school, a unique environment to study acute stress and resiliency in real-world circumstances. DESIGN A preliminary correlational study was conducted to identify genetic markers for resilience to stress. METHODS Mood state, resiliency and dissociative state of 73 soldiers were assessed using: Connor-Davidson Resilience Scale (CD-RISC); Profile of Mood States (POMS); and Clinician-Administered Dissociative States Scale (CADSS). Change scores for resilience-related stress markers were computed; 116 single nucleotide polymorphisms (SNPs) associated with stress, depression, anxiety, sleep, or psychiatric disorders were assessed. RESULTS A significant association between change in CD-RISC score and SNP rs4251417, present in an intron of SLC6A4, the serotonin transporter gene, was observed. CONCLUSIONS Individuals with the minor allele of SNP rs4251417 had a greater positive change in CD-RISC, indicating increased self-assessed resilience. This study suggests the minor allele of SNP rs4251417 of SLC6A4 is associated with resilience when individuals are exposed to high stress.
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Affiliation(s)
- Martha Petrovick
- Biological & Chemical Technologies, MIT Lincoln Laboratory, Lexington, MA, USA
| | - Anna Shcherbina
- Biological & Chemical Technologies, MIT Lincoln Laboratory, Lexington, MA, USA
| | - Emily K Farina
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Lauren A Thompson
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Philip J Niro
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - James P McClung
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Harris R Lieberman
- Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA
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6
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Guo CCG, Xu Y, Shan L, Foka K, Memoli S, Mulveen C, Gijsbrechts B, Verheij MM, Homberg JR. Quantifying multilabeled brain cells in the whole prefrontal cortex reveals reduced inhibitory and a subtype of excitatory neuronal marker expression in serotonin transporter knockout rats. Cereb Cortex 2025; 35:bhae486. [PMID: 39932853 DOI: 10.1093/cercor/bhae486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 11/25/2024] [Accepted: 12/05/2024] [Indexed: 02/13/2025] Open
Abstract
The prefrontal cortex regulates emotions and is influenced by serotonin. Rodents lacking the serotonin transporter (5-HTT) show increased anxiety and changes in excitatory and inhibitory cell markers in the prefrontal cortex. However, these observations are constrained by limitations in brain representation and cell segmentation, as standard immunohistochemistry is inadequate to consider volume variations in regions of interest. We utilized the deep learning network of the StarDist method in combination with novel open-source methods for automated cell counts in a wide range of prefrontal cortex subregions. We found that 5-HTT knockout rats displayed increased anxiety and diminished relative numbers of subclass excitatory VGluT2+ and activated ΔFosB+ cells in the infralimbic and prelimbic cortices and of inhibitory GAD67+ cells in the prelimbic cortex. Anxiety levels and ΔFosB cell counts were positively correlated in wild-type, but not in knockout, rats. In conclusion, we present a novel method to quantify whole brain subregions of multilabeled cells in animal models and demonstrate reduced excitatory and inhibitory neuronal marker expression in prefrontal cortex subregions of 5-HTT knockout rats.
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Affiliation(s)
- Chao Ciu-Gwok Guo
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
| | - Yifan Xu
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
| | - Ling Shan
- Department of Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA, Amsterdam, the Netherlands
| | - Kyriaki Foka
- Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland
| | - Simone Memoli
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
| | - Calum Mulveen
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
| | - Barend Gijsbrechts
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
| | - Michel M Verheij
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
| | - Judith R Homberg
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, the Netherlands
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7
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Vergunov EG, Savostyanov VA, Makarova AA, Nikolaeva EI, Savostyanov AN. Computer reconstruction of gene networks controlling anxiety levels in humans and laboratory mice. Vavilovskii Zhurnal Genet Selektsii 2025; 29:162-170. [PMID: 40144367 PMCID: PMC11937012 DOI: 10.18699/vjgb-25-19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/16/2024] [Accepted: 12/16/2024] [Indexed: 03/28/2025] Open
Abstract
Anxiety is a normotypic human condition, and like any other emotion has an adaptive value. But excessively high or low anxiety has negative consequences for adaptation, which primarily determines the importance of studying these two extreme conditions. At the same time, it is known that the perception of aversive stimuli associated with anxiety leads to changes in the activity of the brain's cingulate cortex. The advantage of animals as models in studying the genetic bases of anxiety in humans is in the ability to subtly control the external conditions of formation of a certain state, the availability of brain tissues, and the ability to create and study transgenic models, including through the use of differentially expressed genes of small laboratory animals from the family Muridae with low and high anxiety. Within the framework of the translational approach, a three-domain potential gene network, which is associated with generalized anxiety in humans, was reconstructed using mouse models with different levels of anxiety by automatically analyzing the texts of scientific articles. One domain is associated with reduced anxiety in humans, the second with increased anxiety, and the third is a dispatcher who activates one of the two domains depending on the status of the organism (genetic, epigenetic, physiological). Stages of work: (I) A list of genes expressed in the cingulate cortex of the wild type CD-1 mouse line from the NCBI GEO database (experiment GSE29014). Using the tools of this database, differences in gene expression levels were revealed in groups of mice with low and high (relatively normal) anxiety. (II) Search for orthologs of DEG in humans and mice associated with anxiety in the OMA Orthology database. (III) Computer reconstruction using the ANDSystem cognitive system based on (a) human orthologous genes from stage (III), (b) human genes from the MalaCards database associated with human anxiety. The proven methods of the translational approach for the reconstruction of gene networks for behavior regulation can be used to identify molecular genetic markers of human personality traits, propensity to psychopathology.
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Affiliation(s)
- E G Vergunov
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Scientific Research Institute of Neurosciences and Medicine, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | | | - A A Makarova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | | | - A N Savostyanov
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Scientific Research Institute of Neurosciences and Medicine, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
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8
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Lima J, Panayi MC, Sharp T, McHugh SB, Bannerman DM. More and Less Fear in Serotonin Transporter Knockout Mice. GENES, BRAIN, AND BEHAVIOR 2025; 24:e70016. [PMID: 39917838 PMCID: PMC11803413 DOI: 10.1111/gbb.70016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 02/11/2025]
Abstract
Recent theories suggest that reduced serotonin transporter (5-HTT) function, which increases serotonin (5-HT) levels at the synapse, enhances neural plasticity and affects sensitivity to environmental cues. This may promote learning about emotionally relevant events. However, the boundaries that define such emotional learning remain to be established. This was investigated using 5-HTT knockout (5-HTTKO) mice which provide a model of long-term elevated 5-HT transmission and are associated with increased anxiety. Compared to wild-type controls, 5-HTTKO mice were faster to discriminate between an auditory cue that predicted footshock (CS+) and a cue predicting no footshock (CS-). Notably, this enhanced discrimination performance was driven not by faster learning that the CS+ predicted footshock, but rather by faster learning that the CS- cue signals the absence of footshock and thus provides temporary relief from fear/anxiety. Similarly, 5-HTTKO mice were also faster to reduce their fear of the CS+ cue during subsequent extinction. These findings are consistent with facilitated inhibitory learning that predicts the absence of potential threats in 5-HTTKO mice. However, 5-HTTKO mice also exhibited increased generalisation of fear learning about ambiguous aversive cues in a novel context, different from the training context. Thus, 5-HTTKO mice can exhibit both more and less fear compared to wild-type controls. Taken together, our results support the idea that loss of 5-HTT function, and corresponding increases in synaptic 5-HT availability, may facilitate learning by priming of aversive memories. This both facilitates inhibitory learning for fear memories but also enhances generalisation of fear.
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Affiliation(s)
- João Lima
- Department of Experimental PsychologyUniversity of OxfordOxfordUK
- Danish Research Centre for Magnetic Resonance (DRCMR), Department of Radiology and Nuclear MedicineCopenhagen University Hospital—Amager and HvidovreCopenhagenDenmark
| | - Marios C. Panayi
- Department of Experimental PsychologyUniversity of OxfordOxfordUK
- School of PsychologyUniversity of New South WalesSydneyNew South WalesAustralia
| | - Trevor Sharp
- Department of PharmacologyUniversity of OxfordOxfordUK
| | - Stephen B. McHugh
- Department of Experimental PsychologyUniversity of OxfordOxfordUK
- Medical Research Council Brain Network Dynamics UnitOxfordUK
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9
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Toma FM, Kalam KT, Haque MA, Reza S, Akter R, Islam MS, Islam MR, Nahar Z. Interleukin-1β rs16944 and rs1143627 polymorphisms and risk of developing major depressive disorder: A case-control study among Bangladeshi population. PLoS One 2025; 20:e0317665. [PMID: 39841732 PMCID: PMC11753680 DOI: 10.1371/journal.pone.0317665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 01/02/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Epidemiological research suggests that altered levels of cytokine are associated with pathophysiology and the development of major depressive disorder (MDD). Based on earlier study, IL-1β rs16944 and rs1143627 polymorphisms may increase the risk of depression. Here, we aimed to evaluate the correlation between these polymorphisms and MDD susceptibility among the population in Bangladesh. METHODS Blood samples were collected from 100 MDD patients and 70 matched controls. Study participants were evaluated by DSM-5 criteria and PCR-RFLP method were applied for genotyping. RESULTS The IL1β rs1143627 and rs16944 polymorphisms were found to have a significant association with the risk of MDD. In case of rs1143627 CT heterozygous genotype (OR = 2.22, 95% CI = 1.08-4.55, p-value = 0.029) and combined CT+TT (OR = 2.35, 95% CI = 1.15-4.79, p-value = 0.019) genotype was strongly associated with the increased risk of MDD in comparison to CC common genotype. Moreover, the over-dominant model indicated a 2.15-fold higher risk for MDD development (OR = 2.15, 95% CI = 1.05-4.40, p-value = 0.036). On the other hand, the IL1β rs16944 polymorphisms revealed that the TC+CC combined genotype in the dominant model showed a 2.06-fold increased risk for MDD development compared to the TT common homozygote (OR = 2.06, 95% CI = 1.06-3.99, p-value = 0.032). CONCLUSION Studies suggests that IL1β rs16944 and rs1143627 polymorphisms are associated with an increased risk of MDD. These findings will provide us with valuable insights into the pathophysiology of MDD.
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Affiliation(s)
| | | | | | - Sejuti Reza
- Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
| | | | - Mohammad Safiqul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | | | - Zabun Nahar
- Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
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10
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Zhang Y, Rehman S, Addas A, Ahmad M, Khan A. The Mediating Role of Cognitive Reappraisal on Bedtime Procrastination and Sleep Quality in Higher Educational Context: A Three-Wave Longitudinal Study. Nat Sci Sleep 2025; 17:129-142. [PMID: 39867574 PMCID: PMC11766220 DOI: 10.2147/nss.s497183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/15/2025] [Indexed: 01/28/2025] Open
Abstract
Background While bedtime procrastination is commonly associated with adverse outcomes such as poor sleep quality, the mechanisms mediating these effects remain underexplored. Grounded in the Self-Regulation Model of Behavior and the Transactional Model of Stress and Coping, this study examines the mediating role of cognitive reappraisal in the relationship between bedtime procrastination and sleep quality over time. Methods Employing a longitudinal design, the study examined the progression of bedtime procrastination, cognitive reappraisal, and sleep quality among university students at three distinct time points throughout an academic semester. Structural equation modeling and autoregressive time-lagged panel models were utilized to analyze the data, assessing both the direct effects and the mediating role of cognitive reappraisal over time. Results The results revealed that bedtime procrastination exhibited significant stability across time points (β = 0.619 to 0.658, p<0.001). Bedtime procrastination at earlier time points predicted poorer cognitive reappraisal (β= -0.169, p<0.05 to -0.215, p<0.01) and subsequent sleep quality (β=0.256, p<0.001). Additionally, cognitive reappraisal significantly mediated the relationship between bedtime procrastination and sleep quality (β= -0.359, Boot 95% CI: -0.51 to -0.234), emphasizing the role of emotional regulation strategies in sleep-related outcomes. Conclusion These findings underscored the impact of bedtime procrastination on sleep quality and highlight cognitive reappraisal as a key mediator. Interventions focusing on enhancing emotion regulation skills could mitigate the adverse effects of bedtime procrastination and improve sleep outcomes among university students.
