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Yao TT, Chen L, Du Y, Jiang ZY, Cheng Y. MicroRNAs as Regulators, Biomarkers, and Therapeutic Targets in Autism Spectrum Disorder. Mol Neurobiol 2025; 62:5039-5056. [PMID: 39503812 DOI: 10.1007/s12035-024-04582-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 10/22/2024] [Indexed: 03/05/2025]
Abstract
The pathogenesis of autism spectrum disorder (ASD) is complex and is mainly influenced by genetic and environmental factors. Some research has indicated that environmental aspects may interplay with genetic aspects to enhance the risk, and microRNAs (miRNAs) are probably factors in explaining this link between heredity and the environment. MiRNAs are single-stranded noncoding RNAs that can regulate gene expression at the posttranscriptional level. Some research has indicated that miRNAs are closely linked to neurological diseases. Many aberrantly expressed miRNAs have been observed in autism, and these dysregulated miRNAs are expected to be potential biomarkers and provide new strategies for the treatment of this disease. This article reviews the research progress of miRNAs in autism, including their biosynthesis and function. It is found that some miRNAs show aberrant expression patterns in brain tissue and peripheral blood of autistic patients, which may serve as biomarkers of the disease. In addition, the article explores the novel role of exosomes as carriers of miRNAs with the ability to cross the blood-brain barrier and unique expression profiles, offering new possibilities for diagnostic and therapeutic interventions in ASD. The potential of miRNAs in exosomes as diagnostic markers for ASD is specifically highlighted, as well as the prospect of using engineered exosome-encapsulated miRNAs for targeted therapies.
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Affiliation(s)
- Tong-Tong Yao
- Center On Translational Neuroscience, Institute of National Security, Minzu University of China, 27th South Zhongguancun Avenue, Beijing, 100081, China
- School of Ethnology and Sociology, Minzu University of China, Beijing, China
| | - Lei Chen
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Yang Du
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Zhong-Yong Jiang
- Department of Medical Laboratory, Affiliated Cancer Hospital of Chengdu Medical College, Chengdu Seventh People's Hospital, Chengdu, China.
| | - Yong Cheng
- Center On Translational Neuroscience, Institute of National Security, Minzu University of China, 27th South Zhongguancun Avenue, Beijing, 100081, China.
- Center On Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
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Tonk O, Tokgun PE, Yılmaz ÖS, Tokgun O, Inci K, Çelikkaya B, Altintas N. An In Vitro Study for the Role of Schizophrenia-Related Potential miRNAs in the Regulation of COMT Gene. Mol Neurobiol 2024; 61:7680-7690. [PMID: 38427212 PMCID: PMC11415445 DOI: 10.1007/s12035-024-04070-2] [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: 10/16/2023] [Accepted: 02/25/2024] [Indexed: 03/02/2024]
Abstract
This study aimed to analyze the possible association of miR-30a-5p, miR-30e-5p, and miR-34a-5p identified as potential candidate miRNAs in schizophrenia, with the COMT gene. Candidate miRNAs were obtained from the TargetScan database. The SH-SY5Y human neuroblastoma cell line was used as a cellular model for schizophrenia. miR-30a-5p, miR-30e-5p, and miR-34a-5p mimics were transfected into the SH-SY5Y cell line. Total RNA was isolated from transfected cells and RNA-IP samples and reverse transcripted for miRNA and mRNA analysis. RT-qPCR and western blot were performed to observe changes in expression levels of COMT. RNA-ımmunoprecipitation was performed to determine RNA-protein interactions after mimic transfection. In the study, it was observed that COMT gene expression levels decreased significantly after miR-30a-5p and miR-34a-5p expressions, whereas increased significantly as a result of miR-30e-5p transfection. RNA-IP data have shown that the amount of COMT pulled down by Ago2 was increased after miR-30a-5p and miR-34a-5p transfections. RNA-IP results revealed that miR-30a-5p and miR-34a-5p are direct targets for the COMT gene.
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Affiliation(s)
- Onur Tonk
- Faculty of Medicine, Department of Medical Biology, Celal University, Manisa, Turkey
| | - Pervin Elvan Tokgun
- Faculty of Medicine, Department of Medical Genetics, Pamukkale University, Kınıklı, Denizli, Turkey.
| | - Özge Sarıca Yılmaz
- Faculty of Medicine, Department of Medical Biology, Celal University, Manisa, Turkey
| | - Onur Tokgun
- Faculty of Medicine, Department of Medical Genetics, Pamukkale University, Kınıklı, Denizli, Turkey
- Department of Cancer Molecular Biology, Institute of Health Sciences, Pamukkale University, Denizli, Turkey
| | - Kubilay Inci
- Department of Cancer Molecular Biology, Institute of Health Sciences, Pamukkale University, Denizli, Turkey
| | - Büşra Çelikkaya
- Department of Cancer Molecular Biology, Institute of Health Sciences, Pamukkale University, Denizli, Turkey
| | - Nuray Altintas
- Faculty of Medicine, Department of Medical Biology, Celal University, Manisa, Turkey
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3
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He J, Xie P, An XQ, Guo DF, Bi B, Wu G, Yu WF, Ren ZK, Zuo L. LncRNA NPTN-IT1-201 Ameliorates Depressive-like Behavior by Targeting miR-142-5p and Regulating Inflammation and Apoptosis via BDNF. Curr Med Sci 2024; 44:971-986. [PMID: 39145838 DOI: 10.1007/s11596-024-2917-8] [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: 08/21/2023] [Accepted: 06/26/2024] [Indexed: 08/16/2024]
Abstract
OBJECTIVE Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are widely expressed in the brain and are associated with the development of neurological and neurodegenerative diseases. However, their roles and molecular mechanisms in major depressive disorder (MDD) remain largely unknown. This study aimed to identify lncRNAs and miRNAs involved in the development of MDD and elucidate their molecular mechanisms. METHODS Transcriptome and bioinformatic analyses were performed to identify miRNAs and lncRNAs related to MDD. C57 mice were subjected to chronic unpredictable mild stress (CUMS) to establish a depression model. Lentiviruses containing either lncRNA NPTN-IT1-201 or miR-142-5p were microinjected into the hippocampal region of these mice. Behavioral tests including the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST) were conducted to evaluate depressive-like behaviors. RESULTS The results revealed that overexpression of lncRNA NPTN-IT1-201 or inhibition of miR-142-5p significantly ameliorated depressive-like behaviors in CUMS-treated mice. Dual-luciferase reporter assays confirmed interactions between miR-142-5p with both brain-derived neurotrophic factor (BDNF) and NPTN-IT1-201. ELISA analysis revealed significant alterations in relevant biomarkers in the blood samples of MDD patients compared to healthy controls. Histological analyses, including HE and Nissl staining, showed marked structural changes in brain tissues following CUMS treatment, which were partially reversed by lncRNA NPTN-IT1-201 overexpression or miR-142-5p inhibition. Immunofluorescence imaging demonstrated significant differences in the levels of BAX, Bcl2, p65, Iba1 among different treatment groups. TUNEL assays confirmed reduced apoptosis in brain tissues following these interventions. Western blotting showed the significant differences in BDNF, BAX, and Bcl2 protein levels among different treatment groups. CONCLUSION NPTN-IT1-201 regulates inflammation and apoptosis in MDD by targeting BDNF via miR-142-5p, making it a potential therapeutic target for MDD.