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Affiliation(s)
- Yuan Zhang
- College of Art, Nanyang Vocational College of Agriculture, Nan Yang, Henan, 47300, People’s Republic of China
| | - Shazia Rehman
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of China
| | - Abdullah Addas
- Department of Civil Engineering, College of Engineering, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
- Landscape Architecture Department, Faculty of Architecture and Planning, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Mehmood Ahmad
- Department of Pharmacology and Toxicology, Faculty of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Ayesha Khan
- Department of Applied Psychology, Faculty of Social Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
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11
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Cespuglio R, Gorlova A, Zabegalov K, Chaprov K, Svirin E, Sitdikova K, Burova A, Shulgin B, Lebedeva K, Deikin AV, Morozov S, Strekalova T. SERT-Deficient Mice Fed Western Diet Reveal Altered Metabolic and Pro-Inflammatory Responses of the Liver: A Link to Abnormal Behaviors. FRONT BIOSCI-LANDMRK 2025; 30:26778. [PMID: 39862090 DOI: 10.31083/fbl26778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/15/2024] [Accepted: 11/28/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND The inheritance of the short SLC6A4 allele, encoding the serotonin transporter (SERT) in humans, increases susceptibility to neuropsychiatric and metabolic disorders, with aging and female sex further exacerbating these conditions. Both central and peripheral mechanisms of the compromised serotonin (5-HT) system play crucial roles in this context. Previous studies on SERT-deficient (Sert-/-) mice, which model human SERT deficiency, have demonstrated emotional and metabolic disturbances, exacerbated by exposure to a high-fat Western diet (WD). Growing evidence suggests the significance of hepatic regulatory mechanisms in the neurobiology of central nervous system disorders, supporting the 'liver-brain' concept. However, the relationship between aberrant behavior and hepatic alterations under conditions of SERT deficiency remains poorly investigated. METHODS One-year-old female Sert-/- mice and their wild-type (WT) littermates were subjected to a control diet (CD) or the WD for a duration of three weeks. The WD had a higher caloric content and was characterized by an elevated saturated fat content (21%) compared to the CD (4.5%) and contained 0.2% cholesterol. Mice were evaluated for anxiety-like behavior, exploration and locomotor activity in the open field test, as well as glucose tolerance and histological indicators of hepatic steatosis. Hepatic pro-inflammatory and metabolism-related gene expression and markers of nitrosative stress, were analyzed utilizing real-time polymerase chain reaction (RT-PCR) and correlated with behavioral and histological outcomes. RESULTS In comparison to unchallenged mice, Sert-/-/WD mutants, but not the WT/WD group, had increased locomotion and anxiety-like behavior, increased hepatic steatosis, and elevated expression of insulin receptor B and pro-inflammatory cytokines interleukin-1β (Il-1β) and Tnf, as well as decreased expression of leptin receptor B. The two genotypes displayed distinct gene expression patterns of nitric oxide (NO)-related molecules inducible NO synthase (iNos) and arginase (Arg2), insulin receptor-related signaling factors: cluster of differentiation 36 (Cd36), ecto-nucleotide pyrophosphatase/phosphodiesterase (Enpp), protein tyrosine phosphatase N1 (Ptpn1), cytochrome P450 omega-hydroxylase 4A14 (Cyp4a14), acyl-CoA synthetase 1 (Acsl1) and phosphatase and tensin homolog (Pten). Furthermore, there were profound differences in correlations between molecular, histological, and behavioral measurements across the two genotypes. CONCLUSIONS Our findings suggest that the genetic deficiency of SERT results in abnormal hepatic pro-inflammatory and metabolic adaptations in response to WD. The significant correlations observed between behavioral measures and pro-inflammatory and metabolic alterations in WD-fed mice suggest the importance of liver-brain interactions and their role in the aberrant behaviors exhibited by Sert-/- mutants. This study presents the first evidence that altered liver functions are associated with pathological behaviors arising from genetic SERT deficiency.
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Affiliation(s)
- Raymond Cespuglio
- Neuroscience Research Center of Lyon, Claude-Bernard Lyon-1 University, 69675 Bron, France
| | - Anna Gorlova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | | | - Kirill Chaprov
- National Laboratory of Astana, Nazarbaev University, 010000 Astana, Kazakhstan
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia
| | - Evgeniy Svirin
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | - Kseniia Sitdikova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | - Alisa Burova
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | - Boris Shulgin
- Laboratory of Engineering Profile Physical and Chemical Methods of Analysis, Korkyt Ata Kyzylorda State University, 120014 Kyzylorda, Kazakhstan
- Department of Normal Physiology, Sechenov University, 117198 Moscow, Russia
| | - Ksenia Lebedeva
- Department of Normal Physiology, Sechenov University, 117198 Moscow, Russia
| | - Alexei V Deikin
- Laboratory of Genetic Technology and gene editing for Biomedicine and Veterinary, National Research Belgorod state University, 308015 Belgorod, Russia
| | - Sergey Morozov
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | - Tatyana Strekalova
- Division of Molecular Psychiatry, Center of Mental Health, University of Hospital Würzburg, 97080 Würzburg, Germany
- Maastricht University, Department of Psychiatry and Neuropsychology, 6229 ER Maastricht, The Netherlands
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12
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Yanagida Y, Naka I, Nakachi Y, Ikegame T, Kasai K, Kajitani N, Takebayashi M, Bundo M, Ohashi J, Iwamoto K. Development of a method for the imputation of the multi-allelic serotonin-transporter-linked polymorphic region (5-HTTLPR) in the Japanese population. J Hum Genet 2025; 70:41-45. [PMID: 39322647 DOI: 10.1038/s10038-024-01296-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/10/2024] [Accepted: 09/14/2024] [Indexed: 09/27/2024]
Abstract
Serotonin-transporter-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the promoter region of serotonin transporter gene, is classified into short (S) and long (L) alleles. Initial case-control association studies claiming the risks of the S allele in depression and anxiety were not completely supported by recent studies. However, most studies, especially those on East Asian populations, have overlooked the complexity of 5-HTTLPR, which involves multiple different alleles with distinct functional properties. To address this issue, distinguishing multiple 5-HTTLPR alleles is essential. Here, using the 5-HTTLPR genotypes previously determined by exhaustive Sanger sequencing of approximately 1,500 Japanese subjects and their comprehensive SNP data, we constructed a method for 5-HTTLPR genotype imputation. We identified 28 tag SNPs for the imputation of four major 5-HTTLPR alleles, which collectively account for 97.6% of 5-HTTLPR alleles in the Japanese population. Our imputation method, achieved an accuracy of 0.872 in cross-validation, will contribute to association analysis of 5-HTTLPR in the Japanese subjects.
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Affiliation(s)
- Yutaro Yanagida
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Izumi Naka
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Yutaka Nakachi
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tempei Ikegame
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoto Kasai
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- University of Tokyo Institute for Diversity and Adaptation of Human Mind (UTIDAHM), Tokyo, Japan
- The International Research Center for Neurointelligence (WPI-IRCN), Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo, Japan
| | - Naoto Kajitani
- Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Minoru Takebayashi
- Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Miki Bundo
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Jun Ohashi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
| | - Kazuya Iwamoto
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
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13
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Wang D, Wang J, Yan D, Wang M, Yang L, Demin KA, de Abreu MS, Kalueff AV. Minocycline reduces neurobehavioral deficits evoked by chronic unpredictable stress in adult zebrafish. Brain Res 2024; 1845:149209. [PMID: 39233136 DOI: 10.1016/j.brainres.2024.149209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/28/2024] [Indexed: 09/06/2024]
Abstract
Chronic stress-related brain disorders are widespread and debilitating, and often cause lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light-dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), and upregulated brain expression of the 'neurotoxic M1' microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1β, IL-6 and IFN-γ). CUS also elevated peripheral (whole-body) pro-inflammatory (IL-1β, IFN-γ) and lowered anti-inflammatory cytokines (IL-4 and IL-10), as well as reduced whole-brain serotonin, dopamine and norepinephrine levels, and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.
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Affiliation(s)
- Dongmei Wang
- School of Pharmacy, Southwest University, Chongqing, China
| | - Jingtao Wang
- School of Pharmacy, Southwest University, Chongqing, China
| | - Dongni Yan
- School of Pharmacy, Southwest University, Chongqing, China
| | - Mengyao Wang
- School of Pharmacy, Southwest University, Chongqing, China
| | - Longen Yang
- School of Pharmacy, Southwest University, Chongqing, China; Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China; Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China
| | - Konstantin A Demin
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Murilo S de Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil; Western Caspian University, Baku, Azerbaijan; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
| | - Allan V Kalueff
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Center, St. Petersburg, Russia; Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China; Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
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14
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Shokrnejad-namin T, Amini E, Khakpai F, Zarrindast MR. The additive effect between citalopram and muscimol upon induction of antinociceptive effect in male mice. IBRO Neurosci Rep 2024; 17:58-64. [PMID: 39807389 PMCID: PMC11725972 DOI: 10.1016/j.ibneur.2024.05.003] [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: 12/17/2023] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 01/16/2025] Open
Abstract
Previous investigations have revealed the role of GABAergic and serotonergic systems in the modulation of pain behavior. This research aimed to examine the effects of intracerebroventricular (i.c.v.) infusion of GABAA receptor agonist and antagonist as well as citalopram on pain behavior in male mice. For i.c.v. microinjection, a guide cannula was surgically implanted in the left lateral ventricle of male mice. Pain behavior was evaluated using a tail-flick test. Tail flick latency was measured in each experimental group of mice every 15 min (for 60 min). I.c.v. microinjection of muscimol (0.5 and 1 µg/mouse; GABAA receptor agonist) into the left lateral ventricle dose-dependently induced an antinociceptive effect. On the other hand, i.c.v. infusion of bicuculline (1 µg/mouse; GABAA receptor antagonist) induced a hyperalgesia response. Moreover, intraperitoneally (i.p.) administration of citalopram (8 mg/kg) produced an antinociceptive effect. Co-treatment of citalopram (8 mg/kg) along with muscimol (0.25 µg/mouse) or bicuculline (0.25 µg/mouse) potentiated the antinociceptive effect produced by citalopram. We found an additive antinociceptive effect of citalopram and muscimol in male mice. In conclusion, our results suggested an interaction between citalopram and GABAergic agents on the modulation of pain behavior in male mice.
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Affiliation(s)
- Taha Shokrnejad-namin
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elnaz Amini
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khakpai
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad-Reza Zarrindast
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran
- Institute for Cognitive Science Studies (ICSS), Tehran, Iran
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15
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Grigorenko EL. The extraordinary "ordinary magic" of resilience. Dev Psychopathol 2024; 36:2481-2498. [PMID: 39363871 DOI: 10.1017/s0954579424000841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
In this essay, I will briefly sample different instances of the utilization of the concept of resilience, attempting to complement a comprehensive representation of the field in the special issue of Development and Psychopathology inspired by the 42nd Minnesota Symposium on Child Psychology, hosted by the Institute of Child Development at the University of Minnesota and held in October of 2022. Having established the general context of the field, I will zoom in on some of its features, which I consider "low-hanging fruit" and which can be harvested in a systematic way to advance the study of resilience in the context of the future of developmental psychopathology.
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16
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Pei J, Zhang C, Zhang Q, Yu H, Yuan H, Guo Y, Shen H, Liu H, Wang C, Meng F, Yu C, Tie J, Chen X, Wu X, Zhang G, Wang X. Probiotics alleviate chronic ethanol exposure-induced anxiety-like behavior and hippocampal neuroinflammation in male mice through gut microbiota-derived extracellular vesicles. J Nanobiotechnology 2024; 22:730. [PMID: 39578835 PMCID: PMC11585232 DOI: 10.1186/s12951-024-03017-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Probiotics can colonize both the human and animal bodies and consist of active microorganisms that are beneficial to health. The use of probiotics has been shown to alleviate certain neurological diseases and disturbances in gut microbiota resulting from chronic ethanol exposure. Research indicates that probiotics can influence the nervous system via the microbial-gut-brain axis, wherein extracellular vesicles secreted by the gut microbiota play a significant role in this process. RESULTS In this study, we first established a 30-day ethanol exposure and probiotic gavage mouse model, both of which influenced behavior and the composition of gut microbiota. We then extracted gut microbiota-derived extracellular vesicles from the feces of these model mice and injected them into new mice via the tail vein to assess the role of each set of extracellular vesicles. The results indicated that the extracellular vesicles derived from the intestinal microbiota in the ethanol group induced anxiety-like behavior and hippocampal neuroinflammation in the recipient mice. In contrast, the extracellular vesicles secreted by the gut microbiota from the probiotic group mitigated the anxiety-like behavior and neuroinflammation induced by ethanol-influenced extracellular vesicles. CONCLUSIONS Our study demonstrates that extracellular vesicles secreted by the gut microbiota can influence the nervous system via the microbial-gut-brain axis. Furthermore, we found that the extracellular vesicles secreted by the gut microbiota from the probiotic group exert a beneficial therapeutic effect on anxiety and hippocampal neuroinflammation.
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Affiliation(s)
- Jiaxin Pei
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Chaoxu Zhang
- Department of Hematology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Qian Zhang
- Department of Health Statistics, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
- Department of Reproductive Medicine, General Hospital of Northern Theater Command, Shenyang, Liaoning, People's Republic of China
| | - Hao Yu
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Huiya Yuan
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
- Department of Forensic Analytical Toxicology, China Medical University School of Forensic Medicine, Shenyang, 110122, Liaoning, People's Republic of China
| | - Yufu Guo
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Hui Shen
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Hao Liu
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Changliang Wang
- The People's Procuratorate of Liaoning Province Judicial Authentication Center, Shenyang, Liaoning, People's Republic of China
- Collaborative Laboratory of Intelligentized Forensic Science (CLIFS), Shenyang, Liaoning, People's Republic of China
| | - Fanyue Meng
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
- Department of Morphology, Medical College of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Chenyang Yu
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Jinming Tie
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Xiaohuan Chen
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China
| | - Xu Wu
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China.
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China.
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China.
| | - Guohua Zhang
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China.
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China.
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China.
| | - Xiaolong Wang
- Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, Liaoning, People's Republic of China.
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang, Liaoning, People's Republic of China.
- China Medical University Center of Forensic Investigation, Shenyang, Liaoning, People's Republic of China.