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Affiliation(s)
- Jun He
- Department of Immunology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China
- Department of Laboratory Medicine, The Second People's Hospital of Guizhou Province, Guiyang, 550004, China
- Guizhou Provincial Center for Clinical Laboratory, Guiyang, 550002, China
| | - Peng Xie
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China
| | - Xiao-Qiong An
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China
| | - Dong-Fen Guo
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China
| | - Bin Bi
- Psychosomatic Department, The Second People's Hospital of Guizhou Province, Guiyang, 550004, China
| | - Gang Wu
- Psychosomatic Department, The Second People's Hospital of Guizhou Province, Guiyang, 550004, China
| | - Wen-Feng Yu
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China.
| | - Zhen-Kui Ren
- Department of Laboratory Medicine, The Second People's Hospital of Guizhou Province, Guiyang, 550004, China.
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China.
| | - Li Zuo
- Department of Immunology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China.
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Hudock A, Leal ZP, Sharma A, Mei A, Santos R, Marchetto MC. Exploring mood disorders and treatment options using human stem cells. Genet Mol Biol 2024; 47Suppl 1:e20230305. [PMID: 38954533 PMCID: PMC11223183 DOI: 10.1590/1678-4685-gmb-2023-0305] [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: 10/26/2023] [Accepted: 04/16/2024] [Indexed: 07/04/2024] Open
Abstract
Despite their global prevalence, the mechanisms for mood disorders like bipolar disorder and major depressive disorder remain largely misunderstood. Mood stabilizers and antidepressants, although useful and effective for some, do not have a high responsiveness rate across those with these conditions. One reason for low responsiveness to these drugs is patient heterogeneity, meaning there is diversity in patient characteristics relating to genetics, etiology, and environment affecting treatment. In the past two decades, novel induced pluripotent stem cell (iPSC) research and technology have enabled the use of human-derived brain cells as a new model to study human disease that can help account for patient variance. Human iPSC technology is an emerging tool to better understand the molecular mechanisms of these disorders as well as a platform to test novel treatments and existing pharmaceuticals. This literature review describes the use of iPSC technology to model bipolar and major depressive disorder, common medications used to treat these disorders, and novel patient-derived alternative treatment methods for non-responders stemming from past publications, as well as presenting new data derived from these models.
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Affiliation(s)
- Autumn Hudock
- University of California San Diego, Department of Anthropology, La
Jolla, CA, USA
| | - Zaira Paulina Leal
- University of California San Diego, Department of Anthropology, La
Jolla, CA, USA
| | - Amandeep Sharma
- The Salk Institute for Biological Studies, Laboratory of Genetics,
La Jolla, CA, USA
| | - Arianna Mei
- The Salk Institute for Biological Studies, Laboratory of Genetics,
La Jolla, CA, USA
| | - Renata Santos
- The Salk Institute for Biological Studies, Laboratory of Genetics,
La Jolla, CA, USA
- Université Paris Cité, Institute of Psychiatry and Neuroscience of
Paris (IPNP), INSERM U1266, Signaling Mechanisms in Neurological Disorders, Paris,
France
- Institut des Sciences Biologiques, Centre National de la Recherche
Scientifique (CNRS), Paris, France
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Xu WM, Zhang HF, Feng YH, Li SJ, Xie BY. Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study. World J Clin Cases 2024; 12:2359-2369. [PMID: 38765736 PMCID: PMC11099412 DOI: 10.12998/wjcc.v12.i14.2359] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/18/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ArLD) constitute the primary forms of chronic liver disease, and their incidence is progressively increasing with changes in lifestyle habits. Earlier studies have documented a correlation between the occurrence and development of prevalent mental disorders and fatty liver. AIM To investigate the correlation between fatty liver and mental disorders, thus necessitating the implementation of a mendelian randomization (MR) study to elucidate this association. METHODS Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog, while information on mental disorders, including Alzheimer's disease, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple personality disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia was acquired from the psychiatric genomics consortium. A two-sample MR method was applied to investigate mediators in significant associations. RESULTS After excluding weak instrumental variables, a causal relationship was identified between fatty liver disease and the occurrence and development of some psychiatric disorders. Specifically, the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD (OR: 5.81, 95%CI: 5.59-6.03, P < 0.01), bipolar disorder (OR: 5.73, 95%CI: 5.42-6.05, P = 0.03), OCD (OR: 6.42, 95%CI: 5.60-7.36, P < 0.01), and PTSD (OR: 5.66, 95%CI: 5.33-6.01, P < 0.01). Meanwhile, NAFLD significantly increased the risk of developing bipolar disorder (OR: 55.08, 95%CI: 3.59-845.51, P < 0.01), OCD (OR: 61.50, 95%CI: 6.69-565.45, P < 0.01), and PTSD (OR: 52.09, 95%CI: 4.24-639.32, P < 0.01). CONCLUSION Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders, namely bipolar disorder, OCD, and PTSD, highlighting the significance of preventive measures against psychiatric disorders in patients with fatty liver disease.
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Affiliation(s)
- Wei-Ming Xu
- Department of Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Hai-Fu Zhang
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Yong-Hang Feng
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Shuo-Jun Li
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Bi-Yun Xie
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
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Li X, Fu Q, Zhong M, Long Y, Zhao F, Huang Y, Zhang Z, Wen M, Chen K, Chen R, Ma X. Quantitative proteomics of the miR-301a/SOCS3/STAT3 axis reveals underlying autism and anxiety-like behavior. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102136. [PMID: 38439911 PMCID: PMC10909786 DOI: 10.1016/j.omtn.2024.102136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/30/2024] [Indexed: 03/06/2024]
Abstract
Autism is a widespread neurodevelopmental disorder. Although the research on autism spectrum disorders has been increasing in the past decade, there is still no specific answer to its mechanism of action and treatment. As a pro-inflammatory microRNA, miR-301a is abnormally expressed in various psychiatric diseases including autism. Here, we show that miR-301a deletion and inhibition exhibited two distinct abnormal behavioral phenotypes in mice. We observed that miR-301a deletion in mice impaired learning/memory, and enhanced anxiety. On the contrary, miR-301a inhibition effectively reduced the maternal immune activation (MIA)-induced autism-like behaviors in mice. We further demonstrated that miR-301a bound to the 3'UTR region of the SOCS3, and that inhibition of miR-301a led to the upregulation of SOCS3 in hippocampus. The last result in the reduction of the inflammatory response by inhibiting phosphorylation of AKT and STAT3, and the expression level of IL-17A in poly(I:C)-induced autism-like features in mice. The obtained data revealed the miR-301a as a critical participant in partial behavior phenotypes, which may exhibit a divergent role between gene knockout and knockdown. Our findings ascertain that miR-301a negatively regulates SOCS3 in MIA-induced autism in mice and could present a new therapeutic target for ameliorating the behavioral abnormalities of autism.