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Ziegler GC, Groß S, Boreatti A, Heine M, McNeill RV, Kranz TM, Romanos M, Jacob CP, Reif A, Kittel-Schneider S, Lesch KP. Suicidal behavior in ADHD: the role of comorbidity, psychosocial adversity, personality and genetic factors. DISCOVER MENTAL HEALTH 2024; 4:51. [PMID: 39499453 PMCID: PMC11538115 DOI: 10.1007/s44192-024-00103-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 10/09/2024] [Indexed: 11/07/2024]
Abstract
Adult ADHD is associated with increased risk for suicide attempts, as indicated by investigations of population- and community-based cohorts. However, there is little data regarding suicide attempts in a clinical setting. To address this, we used a comprehensively phenotyped clinical adult ADHD (aADHD) cohort to assess to which extent comorbidity, psychosocial adversity, personality, and ADHD symptoms contribute to suicidal behavior in ADHD. Furthermore, we investigated a triallelic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR), which has previously been associated with suicidal behavior. Depression, substance use, eating, and posttraumatic stress disorders were independently associated with past suicide attempts, whereas anxiety, somatoform, and obsessive-compulsive spectrum disorders showed no association. Pulmonary diseases also showed an association with suicidal behavior. Psychosocial factors including occupational status, marital status/living situation, externalizing behavior and psychiatric family history were strongly associated with past suicide attempts. ADHD symptoms of inattention and hyperactivity/impulsivity were not associated with past suicide attempts after adjustment for psychiatric comorbidity and psychosocial adversity. However, the personality trait of neuroticism fully mediated the association between depression and suicidal behavior. 5-HTTLPR was not associated with suicidal behavior, but an interaction with ADHD symptoms and subtype was found. Our data suggest that psychiatric comorbidity and psychosocial adversity are key factors for suicidal behavior in aADHD, with neuroticism representing a critical mediator of the association between depression and suicidality. Further research, preferentially with longitudinal study designs is needed to better understand causal factors for suicidal behavior to enable effective preventive action.
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Affiliation(s)
- Georg C Ziegler
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany.
| | - Silke Groß
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Andrea Boreatti
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Monika Heine
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Rhiannon V McNeill
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Thorsten M Kranz
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Marcel Romanos
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Christian P Jacob
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
- Department of Psychiatry and Psychotherapy, Medius Hospital of Kirchheim, Kirchheim Unter Teck, Germany
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
| | - Sarah Kittel-Schneider
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Klaus-Peter Lesch
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
- Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
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18
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Mishra S, Stany B, Das A, Kanagavel D, Vijayan M. A Comprehensive Review of Membrane Transporters and MicroRNA Regulation in Alzheimer's Disease. Mol Neurobiol 2024; 61:8739-8758. [PMID: 38558361 DOI: 10.1007/s12035-024-04135-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 03/15/2024] [Indexed: 04/04/2024]
Abstract
Alzheimer's disease (AD) is a distressing neurodegenerative condition characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles within the brain. The interconnectedness between membrane transporters (SLCs) and microRNAs (miRNAs) in AD pathogenesis has gained increasing attention. This review explores the localization, substrates, and functions of SLC transporters in the brain, emphasizing the roles of transporters for glutamate, glucose, nucleosides, and other essential compounds. The examination delves into the significance of SLCs in AD, their potential for drug development, and the intricate realm of miRNAs, encompassing their transcription, processing, functions, and regulation. MiRNAs have emerged as significant players in AD, including those associated with mitochondria and synapses. Furthermore, this review discusses the intriguing nexus of miRNAs targeting SLC transporters and their potential as therapeutic targets in AD. Finally, the review underscores the interaction between SLC transporters and miRNA regulation within the context of Alzheimer's disease, underscoring the need for further research in this area. This comprehensive review aims to shed light on the complex mechanisms underlying the causation of AD and provides insights into potential therapeutic approaches.
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Affiliation(s)
- Shatakshi Mishra
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - B Stany
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - Anushka Das
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - Deepankumar Kanagavel
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India.
| | - Murali Vijayan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX, 79430, USA.
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Jaros A, Rybakowski F, Cielecka-Piontek J, Paczkowska-Walendowska M, Czerny B, Kamińki A, Wafaie Mahmoud Elsorady R, Bienert A. Challenges and Opportunities in Managing Geriatric Depression: The Role of Personalized Medicine and Age-Appropriate Therapeutic Approaches. Pharmaceutics 2024; 16:1397. [PMID: 39598521 PMCID: PMC11597233 DOI: 10.3390/pharmaceutics16111397] [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: 09/23/2024] [Revised: 10/26/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
The global aging population has experienced rapid growth in recent decades, leading to an increased prevalence of psychiatric disorders, particularly depression, among older adults. Depression in the geriatric population is often compounded by chronic physical conditions and various psychosocial factors, significantly impacting their quality of life. The main question raised in this review is as follows: how can personalized medicine and age-appropriate therapeutic approaches improve the management of geriatric depression? This paper explores the epidemiology of geriatric depression, highlighting the influence of gender, race, and socioeconomic status on its prevalence. The classification and diagnosis of geriatric depressive disorders, based on ICD-11 and DSM-5 criteria, reveal the complexity of managing these conditions in older adults. Personalized medicine (PM) emerges as a promising approach, focusing on tailoring treatments to the individual's genetic, clinical, and environmental characteristics. However, the application of PM in this demographic faces challenges, particularly in the context of pharmaceutical forms. The need for age-appropriate drug delivery systems is critical, given the prevalence of polypharmacy and issues such as dysphagia among the older patients. This study emphasizes the importance of developing patient-centric formulations to enhance the effectiveness of personalized therapy in geriatric patients.
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Affiliation(s)
- Agnieszka Jaros
- Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
| | - Filip Rybakowski
- Head of Adult Psychiatry Clinic, Poznan University of Medical Sciences, 60-810 Poznan, Poland;
| | - Judyta Cielecka-Piontek
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, 3 Rokietnicka St., 60-806 Poznan, Poland; (J.C.-P.); (M.P.-W.)
- Institute of Natural Fibers and Medicinal Plants National Research Institute, ul. Wojska Polskiego 71 b, 60-630 Poznan, Poland;
| | - Magdalena Paczkowska-Walendowska
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, 3 Rokietnicka St., 60-806 Poznan, Poland; (J.C.-P.); (M.P.-W.)
| | - Bogusław Czerny
- Institute of Natural Fibers and Medicinal Plants National Research Institute, ul. Wojska Polskiego 71 b, 60-630 Poznan, Poland;
- Departament of General Pharmacology and Pharmacoeconomics, Promeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Adam Kamińki
- Department of Orthopedics nad Traumatology, Independent Public Clinical Hospital No. 1, Promeranian Medical University in Szczecin, Unii Lubleskiej 1, 71-252 Szczecin, Poland;
| | - Rasha Wafaie Mahmoud Elsorady
- Head of Clinical Pharmacy Departments at Alexandria University Hospitals, Alexandria University, Alexandria 21523, Egypt;
| | - Agnieszka Bienert
- Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
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20
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Yatabe K, Ashikaga K, Muroi R, Somemura S, Takemoto M, Yudoh K, Miyano H, Fujiya H. Pain Candidate Genes 5-HTTLPR and COMT Affect Anxiety and Mood in Japanese Ballet Dancers: A Cross-Sectional and Longitudinal Study. Sports (Basel) 2024; 12:293. [PMID: 39590895 PMCID: PMC11598313 DOI: 10.3390/sports12110293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/28/2024] Open
Abstract
The balance of mental, physical, and technical aspects is essential in improving ballet performance. Ballet dancers' emotional and behavioral characteristics vary, even under identical stress conditions. This study aimed to investigate the association between the pain candidate genes 5-HTTLPR and COMT and anxiety in Japanese ballet dancers. Participants were 18 youth elite ballet students with professional aspirations (Y-Elite) and 16 dancers in a professional ballet company (Pro). We administered psychological questionnaires, the State-Trait Anxiety Inventory (STAI) and Brunel Mood Scale (BRUMS), to participants under the following four different stress conditions: standard practice day, cast decision day, rehearsal day, and one week before competition day. In addition, the genotypes of 5-HTTLPR and COMT Val158Met were examined. The distribution of 5-HTTLPR was not different between Y-Elite and Pro dancers, although one of the COMT genotypes was different. Y-Elite dancers had higher trait anxiety scores than Pro dancers for these genotypes before competition (ps < 0.03), although no significant association was observed between both genotypes and scores on the STAI across conditions. Their moods were significantly different through the four conditions (p < 0.004). Pro dancers' moods were also more stable than those of the Y-Elite dancers in the presence of pain. The results indicate that 5-HTTLPR and COMT play a crucial role in dancers' anxiety and mood during pain (ps < 0.05). Pro dancers are probably predicted by their lower neuroticism and mood scores and their better adaptation to stress than Y-Elite dancers. The 5-HTTLPR and COMT genes may be influencing the sensitivity to the environment. Youth elite ballet dancers need to understand the relationship between pain and physical activity from an early stage.
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Affiliation(s)
- Kanaka Yatabe
- Department of Sports Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
| | - Kohei Ashikaga
- Department of Sports Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
| | - Ryota Muroi
- Department of Sports Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
| | - Shu Somemura
- Department of Orthopaedic Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
| | - Masahiro Takemoto
- Department of Orthopaedic Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
| | - Kazuo Yudoh
- Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Hisao Miyano
- Department of Cognitive and Information Sciences, Faculty of Letters, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Hiroto Fujiya
- Department of Sports Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
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21
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Suktas A, Ekalaksananan T, Aromseree S, Bumrungthai S, Songserm N, Pientong C. Genetic polymorphism involved in major depressive disorder: a systemic review and meta-analysis. BMC Psychiatry 2024; 24:716. [PMID: 39438912 PMCID: PMC11515766 DOI: 10.1186/s12888-024-06195-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Genetic polymorphism studies in families and twins indicated the heritability of depression. However, the association between genes with genetic polymorphism and depression provides various findings and remains unclear. Therefore, we conducted a systematic review and meta-analysis to determine the genes with their polymorphism associated with the symptomatic depression known as major depressive disorder (MDD). MATERIALS AND METHODS PubMed and Scopus were searched for relevant studies published before May 22, 2023 (1968-2023), and 62 were selected for this review. The study's bias risk was investigated using the Newcastle-Ottawa scale. Gene functional enrichment analysis was investigated for molecular function (MF) and biological process (BP) and pathways. A meta-analysis of the studied genes that were replicative in the same single nucleotide polymorphism was conducted using a random-effect model. RESULTS The 49 genes involved in MDD were studied and engaged in several pathways, such as tryptophan metabolism or dopaminergic and serotonergic synapses. Based on gene overlapping in MF and BP, 13 genes with polymorphisms were identified as related to MDD. Most of them were only studied once. Solute carrier family 6 member 4 (SLC6A4) overlapping between MF and BP and brain-derived neurotrophic factor (BDNF) as unique to BP were replicative studied and used in the meta-analysis. The polymorphism of SLC6A4 SS and LS genotypes increased the occurrence of MDD development but not significantly [odd ratio (OR) = 1.39; 95% confidence interval (CI) = 0.87-2.22; P = 0.16 and OR = 1.13; 95% CI = 0.84-1.53; P = 0.42, respectively]. A similar result was observed for BDNF rs6265 GG (OR = 1.26; 95% CI = 0.78-2.06; P = 0.35) and BDNF rs6265 AA genotypes (OR = 1.12; 95% CI = 0.77-1.64; P = 0.56). These studies indicated low bias and significant heterogeneity. CONCLUSION At least 13 studied genes with polymorphisms were involved in MDD development according to MF and BP, but not significantly. These results suggest that MDD development risk factors might require genetic and other factors for interaction and induction.
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Grants
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
- IN66093 Faculty of Medicine, Khon Kaen University, Thailand
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Affiliation(s)
- Areeya Suktas
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sirinart Aromseree
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sureewan Bumrungthai
- Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand
| | - Nopparat Songserm
- Faculty of Public Health, Ubon Ratchathani Rajabhat University, Ubon Ratchathani, Thailand
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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22
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Landoni M, Di Tella S, Ciuffo G, Ionio C. The Association between Post-Traumatic Stress Disorder, 5HTTLPR, and the Role of Ethnicity: A Meta-Analysis. Genes (Basel) 2024; 15:1270. [PMID: 39457394 PMCID: PMC11508081 DOI: 10.3390/genes15101270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES The current meta-analysis looks at the effect of ethnicity on the connection between 5-HTTLPR SNPs and PTSD patients in all published genetic association studies. TECHNIQUES In accordance with PRISMA principles, the literature was searched in PubMed, Scopus, and ScienceDirect. A consistent method was followed by two reviewers who independently chose publications for inclusion and extracted data. Using a random-effects model, a meta-analysis of the biallelic and triallelic studies was conducted in order to determine the pooled OR and the associated 95% CI. The impact estimates were corrected for minor study effects, including publication bias, using the trim-and-fill approach. FINDINGS After 17 studies were deemed eligible for inclusion, the overall sample size was 8838 controls and 2586 PTSD patients, as opposed to 627 and 3524 in the triallelic meta-analysis. The results of our meta-analysis and comprehensive review do not point to a direct main effect of the 5-HTTLPR polymorphisms on PTSD. Nonetheless, preliminary data suggest that ethnicity influences the association between 5-HTTLPR and PTSD. CONCLUSIONS According to our findings, ethnicity-especially African ethnicity-has a major influence on the relationship between 5-HTTLPR and PTSD and needs to be taken into account as a crucial moderating factor in further studies.
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Affiliation(s)
- Marta Landoni
- Developmental and Educational Dynamics Research Center (CRIdee), Università Cattolica del Sacro Cuore, 20123 Milan, Italy; (G.C.); (C.I.)
| | - Sonia Di Tella
- Department of Psychology, Università Cattolica del Sacro Cuore, 20123 Milan, Italy;
| | - Giulia Ciuffo
- Developmental and Educational Dynamics Research Center (CRIdee), Università Cattolica del Sacro Cuore, 20123 Milan, Italy; (G.C.); (C.I.)
| | - Chiara Ionio
- Developmental and Educational Dynamics Research Center (CRIdee), Università Cattolica del Sacro Cuore, 20123 Milan, Italy; (G.C.); (C.I.)
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23
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Bellia F, Piccinini A, Annunzi E, Cannito L, Lionetti F, Dell’Osso B, Adriani W, Dainese E, Di Domenico A, Pucci M, Palumbo R, D’Addario C. Dopamine and Serotonin Transporter Genes Regulation in Highly Sensitive Individuals during Stressful Conditions: A Focus on Genetics and Epigenetics. Biomedicines 2024; 12:2149. [PMID: 39335662 PMCID: PMC11429336 DOI: 10.3390/biomedicines12092149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Background: Coping with stress is essential for mental well-being and can be critical for highly sensitive individuals, characterized by a deeper perception and processing of stimuli. So far, the molecular bases characterizing high-sensitivity traits have not been completely investigated and gene × environment interactions might play a key role in making some people more susceptible than others. Methods: In this study, 104 young adult university students, subjects that might face overwhelming experiences more than others, were evaluated for the genetics and epigenetics of dopamine (DAT1) and serotonin (SERT) transporter genes, in addition to the expression of miR-132, miR-491, miR-16, and miR-135. Results: We found an increase in DNA methylation at one specific CpG site at DAT1 5'UTR in highly sensitive students reporting high levels of perceived stress when compared to those less sensitive and/or less stressed. Moreover, considering DAT1 VNTR at 3'UTR, we observed that this effect was even more pronounced in university students having the 9/9 genotype when compared to those with the 9/10 genotype. These data are corroborated by the higher levels of miR-491, targeting DAT1, in highly sensitive subjects with high levels of perceived stress. SERT gene DNA methylation at one specific CpG site was reported to instead be higher in subjects reporting lower perceived stress when compared to more stressed subjects. Consistently, miR-135 expression, regulating SERT, was lower in subjects with higher perceived stress. Conclusions: We here suggest that the correlation of DAT1 and SERT genetic and epigenetic data with the analysis of stress and sensitivity might be useful to suggest possible biomarkers to monitor mental health wellness in vulnerable subjects.
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Affiliation(s)
- Fabio Bellia
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (F.B.); (A.P.); (E.A.); (E.D.); (M.P.)
- Department of Innovative Technologies in Medicine and Dentistry, University “G. D’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Alessandro Piccinini
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (F.B.); (A.P.); (E.A.); (E.D.); (M.P.)
| | - Eugenia Annunzi
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (F.B.); (A.P.); (E.A.); (E.D.); (M.P.)
| | - Loreta Cannito
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
- Department of Social Sciences, University of Foggia, 71122 Foggia, Italy
| | - Francesca Lionetti
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy;
| | - Bernardo Dell’Osso
- Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, 20019 Milan, Italy;
- “Aldo Ravelli” Center for Nanotechnology and Neurostimulation, University of Milan, 20122 Milan, Italy
| | - Walter Adriani
- Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy;
| | - Enrico Dainese
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (F.B.); (A.P.); (E.A.); (E.D.); (M.P.)
| | - Alberto Di Domenico
- Department of Psychological, Health and Territorial Sciences, University “G. D’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Mariangela Pucci
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (F.B.); (A.P.); (E.A.); (E.D.); (M.P.)
| | - Riccardo Palumbo
- Department of Neuroscience, Imaging and Clinical Sciences, University “G.D’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Claudio D’Addario
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy; (F.B.); (A.P.); (E.A.); (E.D.); (M.P.)
- Department of Clinical Neuroscience, Karolinska Institute, 10316 Stockholm, Sweden
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24
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Ahmed S, Hossain MA, Bristy SA, Ali MS, Rahman MH. Adopting Integrated Bioinformatics and Systems Biology Approaches to Pinpoint the COVID-19 Patients' Risk Factors That Uplift the Onset of Posttraumatic Stress Disorder. Bioinform Biol Insights 2024; 18:11779322241274958. [PMID: 39281421 PMCID: PMC11402063 DOI: 10.1177/11779322241274958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/23/2024] [Indexed: 09/18/2024] Open
Abstract
Owing to the recent emergence of COVID-19, there is a lack of published research and clinical recommendations for posttraumatic stress disorder (PTSD) risk factors in patients who contracted or received treatment for the virus. This research aims to identify potential molecular targets to inform therapeutic strategies for this patient population. RNA sequence data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and PTSD (from the National Center for Biotechnology Information [NCBI]) were processed using the GREIN database. Protein-protein interaction (PPI) networks, pathway enrichment analyses, miRNA interactions, gene regulatory network (GRN) studies, and identification of linked drugs, chemicals, and diseases were conducted using STRING, DAVID, Enrichr, Metascape, ShinyGO, and NetworkAnalyst v3.0. Our analysis identified 15 potentially unique hub proteins within significantly enriched pathways, including PSMB9, MX1, HLA-DOB, HLA-DRA, IFIT3, OASL, RSAD2, and so on, filtered from a pool of 201 common differentially expressed genes (DEGs). Gene ontology (GO) terms and metabolic pathway analyses revealed the significance of the extracellular region, extracellular space, extracellular exosome, adaptive immune system, and interleukin (IL)-18 signaling pathways. In addition, we discovered several miRNAs (hsa-mir-124-3p, hsa-mir-146a-5p, hsa-mir-148b-3p, and hsa-mir-21-3p), transcription factors (TF) (WRNIP1, FOXC1, GATA2, CREB1, and RELA), a potentially repurposable drug carfilzomib and chemicals (tetrachlorodibenzodioxin, estradiol, arsenic trioxide, and valproic acid) that could regulate the expression levels of hub proteins at both the transcription and posttranscription stages. Our investigations have identified several potential therapeutic targets that elucidate the probability that victims of COVID-19 experience PTSD. However, they require further exploration through clinical and pharmacological studies to explain their efficacy in preventing PTSD in COVID-19 patients.
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Affiliation(s)
- Sabbir Ahmed
- Department of Electrical and Computer Engineering, The University of Texas at El Paso, El Paso, TX, USA
| | - Md Arju Hossain
- Department of Microbiology, Primeasia University, Dhaka, Bangladesh
| | - Sadia Afrin Bristy
- Bioinformatics and Biomedical Research Network of Bangladesh, Dhaka, Bangladesh
| | - Md Shahjahan Ali
- Department of Electrical and Computer Engineering, The University of Texas at El Paso, El Paso, TX, USA
| | - Md Habibur Rahman
- Department of Computer Science and Engineering, Islamic University, Kushtia, Bangladesh
- Center for Advanced Bioinformatics and Artificial Intelligence Research, Islamic University, Kushtia, Bangladesh
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25
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Bremshey S, Groß J, Renken K, Masseck OA. The role of serotonin in depression-A historical roundup and future directions. J Neurochem 2024; 168:1751-1779. [PMID: 38477031 DOI: 10.1111/jnc.16097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024]
Abstract
Depression is one of the most common psychiatric disorders worldwide, affecting approximately 280 million people, with probably much higher unrecorded cases. Depression is associated with symptoms such as anhedonia, feelings of hopelessness, sleep disturbances, and even suicidal thoughts. Tragically, more than 700 000 people commit suicide each year. Although depression has been studied for many decades, the exact mechanisms that lead to depression are still unknown, and available treatments only help a fraction of patients. In the late 1960s, the serotonin hypothesis was published, suggesting that serotonin is the key player in depressive disorders. However, this hypothesis is being increasingly doubted as there is evidence for the influence of other neurotransmitters, such as noradrenaline, glutamate, and dopamine, as well as larger systemic causes such as altered activity in the limbic network or inflammatory processes. In this narrative review, we aim to contribute to the ongoing debate on the involvement of serotonin in depression. We will review the evolution of antidepressant treatments, systemic research on depression over the years, and future research applications that will help to bridge the gap between systemic research and neurotransmitter dynamics using biosensors. These new tools in combination with systemic applications, will in the future provide a deeper understanding of the serotonergic dynamics in depression.
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Affiliation(s)
- Svenja Bremshey
- Synthetic Biology, University of Bremen, Bremen, Germany
- Neuropharmacology, University of Bremen, Bremen, Germany
| | - Juliana Groß
- Synthetic Biology, University of Bremen, Bremen, Germany
| | - Kim Renken
- Synthetic Biology, University of Bremen, Bremen, Germany
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26
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Hu Z, Lin G, Zhang M, Piao S, Fan J, Liu J, Liu P, Fu S, Sun W, Li L, Qiu X, Zhang J, Yang Y, Zhou C. Mechanistic Characterization of De Novo Generation of Variable Number Tandem Repeats in Circular Plasmids during Site-Directed Mutagenesis and Optimization for Coding Gene Application. Adv Biol (Weinh) 2024; 8:e2400084. [PMID: 38880850 DOI: 10.1002/adbi.202400084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/21/2024] [Indexed: 06/18/2024]
Abstract
Site-directed mutagenesis for creating point mutations, sometimes, gives rise to plasmids carrying variable number tandem repeats (VNTRs) locally, which are arbitrarily regarded as polymerase chain reaction (PCR) related artifacts. Here, the alternative end-joining mechanism is reported rather than PCR artifacts accounts largely for that VNTRs formation and expansion. During generating a point mutation on GPLD1 gene, an unexpected formation of VNTRs employing the 31 bp mutagenesis primers is observed as the repeat unit in the pcDNA3.1-GPLD1 plasmid. The 31 bp VNTRs are formed in 24.75% of the resulting clones with copy number varied from 2 to 13. All repeat units are aligned with the same orientation as GPLD1 gene. 43.54% of the repeat junctions harbor nucleotide mutations while the rest don't. Their demonstrated short primers spanning the 3' part of the mutagenesis primers are essential for initial creation of the 2-copy tandem repeats (TRs) in circular plasmids. The dimerization of mutagenesis primers by the alternative end-joining in a correct orientation is required for further expansion of the 2-copy TRs. Lastly, a half-double priming strategy is established, verified the findings and offered a simple method for VNTRs creation on coding genes in circular plasmids without junction mutations.
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Affiliation(s)
- Ziqi Hu
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Guochao Lin
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Mingzhu Zhang
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Shengwen Piao
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jiankun Fan
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Jichao Liu
- The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Peng Liu
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
| | - Songbin Fu
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, China
| | - Wenjing Sun
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, China
| | - Li Li
- The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Xiaohong Qiu
- The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Jinwei Zhang
- The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Yu Yang
- The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Chunshui Zhou
- The Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China
- The Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, China
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Twyman H, Heywood I, Barros M, Zeredo J, Mundy NI, Santangelo AM. Evolution of threat response-related polymorphisms at the SLC6A4 locus in callitrichid primates. Biol Lett 2024; 20:20240024. [PMID: 39013428 PMCID: PMC11251774 DOI: 10.1098/rsbl.2024.0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 05/03/2024] [Accepted: 06/09/2024] [Indexed: 07/18/2024] Open
Abstract
Variation in an upstream repetitive region at the SLC6A4 locus, which encodes the serotonin transporter, is associated with anxiety-related behaviour in a few primate species, including humans and rhesus macaques, and has been suggested to be related to ecological adaptability among macaques. In this study, we investigate evolution of SLC6A4 polymorphisms associated with anxiety-related behaviour in common marmosets (Callithrix jacchus). Assaying variation in the SLC6A4 repeat region across 14 species in eight genera of callitrichid primates (marmosets and tamarins), we find large interspecific variation in the number of repeats present (24-43). The black tufted-ear marmoset (C. penicillata) has sequence polymorphisms similar to those found in the common marmoset, which is its sister species, and no other species has intraspecific variation at these sites. We conclude that, similar to humans and macaques, the functional polymorphism at SLC6A4 in common marmosets has a recent evolutionary origin, and that the anxiety-related allele is evolutionarily derived. Common/black tufted-ear marmosets and rhesus/bonnet macaques share high ecological adaptability and behavioural flexibility that we propose may be related to the maintenance of the polymorphism.