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Affiliation(s)
- Xun Li
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
| | - Qi Fu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Mingtian Zhong
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Yihao Long
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Fengyun Zhao
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Yanni Huang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Zizhu Zhang
- Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Min Wen
- Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kaizhao Chen
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Rongqing Chen
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xiaodong Ma
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
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Nguyen TML, Jollant F, Tritschler L, Colle R, Corruble E, Gardier AM. [Ketamine and suicidal behavior: Contribution of animal models of aggression-impulsivity to understanding its mechanism of action]. ANNALES PHARMACEUTIQUES FRANÇAISES 2024; 82:3-14. [PMID: 37890717 DOI: 10.1016/j.pharma.2023.10.008] [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: 06/19/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023]
Abstract
More than two-thirds of suicides occur during a major depressive episode. Acting out prevention measures and therapeutic options to manage the suicidal crisis are limited. The impulsive-aggressive dimensions are vulnerability factors associated with suicide in patients suffering from a characterized depressive episode: this can be a dimension involved in animals. Impulsive and aggressive rodent models can help analyze, at least in part, the neurobiology of suicide and the beneficial effects of treatments. Ketamine, a glutamatergic antagonist, by rapidly improving the symptoms of depressive episodes, would help reduce suicidal thoughts in the short term. Animal models share with humans impulsive and aggressive endophenotypes modulated by the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation or the hypothalamic-pituitary-adrenal axis and stress. Significant effects of ketamine on these endophenotypes remain to be demonstrated.
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Affiliation(s)
- Thi Mai Loan Nguyen
- Inserm CESP/UMR 1018, équipe MOODS, faculté de pharmacie, université Paris-Saclay, 91400 Orsay, France
| | - Fabrice Jollant
- Inserm CESP/UMR 1018, équipe MOODS, faculté de médecine, université Paris-Saclay, 94270 Le Kremin-Bicêtre, France; Service hospitalo-universitaire de psychiatrie, hôpital de Bicêtre, hôpitaux universitaires Paris-Saclay, Assistance publique-Hôpitaux de Paris (AP-HP), 94275 Le Kremlin-Bicêtre, France; Pôle de psychiatrie, CHU de Nîmes, Nîmes, France; Département de psychiatrie, Université McGill et Groupe McGill d'études sur le suicide, Montréal, Canada
| | - Laurent Tritschler
- Inserm CESP/UMR 1018, équipe MOODS, faculté de pharmacie, université Paris-Saclay, 91400 Orsay, France
| | - Romain Colle
- Inserm CESP/UMR 1018, équipe MOODS, faculté de médecine, université Paris-Saclay, 94270 Le Kremin-Bicêtre, France; Service hospitalo-universitaire de psychiatrie, hôpital de Bicêtre, hôpitaux universitaires Paris-Saclay, Assistance publique-Hôpitaux de Paris (AP-HP), 94275 Le Kremlin-Bicêtre, France
| | - Emmanuelle Corruble
- Inserm CESP/UMR 1018, équipe MOODS, faculté de médecine, université Paris-Saclay, 94270 Le Kremin-Bicêtre, France; Service hospitalo-universitaire de psychiatrie, hôpital de Bicêtre, hôpitaux universitaires Paris-Saclay, Assistance publique-Hôpitaux de Paris (AP-HP), 94275 Le Kremlin-Bicêtre, France
| | - Alain M Gardier
- Inserm CESP/UMR 1018, équipe MOODS, faculté de pharmacie, université Paris-Saclay, 91400 Orsay, France.
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Thomaidis GV, Papadimitriou K, Michos S, Chartampilas E, Tsamardinos I. A characteristic cerebellar biosignature for bipolar disorder, identified with fully automatic machine learning. IBRO Neurosci Rep 2023; 15:77-89. [PMID: 38025660 PMCID: PMC10668096 DOI: 10.1016/j.ibneur.2023.06.008] [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: 01/06/2023] [Revised: 05/19/2023] [Accepted: 06/29/2023] [Indexed: 12/01/2023] Open
Abstract
Background Transcriptomic profile differences between patients with bipolar disorder and healthy controls can be identified using machine learning and can provide information about the potential role of the cerebellum in the pathogenesis of bipolar disorder.With this aim, user-friendly, fully automated machine learning algorithms can achieve extremely high classification scores and disease-related predictive biosignature identification, in short time frames and scaled down to small datasets. Method A fully automated machine learning platform, based on the most suitable algorithm selection and relevant set of hyper-parameter values, was applied on a preprocessed transcriptomics dataset, in order to produce a model for biosignature selection and to classify subjects into groups of patients and controls. The parent GEO datasets were originally produced from the cerebellar and parietal lobe tissue of deceased bipolar patients and healthy controls, using Affymetrix Human Gene 1.0 ST Array. Results Patients and controls were classified into two separate groups, with no close-to-the-boundary cases, and this classification was based on the cerebellar transcriptomic biosignature of 25 features (genes), with Area Under Curve 0.929 and Average Precision 0.955. The biosignature includes both genes connected before to bipolar disorder, depression, psychosis or epilepsy, as well as genes not linked before with any psychiatric disease. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed participation of 4 identified features in 6 pathways which have also been associated with bipolar disorder. Conclusion Automated machine learning (AutoML) managed to identify accurately 25 genes that can jointly - in a multivariate-fashion - separate bipolar patients from healthy controls with high predictive power. The discovered features lead to new biological insights. Machine Learning (ML) analysis considers the features in combination (in contrast to standard differential expression analysis), removing both irrelevant as well as redundant markers, and thus, focusing to biological interpretation.