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Affiliation(s)
- Hanlu Twyman
- Department of Zoology, Downing Street, CambridgeCB2 3EJ, UK
| | - India Heywood
- Department of Zoology, Downing Street, CambridgeCB2 3EJ, UK
| | - Marília Barros
- Departamento de Farmácia, Universidade de Brasília, Campus Universitário - Asa Norte, Brasília, Brazil
| | - Jorge Zeredo
- Graduate Program in Health Sciences and Technologies, Universidade de Brasília, Campus Ceilândia – Ceilândia Sul, Brasília, DFCEP 72.220-275, Brazil
| | | | - Andrea M. Santangelo
- MRC Cognition and Brain Sciences Unit, University of Cambridge, 15 Chaucer Road, CambridgeCB2 7EF, UK
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Almaghrbi H, Bawadi H. Genetic polymorphisms and their association with neurobiological and psychological factors in anorexia nervosa: a systematic review. Front Psychol 2024; 15:1386233. [PMID: 38979077 PMCID: PMC11229080 DOI: 10.3389/fpsyg.2024.1386233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/29/2024] [Indexed: 07/10/2024] Open
Abstract
Background and aims Anorexia nervosa (AN) is a complex neuropsychiatric disorder. This systematic review synthesizes evidence from diverse studies to assess and investigate the association between gene polymorphisms and psychological and neurobiological factors in patients with AN. Methods A systematic search across PubMed, PsycINFO, Scopus, and Web of Science databases, along with manual searching, was conducted. The review protocol was approved by PROSPERO (CRD42023452548). Out of 1,250 articles, 11 met the inclusion criteria. The quality of eligible articles was assessed using the Newcastle-Ottawa Scale (NOS) tool. The systematic review followed the PRISMA guidelines. Results The serotoninergic system, particularly the 5-HTTLPR polymorphism, is consistently linked to altered connectivity in the ventral attention network, impaired inhibitory control, and increased susceptibility to AN. The 5-HTTLPR polymorphism affects reward processing, motivation, reasoning, working memory, inhibition, and outcome prediction in patients with AN. The dopaminergic system, involving genes like COMT, DRD2, DRD3, and DAT1, regulates reward, motivation, and decision-making. Genetic variations in these dopaminergic genes are associated with psychological manifestations and clinical severity in patients with AN. Across populations, the Val66Met polymorphism in the BDNF gene influences personality traits, eating behaviors, and emotional responses. Genes like OXTR, TFAP2B, and KCTD15 are linked to social cognition, emotional processing, body image concerns, and personality dimensions in patients with AN. Conclusion There was an association linking multiple genes to the susceptibly and/or severity of AN. This genetic factor contributes to the complexity of AN and leads to higher diversity of its clinical presentation. Therefore, conducting more extensive research to elucidate the underlying mechanisms of anorexia nervosa pathology is imperative for advancing our understanding and potentially developing targeted therapeutic interventions for the disorder.Systematic review registration: [https://clinicaltrials.gov/], identifier [CRD42023452548].
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Affiliation(s)
- Heba Almaghrbi
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Hiba Bawadi
- Department of Human Nutrition, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
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Neukam PT, Müller DK, Deza-Lougovski YI, Pooseh S, Witt SH, Rietschel M, Smolka MN. Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses. Int J Mol Sci 2024; 25:6666. [PMID: 38928372 PMCID: PMC11203796 DOI: 10.3390/ijms25126666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
S/S carriers of 5-HTTLPR have been found to be more risk seeking for losses compared to L/L carriers. This finding may be the result of reduced top-down control from the frontal cortex due to altered signal pathways involving the amygdala and ventral striatum. The serotonergic system is known to be involved in neurodevelopment and neuroplasticity. Therefore, the aim of this study was to investigate whether structural differences in white matter can explain the differences in risk-seeking behaviour. Lower structural connectivity in S/S compared to L/L carriers and a negative relationship between risk seeking for losses and connectivity were assumed. Diffusion-weighted imaging was used to compute diffusion parameters for the frontostriatal and uncinate tract in 175 genotyped individuals. The results showed no significant relationship between diffusion parameters and risk seeking for losses. Furthermore, we did not find significant differences in diffusion parameters of the S/S vs. L/L group. There were only group differences in the frontostriatal tract showing stronger structural connectivity in the S/L group, which is also reflected in the whole brain approach. Therefore, the data do not support the hypothesis that the association between 5-HTTLPR and risk seeking for losses is related to differences in white matter pathways implicated in decision-making.
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Affiliation(s)
- Philipp T. Neukam
- Department of Psychiatry and Psychotherapy, Technische Universität Dresden, 01307 Dresden, Germany;
| | - Dirk K. Müller
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | | | - Shakoor Pooseh
- Center for Interdisciplinary Digital Sciences (CIDS), Technische Universität Dresden, 01069 Dresden, Germany;
| | - Stephanie H. Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, 68159 Mannheim, Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, 68159 Mannheim, Germany
| | - Michael N. Smolka
- Department of Psychiatry and Psychotherapy, Technische Universität Dresden, 01307 Dresden, Germany;
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Rufino KA, Goli P, Patriquin MA, Kosten TR, Nielsen DA, Salas R. Val/Met BDNF as a genetic risk for a false sense of security in post-discharge suicide risk. J Affect Disord 2024; 354:98-103. [PMID: 38447916 DOI: 10.1016/j.jad.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/14/2024] [Accepted: 03/03/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND The time after discharge from psychiatric inpatient care is one of the most dangerous periods in terms of suicide risk. Predicting who is at higher risk could help with resource allocation to assure patients at high risk of suicide attempts are most closely followed. We previously showed that inpatients who improve their suicide ideation levels faster while in inpatient treatment are the ones with highest rates of post-discharge suicide. Here, we studied the possible genetic underpinnings associated with such risk. METHOD We recorded the slope of suicide ideation recovery of 710 psychiatric inpatients from which we studied two genetic variants likely associated with suicide risk: The serotonin transporter variant 5-HTTLPR, and the BDNF gene variant Val66Met. RESULTS We found that inpatients carrying the BDNF Met variant (hypothesized as conferring higher suicide risk) improved their suicide ideation scores faster than Val/Val carrying inpatients. No significant association was found for 5-HTTLPR. LIMITATIONS The present sample was genetically homogenous, and future research should replicate these findings on a more diverse sample. CONCLUSIONS In conclusion, we found a paradoxical result: Carrying the BDNF Met variant allows inpatients to improve faster, which was shown to confer higher risk at the post-discharge period. This may explain some inconsistencies in the literature in terms of the role of BDNF in suicide ideation and attempts.
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Affiliation(s)
- K A Rufino
- The Menninger Clinic, Houston, TX, USA; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Department of Social Sciences, The University of Houston Downtown, Houston, TX, USA
| | - P Goli
- Rice University, Houston, TX, USA
| | - M A Patriquin
- The Menninger Clinic, Houston, TX, USA; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Michael E DeBakey VA Medical Center, Houston, TX, USA
| | - T R Kosten
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Michael E DeBakey VA Medical Center, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - D A Nielsen
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Michael E DeBakey VA Medical Center, Houston, TX, USA
| | - R Salas
- The Menninger Clinic, Houston, TX, USA; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Center for Translational Research on Inflammatory Diseases, Michael E DeBakey VA Medical Center, Houston, TX, USA.
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31
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Nakamura M, Yoshimi A, Tokura T, Kimura H, Kishi S, Miyauchi T, Iwamoto K, Ito M, Sato-Boku A, Mouri A, Nabeshima T, Ozaki N, Noda Y. Duloxetine improves chronic orofacial pain and comorbid depressive symptoms in association with reduction of serotonin transporter protein through upregulation of ubiquitinated serotonin transporter protein. Pain 2024; 165:1177-1186. [PMID: 38227563 DOI: 10.1097/j.pain.0000000000003124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 10/26/2023] [Indexed: 01/18/2024]
Abstract
ABSTRACT Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and depressive symptoms, and to associate with their effectiveness in platelet serotonin transporter (SERT) expression, which is a target molecule of DLX and plasma serotonin concentration in COP patients with depressive symptoms. We assessed for the severity of pain and depressive symptoms using the Visual Analog Scale (VAS) and 17-item Hamilton Depression Rating Scale (HDRS), respectively. Chronic orofacial pain patients were classified into 2 groups based on their HDRS before DLX-treatment: COP patients with (COP-D) and without (COP-ND) depressive symptoms. We found that the VAS and HDRS scores of both groups were significantly decreased after DLX treatment compared with those before DLX treatment. Upregulation of total SERT and downregulation of ubiquitinated SERT were observed before DLX treatment in both groups compared with healthy controls. After DLX treatment, there were no differences in total SERT of both groups and in ubiquitinated SERT of COP-D patients compared with healthy controls; whereas, ubiquitinated SERT of COP-ND patients remained downregulated. There were positive correlations between changes of serotonin concentrations and of VAS or HDRS scores in only COP-D patients. Our findings indicate that DLX improves not only pain but also comorbid depressive symptoms of COP-D patients. Duloxetine also reduces platelet SERT through upregulation of ubiquitinated SERT. As the result, decrease of plasma serotonin concentrations may be related to the efficacy of DLX in relieving pain and depression in COP patients.
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Grants
- 21H04815 Ministry of Education, Culture, Sports, Science and Technology
- 17K10325 Ministry of Education, Culture, Sports, Science and Technology
- 21K06719 Ministry of Education, Culture, Sports, Science and Technology
- 19K17108 Ministry of Education, Culture, Sports, Science and Technology
- JP21dk0307103, Japan Agency for Medical Research and Development
- JP21dk0307087 Japan Agency for Medical Research and Development
- P21wm0425007 Japan Agency for Medical Research and Development
- JP21dm0207075 Japan Agency for Medical Research and Development
- JP21ek0109498 Japan Agency for Medical Research and Development
- AS251Z03018 Adaptable and Seamless Technology Transfer Program through Target-Driven R and D
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Affiliation(s)
- Mariko Nakamura
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, Nagoya, Japan
| | - Akira Yoshimi
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, Nagoya, Japan
- Clinical OMICs and Translation Research Center, Meijo University, Nagoya, Japan
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tatsuya Tokura
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Kimura
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinichi Kishi
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoya Miyauchi
- Department of Psychiatry, KACHI Memorial Hospital, Toyohashi, Japan
| | - Kunihiro Iwamoto
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mikiko Ito
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Aiji Sato-Boku
- Department of Anesthesiology, School of Dentistry, Aichi Gakuin University, Nagoya Japan
| | - Akihiro Mouri
- Department of Regulatory Science for Evaluation & Development of Pharmaceuticals and Devices, Graduate School of Health Science, Fujita Health University, Aichi, Japan
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Toshitaka Nabeshima
- Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
- Laboratory of Health and Medical Science Innovation, Graduate School of Health Sciences, Fujita Health University, Aichi, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihiro Noda
- Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy, Meijo University, Nagoya, Japan
- Clinical OMICs and Translation Research Center, Meijo University, Nagoya, Japan
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Laboratory of Health and Medical Science Innovation, Graduate School of Health Sciences, Fujita Health University, Aichi, Japan
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Camilleri M, Jencks K. Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets and metabolism. Expert Opin Drug Metab Toxicol 2024; 20:319-332. [PMID: 38785066 PMCID: PMC11139426 DOI: 10.1080/17425255.2024.2349716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/26/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION Medications are frequently prescribed for patients with irritable bowel syndrome (IBS) or disorders of gut brain interaction. The level of drug metabolism and modifications in drug targets determine medication efficacy to modify motor or sensory function as well as patient response outcomes. AREAS COVERED The literature search included PubMed searches with the terms: pharmacokinetics, pharmacogenomics, epigenetics, clinical trials, irritable bowel syndrome, disorders of gut brain interaction, and genome-wide association studies. The main topics covered in relation to irritable bowel syndrome were precision medicine, pharmacogenomics related to drug metabolism, pharmacogenomics related to mechanistic targets, and epigenetics. EXPERT OPINION Pharmacogenomics impacting drug metabolism [CYP 2D6 (cytochrome P450 2D6) or 2C19 (cytochrome P450 2C19)] is the most practical approach to precision medicine in the treatment of IBS. Although there are proof of concept studies that have documented the importance of genetic modification of transmitters or receptors in altering responses to medications in IBS, these principles have rarely been applied in patient response outcomes. Genome-wide association (GWAS) studies have now documented the association of symptoms with genetic variation but not the evaluation of treatment responses. Considerably more research, particularly focused on patient response outcomes and epigenetics, is essential to impact this field in clinical medicine.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Kara Jencks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Vilela J, Rasga C, Santos JX, Martiniano H, Marques AR, Oliveira G, Vicente AM. Bridging Genetic Insights with Neuroimaging in Autism Spectrum Disorder-A Systematic Review. Int J Mol Sci 2024; 25:4938. [PMID: 38732157 PMCID: PMC11084239 DOI: 10.3390/ijms25094938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Autism Spectrum Disorder (ASD) is an early onset neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive patterns of behavior. Family studies show that ASD is highly heritable, and hundreds of genes have previously been implicated in the disorder; however, the etiology is still not fully clear. Brain imaging and electroencephalography (EEG) are key techniques that study alterations in brain structure and function. Combined with genetic analysis, these techniques have the potential to help in the clarification of the neurobiological mechanisms contributing to ASD and help in defining novel therapeutic targets. To further understand what is known today regarding the impact of genetic variants in the brain alterations observed in individuals with ASD, a systematic review was carried out using Pubmed and EBSCO databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review shows that specific genetic variants and altered patterns of gene expression in individuals with ASD may have an effect on brain circuits associated with face processing and social cognition, and contribute to excitation-inhibition imbalances and to anomalies in brain volumes.
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Affiliation(s)
- Joana Vilela
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (C.R.); (J.X.S.); (H.M.); (A.R.M.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Célia Rasga
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (C.R.); (J.X.S.); (H.M.); (A.R.M.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - João Xavier Santos
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (C.R.); (J.X.S.); (H.M.); (A.R.M.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Hugo Martiniano
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (C.R.); (J.X.S.); (H.M.); (A.R.M.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Ana Rita Marques
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (C.R.); (J.X.S.); (H.M.); (A.R.M.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Guiomar Oliveira
- Unidade de Neurodesenvolvimento e Autismo, Serviço do Centro de Desenvolvimento da Criança, Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-602 Coimbra, Portugal;
- Coimbra Institute for Biomedical Imaging and Translational Research, University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, 3000-602 Coimbra, Portugal
| | - Astrid Moura Vicente
- Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal; (J.V.); (C.R.); (J.X.S.); (H.M.); (A.R.M.)
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
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Zhang J, Gao L, Yang GL, Kong DZ. The effect of single nucleotide polymorphisms on depression in combination with coronary diseases: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2024; 15:1369676. [PMID: 38745947 PMCID: PMC11091366 DOI: 10.3389/fendo.2024.1369676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 04/03/2024] [Indexed: 05/16/2024] Open
Abstract
Background Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression combined with coronary heart disease. Methods This study was designed according to the PRISMA-P guidelines. We will include case-control studies and cohort studies investigating the relationship between gene SNPs and depression and coronary heart disease comorbidities. The Newcastle-Ottawa Scale (NOS) will be used to assess the risk of bias. When measuring dichotomous outcomes, we will use the odds ratio (OR) and 95% confidence interval (95%CIs) in a case-control study. Five genetic models (allele model, homozygous model, co-dominant model, dominant model, and recessive model) will be evaluated for each included study. Subgroup analysis by ethnicity will be performed. If necessary, post hoc analysis will be made according to different types. Results A total of 13 studies were included in this study, and the types of genes included are FKBP5 and SGK1 genes that act on glucocorticoid; miR-146a, IL-4-589, IL-6-174, TNF-α-308, CRP-717 genes that act on inflammatory mechanisms; eNOS genes from endothelial cells; HSP70 genes that act on the autoimmune response; ACE2 and MAS1 genes that act to mediate Ang(1-7) in the RAS system; 5-HTTLPR gene responsible for the transport of serotonin 5-HT and neurotrophic factor BDNF gene. There were three studies on 5-HTTLPR and BDNF genes, respectively, while there was only one study targeting FKBP5, SGK1, miR-146a, IL-4-589, IL-6-174, TNF-alpha-308, CRP-717, eNOS, HSP70, ACE2, and MAS1 genes. We did not perform a meta-analysis for genes reported in a single study, and meta-analysis was performed separately for studies exploring the 5-HTTLPR and BDNF genes. The results showed that for the 5-HTTLPR gene, there was a statistically significant association between 5-HTTLPR gene polymorphisms and depression in combination with coronary diseases (CHD-D) under the co-dominant model (LS vs LL: OR 1.76, 95%CI 1.20-2.59; SS vs LL: OR 2.80, 95%CI 1.45 to 5.41), the dominant model (LS+SS vs LL: OR 2.06, 95%CI 1.44 to 2.96), and the homozygous model (SS vs LL: OR 2.80 95%CI 1.45 to 5.5.41) were statistically significant for CHD-D, demonstrating that polymorphisms in the 5-HTTLPR gene are associated with the development of CHD-D and that the S allele in the 5-HTTLPR gene is likely to be a risk factor for CHD-D. For the BDNF gene, there were no significant differences between one of the co-dominant gene models (AA vs GG: OR 6.63, 95%CI 1.44 to 30.64), the homozygous gene model (AA vs GG: OR 6.63,95% CI 1.44 to 30.64), the dominant gene model (GA+AA vs GG: OR4.29, 95%CI 1.05 to 17.45), recessive gene model (AA vs GG+GA: OR 2.71, 95%CI 1.16 to 6.31), and allele model (A vs G: OR 2.59, 95%CI 1.18 to 5.67) were statistically significant for CHD-D, demonstrating that BDNFrs6265 gene polymorphisms are associated with the CHD-D development and that the A allele in the BDNFrs6265 gene is likely to be a risk factor for CHD-D. We analyzed the allele frequencies of SNPs reported in a single study and found that the SNPs in the microRNA146a gene rs2910164, the SNPs in the ACE2 gene rs2285666 and the SNPs in the SGK1 gene rs1743963 and rs1763509 were risk factors for the development of CHD-D. We performed a subgroup analysis of three studies involving the BDNFrs6265 gene. The results showed that European populations were more at risk of developing CHD-D than Asian populations in both dominant model (GA+AA vs GG: OR 10.47, 95%CI 3.53 to 31.08) and co-dominant model (GA vs GG: OR 6.40, 95%CI 1.98 to 20.73), with statistically significant differences. In contrast, the studies involving the 5-HTTLPR gene were all Asian populations, so subgroup analyses were not performed. We performed sensitivity analyses of studies exploring the 5-HTTLPR and BDNF rs6265 genes. The results showed that the results of the allele model, the dominant model, the recessive model, the homozygous model and the co-dominant model for both 5-HTTLPR and BDNF rs6265 genes were stable. Due to the limited number of studies of the 5-HTTLPR and BDNF genes, it was not possible to determine the symmetry of the funnel plot using Begg's funnel plot and Egger's test. Therefore, we did not assess publication bias. Discussion SNPs of the microRNA146a gene at rs2910164, the ACE2 gene at the rs2285666 and the SGK1 gene at rs1743963 and rs1763509, and the SNPs at the 5-HTTLPR and BDNF gene loci are associated with the onset of comorbid depression in coronary heart disease. We recommend that future research focus on studying SNPs' impact on comorbid depression in coronary heart disease, specifically targeting the 5-HTTLPR and BDNF gene at rs6265. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42021229371.
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Affiliation(s)
| | | | | | - De Zhao Kong
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
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Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Waldenlind E, Steinberg A, Sjöstrand C, Belin AC. Genetic and Phenotypic Profiling of Triptan Users in a Swedish Cluster Headache Cohort. J Mol Neurosci 2024; 74:45. [PMID: 38634984 PMCID: PMC11026232 DOI: 10.1007/s12031-024-02219-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 04/01/2024] [Indexed: 04/19/2024]
Abstract
Up to 25% of individuals who live with cluster headache (CH), an extremely painful primary headache disorder, do not adequately respond to the first-line treatment, triptans. Studies have indicated that genetic variants can play a role in treatment response. Likewise, differences in clinical characteristics can give clues to mechanisms underlying triptan non-response. Our aim was to investigate five genetic variants previously implicated in triptan response and their relation to triptan usage in our Swedish CH cohort and to investigate potential distinctions in clinical characteristics. 545 CH patients were screened for the genetic variants rs1024905, rs6724624, rs4795541, rs5443, and rs2651899 with a case control design based on triptan usage. Analysis of clinical characteristics was based on self-reported questionnaire data from 893 patients. One genetic variant, rs1024905, was significantly associated with triptan non-usage in CH (Pc = 0.010). In addition, multi-allele effector analysis showed that individuals with a higher number of effector variants were less likely to use triptans (P = 0.007). Analysis of clinical characteristics showed that triptan users were more likely to have alcohol as a trigger (57.4% vs 43.4%, P = 0.002), have autonomic symptoms (95.1% vs 88.1%, P = 0.002), and be current smokers (27.0% vs 21.9%, P = 0.033) compared to non-users. These results support the hypothesis that genetic variants can play a role in triptan usage in CH and that patients with a typical CH phenotype are more likely to use triptans.
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Affiliation(s)
| | - Caroline Ran
- Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Yuyan Qin
- Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Carmen Fourier
- Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Elisabet Waldenlind
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Steinberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Christina Sjöstrand
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Danderyd Hospital, Stockholm, Sweden
| | - Andrea Carmine Belin
- Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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36
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Chiș A, Oltean LE, Bîlc M, Vulturar R, Șoflău R, David D, Szentágotai-Tătar A, Miu AC. Gene-Environment Interactions in Irrational Beliefs: The Roles of Childhood Adversity and Multiple Candidate Genes. Int J Mol Sci 2024; 25:4206. [PMID: 38673790 PMCID: PMC11050227 DOI: 10.3390/ijms25084206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/04/2024] [Accepted: 04/07/2024] [Indexed: 04/28/2024] Open
Abstract
Cognitive behavioral therapy is based on the view that maladaptive thinking is the causal mechanism of mental disorders. While this view is supported by extensive evidence, very limited work has addressed the factors that contribute to the development of maladaptive thinking. The present study aimed to uncover interactions between childhood maltreatment and multiple genetic differences in irrational beliefs. Childhood maltreatment and irrational beliefs were assessed using multiple self-report instruments in a sample of healthy volunteers (N = 452). Eighteen single-nucleotide polymorphisms were genotyped in six candidate genes related to neurotransmitter function (COMT; SLC6A4; OXTR), neurotrophic factors (BDNF), and the hypothalamic-pituitary-adrenal axis (NR3C1; CRHR1). Gene-environment interactions (G×E) were first explored in models that employed one measure of childhood maltreatment and one measure of irrational beliefs. These effects were then followed up in models in which either the childhood maltreatment measure, the irrational belief measure, or both were substituted by parallel measures. Consistent results across models indicated that childhood maltreatment was positively associated with irrational beliefs, and these relations were significantly influenced by COMT rs165774 and OXTR rs53576. These results remain preliminary until independent replication, but they represent the best available evidence to date on G×E in a fundamental mechanism of psychopathology.
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Affiliation(s)
- Adina Chiș
- Cognitive Neuroscience Laboratory, Department of Psychology, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (A.C.); (R.V.)
- Department of Molecular Sciences, “Iuliu Hațieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Lia-Ecaterina Oltean
- Department of Clinical Psychology and Psychotherapy, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (L.-E.O.); (R.Ș.); (D.D.)
- The International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania
| | - Mirela Bîlc
- Institute for General Practice and Interprofessional Care, University Hospital Tuebingen, 72076 Tuebingen, Germany;
| | - Romana Vulturar
- Cognitive Neuroscience Laboratory, Department of Psychology, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (A.C.); (R.V.)
- Department of Molecular Sciences, “Iuliu Hațieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Radu Șoflău
- Department of Clinical Psychology and Psychotherapy, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (L.-E.O.); (R.Ș.); (D.D.)
- The International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania
| | - Daniel David
- Department of Clinical Psychology and Psychotherapy, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (L.-E.O.); (R.Ș.); (D.D.)
- The International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania
| | - Aurora Szentágotai-Tătar
- Department of Clinical Psychology and Psychotherapy, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (L.-E.O.); (R.Ș.); (D.D.)
- The International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania
| | - Andrei C. Miu
- Cognitive Neuroscience Laboratory, Department of Psychology, Babeș-Bolyai University, 400015 Cluj-Napoca, Romania; (A.C.); (R.V.)
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37
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Deng F, Wan J, Li G, Dong H, Xia X, Wang Y, Li X, Zhuang C, Zheng Y, Liu L, Yan Y, Feng J, Zhao Y, Xie H, Li Y. Improved green and red GRAB sensors for monitoring spatiotemporal serotonin release in vivo. Nat Methods 2024; 21:692-702. [PMID: 38443508 PMCID: PMC11377854 DOI: 10.1038/s41592-024-02188-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 01/19/2024] [Indexed: 03/07/2024]
Abstract
The serotonergic system plays important roles in both physiological and pathological processes, and is a therapeutic target for many psychiatric disorders. Although several genetically encoded GFP-based serotonin (5-HT) sensors were recently developed, their sensitivities and spectral profiles are relatively limited. To overcome these limitations, we optimized green fluorescent G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensors and developed a red fluorescent GRAB5-HT sensor. These sensors exhibit excellent cell surface trafficking and high specificity, sensitivity and spatiotemporal resolution, making them suitable for monitoring 5-HT dynamics in vivo. Besides recording subcortical 5-HT release in freely moving mice, we observed both uniform and gradient 5-HT release in the mouse dorsal cortex with mesoscopic imaging. Finally, we performed dual-color imaging and observed seizure-induced waves of 5-HT release throughout the cortex following calcium and endocannabinoid waves. In summary, these 5-HT sensors can offer valuable insights regarding the serotonergic system in both health and disease.
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Affiliation(s)
- Fei Deng
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
- Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China
| | - Jinxia Wan
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Guochuan Li
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Hui Dong
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Xiju Xia
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
- Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Yipan Wang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Xuelin Li
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Chaowei Zhuang
- Department of Automation, Tsinghua University, Beijing, China
| | - Yu Zheng
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
- Peking-Tsinghua Center for Life Sciences, New Cornerstone Science Laboratory, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Laixin Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
- Peking-Tsinghua Center for Life Sciences, New Cornerstone Science Laboratory, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Yuqi Yan
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
- Peking-Tsinghua Center for Life Sciences, New Cornerstone Science Laboratory, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jiesi Feng
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Yulin Zhao
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Hao Xie
- Department of Automation, Tsinghua University, Beijing, China
| | - Yulong Li
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China.
- PKU-IDG/McGovern Institute for Brain Research, Beijing, China.
- Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
- Peking-Tsinghua Center for Life Sciences, New Cornerstone Science Laboratory, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
- Chinese Institute for Brain Research, Beijing, China.