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Affiliation(s)
- Georgios V. Thomaidis
- Greek National Health System, Psychiatric Department, Katerini General Hospital, Katerini, Greece
| | - Konstantinos Papadimitriou
- Greek National Health System, G. Papanikolaou General Hospital, Organizational Unit - Psychiatric Hospital of Thessaloniki, Thessaloniki, Greece
| | | | - Evangelos Chartampilas
- Laboratory of Radiology, AHEPA General Hospital, University of Thessaloniki, Thessaloniki, Greece
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Hewitt T, Alural B, Tilak M, Wang J, Becke N, Chartley E, Perreault M, Haggarty SJ, Sheridan SD, Perlis RH, Jones N, Mellios N, Lalonde J. Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca 2+ entry and accelerated differentiation. Mol Psychiatry 2023; 28:5237-5250. [PMID: 37402854 DOI: 10.1038/s41380-023-02152-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 05/15/2023] [Accepted: 06/19/2023] [Indexed: 07/06/2023]
Abstract
While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca2+) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca2+ entry (SOCE) is not well understood. Here, we report Ca2+ and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca2+ re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.
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Affiliation(s)
- Tristen Hewitt
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Begüm Alural
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Manali Tilak
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Jennifer Wang
- Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Natalina Becke
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Ellis Chartley
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Melissa Perreault
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Stephen J Haggarty
- Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Steven D Sheridan
- Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Roy H Perlis
- Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Nina Jones
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Nikolaos Mellios
- Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Jasmin Lalonde
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
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Dypås LB, Duale N, Olsen AK, Bustamante M, Maitre L, Escaramis G, Julvez J, Aguilar-Lacasaña S, Andrusaityte S, Casas M, Vafeiadi M, Grazuleviciene R, Heude B, Lepeule J, Urquiza J, Wright J, Yang TC, Vrijheid M, Gützkow KB. Blood miRNA levels associated with ADHD traits in children across six European birth cohorts. BMC Psychiatry 2023; 23:696. [PMID: 37749515 PMCID: PMC10521440 DOI: 10.1186/s12888-023-05199-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/17/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable neurodevelopmental disorder of major societal concern. Diagnosis can be challenging and there are large knowledge gaps regarding its etiology, though studies suggest an interplay of genetic and environmental factors involving epigenetic mechanisms. MicroRNAs (miRNAs) show promise as biomarkers of human pathology and novel therapies, and here we aimed to identify blood miRNAs associated with traits of ADHD as possible biomarker candidates and further explore their biological relevance. METHODS Our study population consisted of 1126 children (aged 5-12 years, 46% female) from the Human Early Life Exposome study, a study spanning six ongoing population-based European birth cohorts. Expression profiles of miRNAs in whole blood samples were quantified by microarray and tested for association with ADHD-related measures of behavior and neuropsychological functions from questionnaires (Conner's Rating Scale and Child Behavior Checklist) and computer-based tests (the N-back task and Attention Network Test). RESULTS We identified 29 miRNAs significantly associated (false discovery rate < .05) with the Conner's questionnaire-rated trait hyperactivity, 15 of which have been linked to ADHD in previous studies. Investigation into their biological relevance revealed involvement in several pathways related to neurodevelopment and function, as well as being linked with other neurodevelopmental or psychiatric disorders known to overlap with ADHD both in symptomology, genetic risk, and co-occurrence, such as autism spectrum disorder or schizophrenia. An additional three miRNAs were significantly associated with Conner's-rated inattention. No associations were found with questionnaire-rated total ADHD index or with computer-based tests. CONCLUSIONS The large overlap of our hyperactivity-associated miRNAs with previous studies on ADHD is intriguing and warrant further investigation. Though this study should be considered explorative and preliminary, these findings contribute towards identifying a set of miRNAs for use as blood-based biomarkers to aid in earlier and easier ADHD diagnosis.
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Affiliation(s)
- Lene B Dypås
- Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
| | - Nur Duale
- Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Ann-Karin Olsen
- Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Mariona Bustamante
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Lea Maitre
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Geòrgia Escaramis
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Biomedical Sciences, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Jordi Julvez
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Clinical and Epidemiological Neuroscience (NeuroÈpia), Institut d'investigació Sanitària Pere Virgili (IISPV), Reus, Catalonia, Spain
| | - Sofia Aguilar-Lacasaña
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Sandra Andrusaityte
- Department of Environmental Science, Vytautas Magnus University, Kaunas, Lithuania
| | - Maribel Casas
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Marina Vafeiadi
- Department of Social Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | | | - Barbara Heude
- Centre of Research in Epidemiology and Statistics (CRESS), Inserm, Université de Paris, Paris, France
| | - Johanna Lepeule
- Université Grenoble Alpes, INSERM, CNRS, Institute for Advanced Biosciences (IAB), Team of Environmental Epidemiology Applied to Development and Respiratory Health, La Tronche, France
| | - Jose Urquiza
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - John Wright
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Tiffany C Yang
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Martine Vrijheid
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Kristine B Gützkow
- Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
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Dai J, Zhang MZ, He QQ, Chen R. The emerging role of exosomes in Schizophrenia. Psychiatry Res 2023; 327:115394. [PMID: 37536144 DOI: 10.1016/j.psychres.2023.115394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/25/2023] [Accepted: 07/29/2023] [Indexed: 08/05/2023]
Abstract
Schizophrenia (SCZ), a serious mental disorder, is one of the leading causes of disease burden worldwide. Exosomes, as a natural nanocarrier, are able to cross the blood-brain barrier (BBB) and play a key bridging role in central nervous system (CNS) communication, participating in important physiological processes such as neural regeneration, prominent plasticity, axonal support, and neuroinflammation. In recent years, exosomes have received widespread attention in the field of neurodegenerative diseases and mental disorders, especially Alzheimer's disease. However, there are few reviews on exosomes and SCZ. Therefore, we conducted a literature search in PubMed and Web of Science using the following search terms: "schizophrenia", "mental disorder", "central system", "exosome", "extracellular vesicles" to identify publications from January 2010 to December 2022. Our review summarized exosomes secreted by different cell types in the CNS and the double-edged role of exosomes in the development of SCZ, and discussed their future potential as biomarkers and therapeutic targets. In conclusion, this article provides an up-to-date overview of the current research on the involvement of exosomes in SCZ, while also highlighting the challenges that are currently faced in this field.
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Affiliation(s)
- Jie Dai
- School of Public Health, Wuhan University, Wuhan, China
| | - Min-Zhe Zhang
- School of Public Health, Wuhan University, Wuhan, China
| | - Qi-Qiang He
- School of Public Health, Wuhan University, Wuhan, China; Hubei Biomass-Resource Chemistry and Environmental Biotechnology Key Laboratory, Wuhan University, Wuhan, China
| | - Rui Chen
- School of Public Health, Wuhan University, Wuhan, China.
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12
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Nguyen TML, Jollant F, Tritschler L, Colle R, Corruble E, Gardier AM. Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review. Pharmaceuticals (Basel) 2023; 16:ph16040634. [PMID: 37111391 PMCID: PMC10146327 DOI: 10.3390/ph16040634] [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: 03/06/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive-aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive-aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility.
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Affiliation(s)
- Thi Mai Loan Nguyen
- Université Paris-Saclay, Faculté de Pharmacie, Inserm CESP/UMR 1018, MOODS Team, F-91400 Orsay, France
| | - Fabrice Jollant
- Université Paris-Saclay, Faculté de Médecine, Inserm CESP/UMR 1018, MOODS Team, F-94270 Le Kremin-Bicêtre, France
- Service Hospitalo-Universitaire de Psychiatrie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Saclay, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
- Pôle de Psychiatrie, CHU Nîmes, 30900 Nîmes, France
- Department of Psychiatry, McGill University and McGill Group for Suicide Studies, Montréal, QC H3A 0G4, Canada
| | - Laurent Tritschler
- Université Paris-Saclay, Faculté de Pharmacie, Inserm CESP/UMR 1018, MOODS Team, F-91400 Orsay, France
| | - Romain Colle
- Université Paris-Saclay, Faculté de Médecine, Inserm CESP/UMR 1018, MOODS Team, F-94270 Le Kremin-Bicêtre, France
- Service Hospitalo-Universitaire de Psychiatrie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Saclay, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
| | - Emmanuelle Corruble
- Université Paris-Saclay, Faculté de Médecine, Inserm CESP/UMR 1018, MOODS Team, F-94270 Le Kremin-Bicêtre, France
- Service Hospitalo-Universitaire de Psychiatrie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Saclay, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre, France
| | - Alain M Gardier
- Université Paris-Saclay, Faculté de Pharmacie, Inserm CESP/UMR 1018, MOODS Team, F-91400 Orsay, France
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13
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Petrea O, Stefanescu G, Stefanescu C. Psychological Burden of NAFLD and Psychiatric Disorders as Extrahepatic Manifestations. ESSENTIALS OF NON-ALCOHOLIC FATTY LIVER DISEASE 2023:203-215. [DOI: 10.1007/978-3-031-33548-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Shahcheraghi SH, Ayatollahi J, Lotfi M, Aljabali AAA, Al-Zoubi MS, Panda PK, Mishra V, Satija S, Charbe NB, Serrano-Aroca Á, Bahar B, Takayama K, Goyal R, Bhatia A, Almutary AG, Alnuqaydan AM, Mishra Y, Negi P, Courtney A, McCarron PA, Bakshi HA, Tambuwala MM. Gene Therapy for Neuropsychiatric Disorders: Potential Targets and Tools. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:51-65. [PMID: 35249508 DOI: 10.2174/1871527321666220304153719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/16/2022] [Accepted: 01/16/2022] [Indexed: 01/01/2023]
Abstract
Neuropsychiatric disorders that affect the central nervous system cause considerable pressures on the health care system and have a substantial economic burden on modern societies. The present treatments based on available drugs are mostly ineffective and often costly. The molecular process of neuropsychiatric disorders is closely connected to modifying the genetic structures inherited or caused by damage, toxic chemicals, and some current diseases. Gene therapy is presently an experimental concept for neurological disorders. Clinical applications endeavor to alleviate the symptoms, reduce disease progression, and repair defective genes. Implementing gene therapy in inherited and acquired neurological illnesses entails the integration of several scientific disciplines, including virology, neurology, neurosurgery, molecular genetics, and immunology. Genetic manipulation has the power to minimize or cure illness by inducing genetic alterations at endogenous loci. Gene therapy that involves treating the disease by deleting, silencing, or editing defective genes and delivering genetic material to produce therapeutic molecules has excellent potential as a novel approach for treating neuropsychiatric disorders. With the recent advances in gene selection and vector design quality in targeted treatments, gene therapy could be an effective approach. This review article will investigate and report the newest and the most critical molecules and factors in neuropsychiatric disorder gene therapy. Different genome editing techniques available will be evaluated, and the review will highlight preclinical research of genome editing for neuropsychiatric disorders while also evaluating current limitations and potential strategies to overcome genome editing advancements.
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Affiliation(s)
- Seyed H Shahcheraghi
- Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Jamshid Ayatollahi
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Marzieh Lotfi
- Abortion Research Center, Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alaa A A Aljabali
- Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
| | - Mazhar S Al-Zoubi
- Yarmouk University, Faculty of Medicine, Department of Basic Medical Sciences, Irbid, Jordan
| | - Pritam K Panda
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 75120 Uppsala, Sweden
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Nitin B Charbe
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX 78363, USA
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Lab, Translational Research Centre San Alberto Magno, Catholic University of Valencia San Vicente Mártir, C/Guillem de Castro 94, 46001 Valencia, Spain
| | - Bojlul Bahar
- Nutrition Sciences and Applied Food Safety Studies, Research Centre for Global Development, School of Sport & Health Sciences, University of Central Lancashire, Preston, PR1 2HE, UK
| | - Kazuo Takayama
- Center for IPS Cell Research and Application, Kyoto University, Kyoto, 606-8397, Japan
| | - Rohit Goyal
- Neuropharmacology Laboratory, School of Pharmaceutical Sciences, Shoolini University, Post Box No. 9, Solan, Himachal Pradesh 173212, India
| | - Amit Bhatia
- Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Punjab 151001, India
| | - Abdulmajeed G Almutary
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Saudi Arabia
| | - Abdullah M Alnuqaydan
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Saudi Arabia
| | - Yachana Mishra
- Shri Shakti Degree College, Sankhahari, Ghatampur 209206, India
| | - Poonam Negi
- Shoolini University of Biotechnology and Management Sciences, Solan 173 212, India
| | - Aaron Courtney
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Paul A McCarron
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Hamid A Bakshi
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
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15
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Lim M, Carollo A, Neoh MJY, Esposito G. Mapping miRNA Research in Schizophrenia: A Scientometric Review. Int J Mol Sci 2022; 24:ijms24010436. [PMID: 36613876 PMCID: PMC9820708 DOI: 10.3390/ijms24010436] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/20/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Micro RNA (miRNA) research has great implications in uncovering the aetiology of neuropsychiatric conditions due to the role of miRNA in brain development and function. Schizophrenia, a complex yet devastating neuropsychiatric disorder, is one such condition that had been extensively studied in the realm of miRNA. Although a relatively new field of research, this area of study has progressed sufficiently to warrant dozens of reviews summarising findings from past to present. However, as a majority of reviews cannot encapsulate the full body of research, there is still a need to synthesise the diversity of publications made in this area in a systematic but easy-to-understand manner. Therefore, this study adopted bibliometrics and scientometrics, specifically document co-citation analysis (DCA), to review the literature on miRNAs in the context of schizophrenia over the course of history. From a literature search on Scopus, 992 papers were found and analysed with CiteSpace. DCA analysis generated a network of 13 major clusters with different thematic focuses within the subject area. Finally, these clusters are qualitatively discussed. miRNA research has branched into schizophrenia, among other medical and psychiatric conditions, due to previous findings in other forms of non-coding RNA. With the rise of big data, bioinformatics analyses are increasingly common in this field of research. The future of research is projected to rely more heavily on interdisciplinary collaboration. Additionally, it can be expected that there will be more translational studies focusing on the application of these findings to the development of effective treatments.