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38
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Sun P, Zhao W. Control list of high-priority chemicals based on 5-HT-RI functionality and the human health interference effects selective CNN-GRU deep learning model. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 915:169699. [PMID: 38181943 DOI: 10.1016/j.scitotenv.2023.169699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/22/2023] [Accepted: 12/24/2023] [Indexed: 01/07/2024]
Abstract
The antidepressant drug known as 5-HT reuptake inhibitor (5-HT-RI) was commonly detected in biological tissues and result in significant adverse health effects. Homology modeling was used to characterize the functionalities (efficacy and resistance), and the adverse outcome pathway was used to characterize its human health interferences (olfactory toxicity, neurotoxicity, and gut microbial interference). The convolutional neural network coupled with the gated recurrent unit (CNN-GRU) deep learning method was used to construct a comprehensive model of 5-HT-RI functionality and human health interference effects selectivity with small sample data. The architecture with 2 SE, 320 neuronal nodes and 6-folds cross-validation showed the best applicability. The results showed that the confidence interval of the constructed model reached 90 % indicating that the model had reliable prediction ability and generalization ability. Based on the CNN-GRU deep learning model, seven high-priority chemicals with a weak comprehensive effect, including D-VEN, (1R,4S)-SER, S-FLX, CTP, S-CTP, NEF, and VEN, were screened. Based on the molecular three-dimensional structure information, a comprehensive-effect three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to confirm the reliability of the constructed control list of 5-HT-RI high-priority chemicals. Analysis with the ranking of calculated values based on the molecular dynamics method and predicted values based on the CNN-GRU deep learning model, we found that the consistency of the three methods was above 85 %. Additionally, by analyzing the sensitivity, molecular electrostatic potential, polar surface area of the comprehensive-effect CNN-GRU deep learning model, and the electrostatic field of the 3D-QSAR models, we found that the significant effects of five key characteristics (DM, Qyy, Qxz, I, and BP), molecular electronegativity, and polarity significantly affected the high-priority degree of 5-HT-RI. In this study, we provided reasonable and reliable prediction tools and discussed theoretical methods for the risk assessment of functionality and human health interference of emerging pollutants such as 5-HT-RI.
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Affiliation(s)
- Peixuan Sun
- College of New Energy and Environment, Jilin University, Changchun 130012, China.
| | - Wenjin Zhao
- College of New Energy and Environment, Jilin University, Changchun 130012, China.
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39
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Araki R, Kita A, Ago Y, Yabe T. Chronic social defeat stress induces anxiety-like behaviors via downregulation of serotonin transporter in the prefrontal serotonergic system in mice. Neurochem Int 2024; 174:105682. [PMID: 38301899 DOI: 10.1016/j.neuint.2024.105682] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/14/2024] [Accepted: 01/30/2024] [Indexed: 02/03/2024]
Abstract
The serotonergic (5-HTergic) system is closely involved in the pathophysiology of mood and anxiety disorders and the responsibility of this system may differ for each symptom. In this study, we examined the relationship between the dysfunction of the 5-HTergic system and abnormal behaviors in the social defeat stress model, an animal model of mood and anxiety disorders and in mice with knockdown of Slc6a4, the gene encoding SERT. Monoamine content, serotonin (5-HT) release, 5-HT uptake, 5-HT transporter (SERT) protein levels, and behaviors were investigated in mice subjected to chronic social defeat stress and in mice with knockdown of Slc6a4, in 5-HTergic neurons projecting to the prefrontal cortex (PFC). Furthermore, DNA methylation of Slc6a4 was examined in mice subjected to chronic social defeat stress. Increased turnover, increased extracellular basal levels, decreased release and decreased uptake of 5-HT, and decreased SERT protein levels were observed in the PFC of the stressed mice. The decreased 5-HT uptake correlated with anxiety-like behavior characterized by decreased time spent in the open arms of the elevated plus maze. DNA methylation was increased in the CpG island of Slc6a4 in 5-HTergic neurons projecting to the PFC of the stressed mice. Similar to the stressed mice, mice with Slc6a4 knockdown in 5-HTergic neurons projecting to the PFC also showed decreased release and uptake of 5-HT in the PFC and increased anxiety-like behavior. Chronic stress may induce anxiety due to dysfunction in the prefrontal 5-HTergic system via decreased SERT expression in the PFC.
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Affiliation(s)
- Ryota Araki
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
| | - Ayami Kita
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
| | - Yukio Ago
- Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takeshi Yabe
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
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40
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Huang C, van Wijnen AJ, Im HJ. Serotonin Transporter (5-Hydroxytryptamine Transporter, SERT, SLC6A4) and Sodium-dependent Reuptake Inhibitors as Modulators of Pain Behaviors and Analgesic Responses. THE JOURNAL OF PAIN 2024; 25:618-631. [PMID: 37852405 PMCID: PMC11781314 DOI: 10.1016/j.jpain.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023]
Abstract
The serotonin transporter (5-hydroxytryptamine transporter [5-HTT], Serotonin Transporter (SERT), SLC6A4) modulates the activity of serotonin via sodium-dependent reuptake. Given the established importance of serotonin in the control of pain, 5-HTT has received much interest in studies of pain states and as a pharmacological target for serotonin reuptake inhibitors (SRIs). Animal models expressing varying levels of 5-HTT activity show marked differences in pain behaviors and analgesic responses, as well as many serotonin-related physiological effects. In humans, functional nucleotide variations in the SLC6A4 gene, which encodes the serotonin transporter 5-HTT, are associated with certain pathologic pain conditions and differences in responses to pharmacological therapy. These findings collectively reflect the importance of 5-HTT in the intricate physiology and management of pain, as well as the scientific and clinical challenges that need to be considered for the optimization of 5-HTT-related analgesic therapies. PERSPECTIVE: The serotonin transporter 5-HTT/SCL6A4 is sensitive to pharmacological SRIs. Experimental studies on the physiological functions of serotonin, as well as genetic mouse models and clinical phenotype/genotype correlations of nucleotide variation in the human 5-HTT/SCL6A4 gene, provide new insights for the use of SRIs in chronic pain management.
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Affiliation(s)
- Cary Huang
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois; Department of Anesthesiology, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York.
| | - Andre J van Wijnen
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois; Department of Biochemistry, University of Vermont, Burlington, Vermont.
| | - Hee-Jeong Im
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center (JBVAMC), Chicago, Illinois.
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41
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Baghaei A, Zoshk MY, Hosseini M, Fasihi H, Nassireslami E, Shayesteh S, Laripour R, Amoli AE, Heidari R, Chamanara M. Prominent genetic variants and epigenetic changes in post-traumatic stress disorder among combat veterans. Mol Biol Rep 2024; 51:325. [PMID: 38393604 DOI: 10.1007/s11033-024-09276-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/19/2024] [Indexed: 02/25/2024]
Abstract
Post-traumatic stress disorder (PTSD) is one of the most widespread and disabling psychiatric disorders among combat veterans. Substantial interindividual variability in susceptibility to PTSD suggests the presence of different risk factors for this disorder. Twin and family studies confirm genetic factors as important risk factors for PTSD. In addition to genetic factors, epigenetic factors, especially DNA methylation, can be considered as a potential mechanism in changing the risk of PTSD. So far, many genetic and epigenetic association studies have been conducted in relation to PTSD. In genetic studies, many single nucleotide polymorphisms have been identified as PTSD risk factors. Meanwhile, the variations in catecholamines-related genes, serotonin transporter and receptors, brain-derived neurotrophic factor, inflammatory factors, and apolipoprotein E are the most prominent candidates. CpG methylation in the upstream regions of many genes is also considered a PTSD risk factor. Accurate identification of genetic and epigenetic changes associated with PTSD can lead to the presentation of suitable biomarkers for susceptible individuals to this disorder. This study aimed to delineate prominent genetic variations and epigenetic changes associated with post-traumatic stress disorder in military veterans who have experienced combat, focusing on genetic and epigenetic association studies.
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Affiliation(s)
- Ahmadali Baghaei
- Trauma Research center, AJA university of Medical sciences, Tehran, Iran
| | | | - Mohsen Hosseini
- The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Fasihi
- Biomaterial and Medicinal Chemistry Research Center, AJA University of Medical Science, Tehran, Iran
| | - Ehsan Nassireslami
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran
- Department of Pharmacology and Toxicology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Sevda Shayesteh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Reza Laripour
- Social and Preventive Medicine Department, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Aynaz Eslami Amoli
- Trauma Research center, AJA university of Medical sciences, Tehran, Iran
| | - Reza Heidari
- Cancer Epidemiology Research Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran.
- Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran.
| | - Mohsen Chamanara
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran.
- Student research committee, AJA University of Medical Sciences, Tehran, Iran.
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42
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Sreeja V, Jose A, Patel S, Menon B, Athira KV, Chakravarty S. Pharmacogenetics of selective serotonin reuptake inhibitors (SSRI): A serotonin reuptake transporter (SERT)-based approach. Neurochem Int 2024; 173:105672. [PMID: 38157886 DOI: 10.1016/j.neuint.2023.105672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/12/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
Neuropsychiatric disorders are considered to be the most common cause of disability worldwide. Serotonin and its transporter is a prominent paradigm in mood disorders. Response to selective serotonin reuptake inhibitors (SSRI) is altered due to heterogeneity in the serotonin transporter gene, SLC6A4 (solute carrier family 6 member 4). The reported polymorphisms are found to be in different regions of the transporter gene: promoter region (5-HTTLPR and various single nucleotide polymorphisms within it), intron (STin2), and exon 9 (I425V). The long and short alleles of the 5-HTTLPR gene, which are prevalent among variations, may mediate differential effects. In long allelic variant carriers, an increased response to SSRI and timely recovery is due to increased availability of SERT. Whereas, SERT availability is significantly decreased in short allelic carriers, necessitating a reduction in SSRI dosage due to the increased risk of adverse drug reactions. Thus, pharmacogenetic investigations are required to understand the impact of functional variations on the efficacy and tolerability of SSRI. Identifying the carrier variants may aid in clear-decision making of the treatment regimen, aiding the approach of personalized medication.
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Affiliation(s)
- V Sreeja
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, Kerala, India
| | - Anju Jose
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, Kerala, India
| | - Shashikant Patel
- Applied Biology Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, 500007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Bindu Menon
- Department of Psychiatry, Amrita School of Medicine, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, Kerala, India
| | - K V Athira
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, Kerala, India.
| | - Sumana Chakravarty
- Applied Biology Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, 500007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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43
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Ali E, Embaby A, Arafa SM, Elbana AK, Ghazala M, Ibrahim D. Electroconvulsive therapy improves hematological inflammatory markers in bipolar disorder. Psychopharmacology (Berl) 2024; 241:351-357. [PMID: 37999745 DOI: 10.1007/s00213-023-06491-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/26/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Immune dysfunction and inflammation participate in the pathophysiology of bipolar disorder (BD). Abnormal levels of inflammatory markers, namely, red cell distribution width (RDW) and platelet distribution width (PDW), were detected in BD. Electroconvulsive therapy (ECT) for various mental disorders including BD was linked to changes in these inflammatory mediators. Hence, we aimed to assess the impact of ECT on PDW and RDW in patients with BD. METHODS Seventy-two patients aged ≥ 16 were enrolled in the current prospective cohort study over 6 months, diagnosed as BD based on DSM-IV and indicated for ECT and complete blood count (CBC) drawn pre-ECT and after four ECT sessions. RESULTS By the end of the ECT sessions, we noticed a significant elevation in PDW with lowering in RDW levels. However, no significant differences were detected before and after ECT regarding platelet (PLTs) count, mean platelet volume (MPV), and Plateletcrit (PCT). CONCLUSION ECT seems to improve the CBC-derived inflammatory markers (RDW and PDW) subsequently, improving the underlying inflammatory process in BD without disturbing PLT homeostasis which support its anti-inflammatory role in BD.
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Affiliation(s)
- Eman Ali
- Psychiatry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ahmed Embaby
- Clinical Hematology Unit, Internal Medicine Department, Faculty of Medicine, Zagazig University, Al-Sharika, Zagazig, 44519, Egypt.
| | - Shaymaa M Arafa
- Psychiatry Department, Faculty of Medicine, Al Azhar University for Girls, Cairo, Egypt
| | - Ahmed Kamal Elbana
- Anatomy Department, Faculty of Medicine, Al Azhar University for Men, Cairo, Egypt
- Basic Medical Sciences Department, Sulaiman AlRajhi University, Al Bukayriyah, Saudi Arabia
| | - Mohamed Ghazala
- Clinical Sciences Department, Sulaiman AlRajhi University, Al Bukayriyah, Saudi Arabia
| | - Doaa Ibrahim
- Psychiatry Department, Faculty of Medicine, Al Azhar University for Girls, Cairo, Egypt
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Wannemüller A, Kumsta R, Moser D, Jöhren HP, Margraf J. DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment. J Psychiatr Res 2024; 170:73-80. [PMID: 38103452 DOI: 10.1016/j.jpsychires.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.