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Affiliation(s)
- Mengyu Lim
- Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore 639818, Singapore
| | - Alessandro Carollo
- Department of Psychology and Cognitive Science, University of Trento, 38068 Rovereto, Italy
| | - Michelle Jin Yee Neoh
- Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore 639818, Singapore
| | - Gianluca Esposito
- Department of Psychology and Cognitive Science, University of Trento, 38068 Rovereto, Italy
- Correspondence:
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16
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Gangopadhyay A, Ibrahim R, Theberge K, May M, Houseknecht KL. Non-alcoholic fatty liver disease (NAFLD) and mental illness: Mechanisms linking mood, metabolism and medicines. Front Neurosci 2022; 16:1042442. [PMID: 36458039 PMCID: PMC9707801 DOI: 10.3389/fnins.2022.1042442] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/21/2022] [Indexed: 09/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world and one of the leading indications for liver transplantation. It is one of the many manifestations of insulin resistance and metabolic syndrome as well as an independent risk factor for cardiovascular disease. There is growing evidence linking the incidence of NAFLD with psychiatric illnesses such as schizophrenia, bipolar disorder and depression mechanistically via genetic, metabolic, inflammatory and environmental factors including smoking and psychiatric medications. Indeed, patients prescribed antipsychotic medications, regardless of diagnosis, have higher incidence of NAFLD than population norms. The mechanistic pharmacology of antipsychotic-associated NAFLD is beginning to emerge. In this review, we aim to discuss the pathophysiology of NAFLD including its risk factors, insulin resistance and systemic inflammation as well as its intersection with psychiatric illnesses.
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Affiliation(s)
| | | | | | | | - Karen L. Houseknecht
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States
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17
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Coradduzza D, Garroni G, Congiargiu A, Balzano F, Cruciani S, Sedda S, Nivoli A, Maioli M. MicroRNAs, Stem Cells in Bipolar Disorder, and Lithium Therapeutic Approach. Int J Mol Sci 2022; 23:ijms231810489. [PMID: 36142403 PMCID: PMC9502703 DOI: 10.3390/ijms231810489] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Bipolar disorder (BD) is a severe, chronic, and disabling neuropsychiatric disorder characterized by recurrent mood disturbances (mania/hypomania and depression, with or without mixed features) and a constellation of cognitive, psychomotor, autonomic, and endocrine abnormalities. The etiology of BD is multifactorial, including both biological and epigenetic factors. Recently, microRNAs (miRNAs), a class of epigenetic regulators of gene expression playing a central role in brain development and plasticity, have been related to several neuropsychiatric disorders, including BD. Moreover, an alteration in the number/distribution and differentiation potential of neural stem cells has also been described, significantly affecting brain homeostasis and neuroplasticity. This review aimed to evaluate the most reliable scientific evidence on miRNAs as biomarkers for the diagnosis of BD and assess their implications in response to mood stabilizers, such as lithium. Neural stem cell distribution, regulation, and dysfunction in the etiology of BD are also dissected.
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Affiliation(s)
| | - Giuseppe Garroni
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | | | - Francesca Balzano
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Stefania Sedda
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Alessandra Nivoli
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy
- Correspondence: (A.N.); (M.M.); Tel.: +39-079-228-277 (A.N.); +39-079-255-406-228350 (M.M.)
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
- Center for Developmental Biology and Reprogramming (CEDEBIOR), Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
- Correspondence: (A.N.); (M.M.); Tel.: +39-079-228-277 (A.N.); +39-079-255-406-228350 (M.M.)
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18
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Schell G, Roy B, Prall K, Dwivedi Y. miR-218: A Stress-Responsive Epigenetic Modifier. Noncoding RNA 2022; 8:ncrna8040055. [PMID: 35893238 PMCID: PMC9326663 DOI: 10.3390/ncrna8040055] [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] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022] Open
Abstract
Understanding the epigenetic role of microRNAs (miRNAs) has been a critical development in the field of neuropsychiatry and in understanding their underlying pathophysiology. Abnormalities in miRNA expression are often seen as key to the pathogenesis of many stress-associated mental disorders, including major depressive disorder (MDD). Recent advances in omics biology have further contributed to this understanding and expanded the role of miRNAs in networking a diverse array of molecular pathways, which are essentially related to the stress adaptivity of a healthy brain. Studies have highlighted the role of many such miRNAs in causing maladaptive changes in the brain's stress axis. One such miRNA is miR-218, which is debated as a critical candidate for increased stress susceptibility. miR-218 is expressed throughout the brain, notably in the hippocampus and prefrontal cortex (PFC). It is expressed at various levels through life stages, as seen by adolescent and adult animal models. Until now, a minimal number of studies have been conducted on human subjects to understand its role in stress-related abnormalities in brain circuits. However, several studies, including animal and cell-culture models, have been used to understand the impact of miR-218 on stress response and hypothalamic-pituitary-adrenal (HPA) axis function. So far, expression changes in this miRNA have been found to regulate signaling pathways such as glucocorticoid signaling, serotonergic signaling, and glutamatergic signaling. Recently, the developmental role of miR-218 has generated interest, given its increasing expression from adolescence to adulthood and targeting the Netrin-1/DCC signaling pathway. Since miR-218 expression affects neuronal development and plasticity, it is expected that a change in miR-218 expression levels over the course of development may negatively impact the process and make individuals stress-susceptible in adulthood. In this review, we describe the role of miR-218 in stress-induced neuropsychiatric conditions with an emphasis on stress-related disorders.
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Tsermpini EE, Kalogirou CI, Kyriakopoulos GC, Patrinos GP, Stathopoulos C. miRNAs as potential diagnostic biomarkers and pharmacogenomic indicators in psychiatric disorders. THE PHARMACOGENOMICS JOURNAL 2022; 22:211-222. [PMID: 35725816 DOI: 10.1038/s41397-022-00283-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 05/23/2022] [Accepted: 06/08/2022] [Indexed: 12/11/2022]
Abstract
The heterogeneity of psychiatric disorders and the lack of reliable biomarkers for prediction and treatments follow-up pose difficulties towards recognition and understanding of the molecular basis of psychiatric diseases. However, several studies based on NGS approaches have shown that miRNAs could regulate gene expression during onset and disease progression and could serve as potential diagnostic and pharmacogenomics biomarkers during treatment. We provide herein a detailed overview of circulating miRNAs and their expression profiles as biomarkers in schizophrenia, bipolar disorder and major depressive disorder and their role in response to specific treatments. Bioinformatics analysis of miR-34a, miR-106, miR-134 and miR-132, which are common among SZ, BD and MDD patients, showed brain enrichment and involvement in the modulation of critical signaling pathways, which are often deregulated in psychiatric disorders. We propose that specific miRNAs support accurate diagnosis and effective precision treatment of psychiatric disorders.
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Affiliation(s)
- Evangelia Eirini Tsermpini
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Christina I Kalogirou
- Department of Biochemistry, School of Medicine, University of Patras, Patras, Greece
| | | | - George P Patrinos
- Laboratory of Pharmacogenomics and Individualized Therapy, School of Health Sciences, Department of Pharmacy, University of Patras, Patras, Greece
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Sotoudeh Anvari M, Vasei H, Najmabadi H, Badv RS, Golipour A, Mohammadi-Yeganeh S, Salehi S, Mohamadi M, Goodarzynejad H, Mowla SJ. Identification of microRNAs associated with human fragile X syndrome using next-generation sequencing. Sci Rep 2022; 12:5011. [PMID: 35322102 PMCID: PMC8943156 DOI: 10.1038/s41598-022-08916-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 03/15/2022] [Indexed: 11/09/2022] Open
Abstract
Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene which can lead to a loss or shortage of the FMR1 protein. This protein interacts with specific miRNAs and can cause a range of neurological disorders. Therefore, miRNAs could act as a novel class of biomarkers for common CNS diseases. This study aimed to test this theory by exploring the expression profiles of various miRNAs in Iranian using deep sequencing-based technologies and validating the miRNAs affecting the expression of the FMR1 gene. Blood samples were taken from 15 patients with FXS (9 males, 6 females) and 12 controls. 25 miRNAs were differentially expressed in individuals with FXS compared to controls. Levels of 9 miRNAs were found to be significantly changed (3 upregulated and 6 downregulated). In Patients, the levels of hsa-miR-532-5p, hsa-miR-652-3p and hsa-miR-4797-3p were significantly upregulated while levels of hsa-miR-191-5p, hsa-miR-181-5p, hsa-miR-26a-5p, hsa-miR-30e-5p, hsa-miR-186-5p, and hsa-miR-4797-5p exhibited significant downregulation; and these dysregulations were confirmed by RT-qPCR. This study presents among the first evidence of altered miRNA expression in blood samples from patients with FXS, which could be used for diagnostic, prognostic, and treatment purposes. Larger studies are required to confirm these preliminary results.
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Affiliation(s)
- Maryam Sotoudeh Anvari
- Department of Molecular Pathology, School of Medicine, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hamed Vasei
- Department of Mathematical Science, Sharif University of Technology, Tehran, Iran
| | - Hossein Najmabadi
- Department of Genetics, School of Rehabilitation Sciences, Genetic Research Center, The University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Reza Shervin Badv
- Department of Pediatrics, School of Medicine, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Golipour
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeede Salehi
- Cell-Based Therapies Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Mohamadi
- Department of Pediatrics, School of Medicine, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Goodarzynejad
- Department of Basic and Clinical Research, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
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21
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Banach E, Szczepankiewicz A, Kaczmarek L, Jaworski T, Urban-Ciećko J. Dysregulation of miRNAs levels in GSK3β overexpressing mice and the role of miR-221-5p in synaptic function. Neuroscience 2022; 490:287-295. [PMID: 35331845 DOI: 10.1016/j.neuroscience.2022.03.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 01/01/2023]
Abstract
Glycogen Synthase Kinase-3β (GSK-3β) is a highly expressed kinase in the brain, where it has an important role in synaptic plasticity. Aberrant activity of GSK-3β leads to synaptic dysfunction which results in the development of several neuropsychiatric and neurological diseases. Notably, overexpression of constitutively active form of GSK-3β (GSK-3β[S9A]) in mice recapitulates the cognitive and structural defects characteristic for neurological and psychiatric disorders. However, the mechanisms by which GSK-3β regulates synaptic functions are not clearly known. Here, we investigate the effects of GSK-3β overactivity on neuronal miRNA expression in the mouse hippocampus. We found that GSK-3β overactivity downregulates miRNA network with a potent effect on miR-221-5p (miR-221*). Next, characterization of miR-221* function in primary hippocampal cell culture transfected by miR-221* inhibitor, showed no structural changes in dendritic spine shape and density. Using electrophysiological methods, we found that downregulation of miR-221* increases excitatory synaptic transmission in hippocampal neurons, probably via postsynaptic mechanisms. Thus, our data reveal potential mechanism by which GSK-3β and miRNAs might regulate synaptic function and therefore also synaptic plasticity.
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Affiliation(s)
- Ewa Banach
- Laboratory of Electrophysiology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Animal Models, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland.
| | | | - Leszek Kaczmarek
- Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland
| | - Tomasz Jaworski
- Laboratory of Animal Models, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland; Research and Development Centre, Celon Pharma SA, Kazun Nowy, Poland
| | - Joanna Urban-Ciećko
- Laboratory of Electrophysiology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland
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22
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Baiap3 regulates depressive behaviors in mice via attenuating dense core vesicle trafficking in subsets of prefrontal cortex neurons. Neurobiol Stress 2022; 16:100423. [PMID: 35028340 PMCID: PMC8715124 DOI: 10.1016/j.ynstr.2021.100423] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 11/21/2022] Open
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are effective first line therapies for treating depression, but are plagued by undesirable side effects and are not effective in all patients. Because SSRIs effectively deplete the neuronal releasable serotonin (5-HT) pool, gaining a deeper understanding of intracellular mechanisms regulating 5-HT pools can help us understand the shortcomings of SSRIs and develop more effective therapies. In this study, we found that BAIAP3 (brain-specific angiogenesis inhibitor 1-associated protein 3) is significantly downregulated in two mouse models of depression (the IR- and CUMS-induced depressive mouse models). In BAIAP3 downregulated models (in vitro and in vivo), we discovered that trafficking of dense core vesicle (DCV), organelles that store, transport and release cargo via exocytosis, was reduced. Accordingly, 5-HT exocytosis and levels in the synapse were lowered, causing defective post-synaptic neurotransmission. In a screen of natural products, we identified eucalyptol, the active components of Eucalyptus, as uniquely capable of increasing neuronal Baiap3 expression and elevate synaptic 5-HT levels. Moreover, eucalyptol treatment relieved depressive behavioral symptoms and restored serotonin levels in mice. Mechanistically, eucalyptol restores Baiap3 expression by reducing inhibitory microRNAs (miR-329, miR-362). These findings illuminate how Baiap3 depletion propagates neurotransmission dysfunction and point to eucalyptol as a novel agent for restoring serotonin exocytosis, suggesting potential for developing eucalyptol as a therapy for treating depression.