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Affiliation(s)
- André Wannemüller
- Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Germany.
| | - Robert Kumsta
- Department of Genetic Psychology, Ruhr-Universität Bochum, Germany
| | - Dirk Moser
- Department of Genetic Psychology, Ruhr-Universität Bochum, Germany
| | | | - Jürgen Margraf
- Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Germany
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Kiive E, Kanarik M, Veidebaum T, Harro J. Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism. Acta Neuropsychiatr 2024; 36:1-8. [PMID: 37070394 DOI: 10.1017/neu.2023.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2023]
Abstract
OBJECTIVE Neuropeptide Y (NPY) is a powerful regulator of anxious states, including social anxiety, but evidence from human genetic studies is limited. Associations of common gene variants with behaviour have been described as subject to birth cohort effects, especially if the behaviour is socially motivated. This study aimed to examine the association of NPY rs16147 and rs5574 with personality traits in highly representative samples of two birth cohorts of young adults, the samples having been formed during a period of rapid societal transition. METHODS Both birth cohorts (original n = 1238) of the Estonian Children Personality Behaviour and Health Study (ECPBHS) self-reported personality traits of the five-factor model at 25 years of age. RESULTS A significant interaction effect of the NPY rs16147 and rs5574 and birth cohort on Agreeableness was found. The T/T genotype of NPY rs16147 resulted in low Agreeableness in the older cohort (born 1983) and in high Agreeableness in the younger cohort (born 1989). The C/C genotype of NPY rs5574 was associated with higher Agreeableness in the younger but not in the older cohort. In the NPY rs16147 T/T homozygotes, the deviations from average in Agreeableness within the birth cohort were dependent on the serotonin transporter promoter polymorphism. CONCLUSIONS The association between the NPY gene variants and a personality domain reflecting social desirability is subject to change qualitatively in times of rapid societal changes, serving as an example of the relationship between the plasticity genes and environment. The underlying mechanism may involve the development of the serotonergic system.
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Affiliation(s)
- Evelyn Kiive
- Division of Special Education, Department of Education, University of Tartu, Jakobi 5, 51005 Tartu, Estonia
| | - Margus Kanarik
- Division of Neuropsychopharmacology, Department of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia
| | - Toomas Veidebaum
- Department of Chronic Diseases, National Institute for Health Development, Hiiu 42, 11619 Tallinn, Estonia
| | - Jaanus Harro
- Division of Neuropsychopharmacology, Department of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia
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Varma R, Staab JP, Matey ET, Wright JA, Deb B, Lazaridis KN, Szarka LA, Bailey KR, Bharucha AE. Most patients with disorders of gut-brain interaction receive pharmacotherapy with major or moderate drug-gene interactions. Neurogastroenterol Motil 2024; 36:e14722. [PMID: 38072827 DOI: 10.1111/nmo.14722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 10/25/2023] [Accepted: 11/28/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND How variations predicted by pharmacogenomic testing to alter drug metabolism and therapeutic response affect outcomes for patients with disorders of gut- brain interaction is unclear. AIMS To assess the prevalence of pharmacogenomics-predicted drug-gene interactions and symptom outcomes for patients with disorders of gut-brain interaction. METHODS Patients who were treated in our clinical practice for functional dyspepsia/bowel disorder underwent pharmacogenomic testing. The change in symptoms from baseline to 6 months was compared for patients with variations in CYP2D6 and CYP2C19, which metabolize neuromodulators, and SLC6A4, which encodes the sodium- dependent serotonin transporter. RESULTS At baseline, 79 of 94 participants (84%) had at least one predicted major drug- gene interaction, and all 94 (100%) had at least one predicted moderate interaction. For the 44 participants who completed a survey of their symptoms at 6 months, the mean (SD) irritable bowel syndrome-symptom severity score decreased from 284 (71) at baseline to 231 (95) at 6 months (p < 0.001). Among patients taking selective serotonin reuptake inhibitors, the decrease in symptom severity (p = 0.03) and pain (p = 0.002) scores from baseline to 6 months was greater for patients with a homozygous SLC6A4 long/long genotype (n = 30) (ie, increased serotonin transporter activity) than for patients with homozygous short/short or heterozygous long/short genotypes (n = 64). Symptom outcomes were not affected by CYP2D6 or CYP2C19 variations. CONCLUSIONS The homozygous SLC6A4 long/long genotype confers better symptom resolution for patients with disorders of gut-brain interaction who take selective serotonin reuptake inhibitors than do the homozygous short/short or heterozygous long/short genotypes.
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Affiliation(s)
- Revati Varma
- Research Fellow in the Division of Gastroenterology and Hepatology, Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Jeffrey P Staab
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA
| | - Eric T Matey
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Brototo Deb
- Research Fellow in the Division of Gastroenterology and Hepatology, Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | | | - Lawrence A Szarka
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kent R Bailey
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Adil E Bharucha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Ochi T, de Vos S, Touw D, Denig P, Feenstra T, Hak E. Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation. J Diabetes Res 2024; 2024:7922486. [PMID: 38288388 PMCID: PMC10824573 DOI: 10.1155/2024/7922486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 11/10/2023] [Accepted: 12/19/2023] [Indexed: 01/31/2024] Open
Abstract
Aims To investigate the effect of serotonin transporter (5-HTT) polymorphisms on change in HbA1c levels six months after metformin initiation in type 2 diabetes patients. Materials and Methods Participants of PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALidation of biomarkers) within the GIANTT (Groningen Initiative to ANalyse Type 2 Diabetes Treatment) cohort who initiated metformin were genotyped for combined 5-HTTLPR/rs25531 (L∗L∗, L∗S∗, and S∗S∗) and 5-HTT VNTR (STin 2.12, 12/-, and 10/-) polymorphisms, respectively. Multiple linear regression was applied to determine the change in HbA1c level from baseline date to six months across 5-HTTLPR/VNTR genotype groups, adjusted for baseline HbA1c, age, gender, triglyceride level, low-density lipoprotein level, and serum creatinine. Results 157 participants were included, of which 56.2% were male. The average age was 59.3 ± 9.23 years, and the mean baseline HbA1c was 7.49% ± 1.21%. 5-HTTLPR was characterized in 46 patients as L∗L∗, 70 patients as L∗S∗, and 41 patients as S∗S∗ genotypes. No significant association was found between 5-HTTLPR and 5-HTT VNTR genotypes and change in HbA1c after adjustments. Conclusions 5-HTT polymorphisms did not affect HbA1c levels six months after the start of metformin. Further long-term studies in large samples would be relevant to determine which polymorphisms can explain the variation in response to metformin treatment.
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Affiliation(s)
- Taichi Ochi
- Groningen Research Institute of Pharmacy, PharmacoTherapy, Epidemiology & Economics, University of Groningen, Groningen, Netherlands
| | - Stijn de Vos
- Groningen Research Institute of Pharmacy, PharmacoTherapy, Epidemiology & Economics, University of Groningen, Groningen, Netherlands
| | - Daan Touw
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pharmacokinetics, Toxicology and Targeting, Groningen, Netherlands
| | - Petra Denig
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Talitha Feenstra
- Groningen Research Institute of Pharmacy, PharmacoTherapy, Epidemiology & Economics, University of Groningen, Groningen, Netherlands
- Dutch National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Eelko Hak
- Groningen Research Institute of Pharmacy, PharmacoTherapy, Epidemiology & Economics, University of Groningen, Groningen, Netherlands
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Cuciureanu DI, Bistriceanu CE, Vulpoi GA, Cuciureanu T, Antochi F, Roceanu AM. Migraine Comorbidities. Life (Basel) 2024; 14:74. [PMID: 38255689 PMCID: PMC10820535 DOI: 10.3390/life14010074] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/14/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
Novel knowledge about the interrelationships and reciprocal effects of migraine and epilepsy, migraine and mood disorders, or migraine and irritable bowel syndrome has emerged in recent decades. Over time, comorbid pathologies associated with migraine that share common physiopathological mechanisms were studied. Among these studied pathologies is epilepsy, a disorder with common ion channel dysfunctions as well as dysfunctions in glutamatergic transmission. A high degree of neuronal excitement and ion channel abnormalities are associated with epilepsy and migraine and antiepileptic drugs are useful in treating both disorders. The coexistence of epilepsy and migraine may occur independently in the same individual or the two may be causally connected. The relationship between cortical spreading depression (CSD) and epileptic foci has been suggested by basic and clinical neuroscience research. The most relevant psychiatric comorbidities associated with migraine are anxiety and mood disorders, which influence its clinical course, treatment response, and clinical outcome. The association between migraine and major depressive disorder can be explained by a robust molecular genetic background. In addition to its role as a potent vasodilator, CGRP is also involved in the transmission of nociception, a phenomenon inevitably linked with the stress and anxiety caused by frequent migraine attacks. Another aspect is the role of gut microbiome in migraine's pathology and the gut-brain axis involvement. Irritable bowel syndrome patients are more likely to suffer migraines, according to other studies. There is no precise explanation for how the gut microbiota contributes to neurological disorders in general and migraines in particular. This study aims to show that migraines and comorbid conditions, such as epilepsy, microbiota, or mood disorders, can be connected from the bench to the bedside. It is likely that these comorbid migraine conditions with common pathophysiological mechanisms will have a significant impact on best treatment choices and may provide clues for future treatment options.
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Affiliation(s)
- Dan Iulian Cuciureanu
- Neurology Department, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Neurology Department I, “Prof. Dr. N. Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania;
| | - Cătălina Elena Bistriceanu
- Neurology Department, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Elytis Hospital Hope, 700010 Iasi, Romania
| | - Georgiana-Anca Vulpoi
- Neurology Department I, “Prof. Dr. N. Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania;
| | - Tudor Cuciureanu
- Gastroenterology Department, Faculty of Medicine, University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Florina Antochi
- Neurology Department, University Emergency Hospital, 050098 Bucharest, Romania; (F.A.); (A.-M.R.)
| | - Adina-Maria Roceanu
- Neurology Department, University Emergency Hospital, 050098 Bucharest, Romania; (F.A.); (A.-M.R.)
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Honan LE, Fraser-Spears R, Daws LC. Organic cation transporters in psychiatric and substance use disorders. Pharmacol Ther 2024; 253:108574. [PMID: 38072333 PMCID: PMC11052553 DOI: 10.1016/j.pharmthera.2023.108574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/01/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023]
Abstract
Psychiatric and substance use disorders inflict major public health burdens worldwide. Their widespread burden is compounded by a dearth of effective treatments, underscoring a dire need to uncover novel therapeutic targets. In this review, we summarize the literature implicating organic cation transporters (OCTs), including three subtypes of OCTs (OCT1, OCT2, and OCT3) and the plasma membrane monoamine transporter (PMAT), in the neurobiology of psychiatric and substance use disorders with an emphasis on mood and anxiety disorders, alcohol use disorder, and psychostimulant use disorder. OCTs transport monoamines with a low affinity but high capacity, situating them to play a central role in regulating monoamine homeostasis. Preclinical evidence discussed here suggests that OCTs may serve as promising targets for treatment of psychiatric and substance use disorders and encourage future research into their therapeutic potential.
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Affiliation(s)
- Lauren E Honan
- The University of Texas Health Science Center at San Antonio, Department of Cellular & Integrative Physiology, USA
| | - Rheaclare Fraser-Spears
- University of the Incarnate Word, Feik School of Pharmacy, Department of Pharmaceutical Sciences, USA
| | - Lynette C Daws
- The University of Texas Health Science Center at San Antonio, Department of Cellular & Integrative Physiology, USA; The University of Texas Health Science Center at San Antonio, Department of Pharmacology, USA.
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Zhang Z, Yang Y, Kong W, Huang S, Tan Y, Huang S, Zhang M, Lu H, Li Y, Li X, Liu S, Wen Y, Shang D. A Bibliometric and Visual Analysis of Single Nucleotide Polymorphism Studies in Depression. Curr Neuropharmacol 2024; 22:302-322. [PMID: 37581520 PMCID: PMC10788886 DOI: 10.2174/1570159x21666230815125430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/30/2022] [Accepted: 02/10/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Genetic polymorphism has been proven to have an important association with depression, which can influence the risk of developing depression, the efficacy of medications, and adverse effects via metabolic and neurological pathways. Nonetheless, aspects of the association between single nucleotide polymorphisms and depression have not been systematically investigated by bibliometric analysis. OBJECTIVE The aim of this study was to analyze the current status and trends of single nucleotide polymorphism research on depression through bibliometric and visual analysis. METHODS The Web of Science Core Collection was used to retrieve 10,043 articles that were published between 1998 and 2021. CiteSpace (6.1 R4) was used to perform collaborative network analysis, co-citation analysis, co-occurrence analysis, and citation burst detection. RESULTS The most productive and co-cited journals were the Journal of Affective Disorders and Biological Psychiatry, respectively, and an analysis of the references showed that the most recent research focused on the largest thematic cluster, "5-HT", reflecting the important research base in this area. "CYP2D6" has been in the spotlight since its emergence in 2009 and has become a research hotspot since its outbreak in 2019. However, "BDNF ", "COMT ", "older adults", "loci", and "DNA methylation" are also the new frontier of research, and some of them are currently in the process of exploration. CONCLUSION These findings offer a useful perspective on existing research and potential future approaches in the study of the association between single nucleotide polymorphisms and depression, which may assist researchers in selecting appropriate collaborators or journals.
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Affiliation(s)
- Zi Zhang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Ye Yang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Wan Kong
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Shanqing Huang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Yaqian Tan
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Shanshan Huang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Ming Zhang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Haoyang Lu
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Yuhua Li
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Xiaolin Li
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Shujing Liu
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Yuguan Wen
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
| | - Dewei Shang
- Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
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