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23
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Gupta S, Guleria RS, Szabo YZ. MicroRNAs as biomarker and novel therapeutic target for posttraumatic stress disorder in Veterans. Psychiatry Res 2021; 305:114252. [PMID: 34739954 PMCID: PMC8857765 DOI: 10.1016/j.psychres.2021.114252] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/04/2021] [Accepted: 10/23/2021] [Indexed: 12/16/2022]
Abstract
Posttraumatic stress disorder (PTSD) is a common psychiatric disorder for military Veterans, characterized by hyperarousal, intrusive thoughts, flashbacks, hypervigilance, and distress after experiencing traumatic events. Some of the known physiological effects of PTSD include hypothalamic-pituitary-adrenal (HPA)-axis imbalance, a cortical function resulting in neuronal deficit and changes in behavior. Moreover, excessive discharge of inflammatory molecules and a dysregulated immune system are implicated in the pathophysiology of PTSD. Due to complex nature of this disorder, the biological underpinnings of PTSD remain inexplicable. Investigating novel biomarkers to understanding the pathogenesis of PTSD may reflect the underlying molecular network for therapeutic use and treatment. Circulatory microRNAs (miRNAs) and exosomes are evolving biomarkers that have shown a key role in psychiatric and neurological disorders including PTSD. Given the unique nature of combat trauma, as well as evidence that a large portion of Veterans do not benefit from frontline treatments, focus on veterans specifically is warranted. In the present review, we delineate the identification and role of several miRNAs in PTSD among veterans. An association of miRNA with HPA-axis regulation through FKBP5, a key modulator in PTSD is discussed as an emerging molecule in psychiatric diseases. We conclude that miRNAs may be used as circulatory biomarker detection in Veterans with PTSD.
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Affiliation(s)
- Sudhiranjan Gupta
- VISN 17 Center of Excellence for Research on Returning War Veterans, Biomarkers & Genetics Core, Central Texas Veterans Health Care System, 4800 Memorial Drive (151C), Waco, TX, 76711, USA.
| | - Rakeshwar S. Guleria
- VISN 17 Center of Excellence for Research on Returning War Veterans, Biomarkers & Genetics Core, Central Texas Veterans Health Care System, 4800 Memorial Drive (151C), Waco, Texas, 76711
| | - Yvette Z. Szabo
- VISN 17 Center of Excellence for Research on Returning War Veterans, Biomarkers & Genetics Core, Central Texas Veterans Health Care System, 4800 Memorial Drive (151C), Waco, Texas, 76711
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24
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Liu W, Zhang F, Zheng Y, He S, Zhang T, Guo Q, Xu H, Chen H, Liu C, Yu S, Jiang K, Li H, Li G, Wang X, Liu X. The role of circulating blood microRNA-374 and microRNA-10 levels in the pathogenesis and therapeutic mechanisms of major depressive disorder. Neurosci Lett 2021; 763:136184. [PMID: 34418506 DOI: 10.1016/j.neulet.2021.136184] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 08/10/2021] [Accepted: 08/16/2021] [Indexed: 12/28/2022]
Abstract
Compelling recent evidence suggests that microRNAs (miRNAs) regulate specific mRNA transcripts at the transcriptomic level and coordinately influence complex regulatory networks, which may play a crucial role in the pathogenesis of major depressive disorder (MDD) and the treatment effects of antidepressants. To evaluate the possible involvement of miRNAs in the pathophysiology and therapeutic response of MDD, we conducted a miRNA expression array analysis of the peripheral blood mononuclear cells (PBMCs) of 5 depressed patients and 5 healthy controls (HCs). Subsequently, we chose 2 miRNAs for validation with real-time PCR (RT-PCR) analysis pre- and post-treatment in another group of 25 MDD patients and 25 HCs. In the array, 5 miRNAs were differentially expressed in medication-naïve MDD patients compared to HCs, of which 2 miRNAs were upregulated and 3 were downregulated. Furthermore, in comparison with HCs, MDD patients showed significantly lower expression levels of miR-374b and miR-10a before treatment. After 8 weeks of antidepressant treatment, both miR-374b and the miR-10a expression levels in MDD patients were significantly elevated only in responders. In conclusion, these results indicate the involvement of miR-374b and miR-10a in the biological mechanisms and therapeutic response of MDD, and provide new insights for exploring miRNAs as potential biomarkers for MDD.
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Affiliation(s)
- Wanying Liu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Fuxu Zhang
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yanqun Zheng
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Shen He
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Tianhong Zhang
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Qian Guo
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Hua Xu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Haiying Chen
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Caiping Liu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Shunying Yu
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kaida Jiang
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Huafang Li
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Institution of Drug Clinical Trials, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Guanjun Li
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Xiaoliang Wang
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Xiaohua Liu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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25
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Pérez-Rodríguez D, López-Fernández H, Agís-Balboa RC. Application of miRNA-seq in neuropsychiatry: A methodological perspective. Comput Biol Med 2021; 135:104603. [PMID: 34216893 DOI: 10.1016/j.compbiomed.2021.104603] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/21/2021] [Accepted: 06/21/2021] [Indexed: 10/21/2022]
Abstract
MiRNAs are emerging as key molecules to study neuropsychiatric diseases. However, despite the large number of methodologies and software for miRNA-seq analyses, there is little supporting literature for researchers in this area. This review focuses on evaluating how miRNA-seq has been used to study neuropsychiatric diseases to date, analyzing both the main findings discovered and the bioinformatics workflows and tools used from a methodological perspective. The objective of this review is two-fold: first, to evaluate current miRNA-seq procedures used in neuropsychiatry; and second, to offer comprehensive information that can serve as a guide to new researchers in bioinformatics. After conducting a systematic search (from 2016 to June 30, 2020) of articles using miRNA-seq in neuropsychiatry, we have seen that it has already been used for different types of studies in three main categories: diagnosis, prognosis, and mechanism. We carefully analyzed the bioinformatics workflows of each study, observing a high degree of variability with respect to the tools and methods used and several methodological complexities that are identified and discussed in this review.
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Affiliation(s)
- Daniel Pérez-Rodríguez
- Translational Neuroscience Group-CIBERSAM, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, 36213, Vigo, Spain; NeuroEpigenetics Lab. University Hospital Complex of Vigo, SERGAS-UVIGO, 36213, Vigo, Spain
| | - Hugo López-Fernández
- Instituto de Investigação e Inovação Em Saúde (I3S), Universidade Do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; CINBIO, Universidade de Vigo, Department of Computer Science, ESEI - Escuela Superior de Ingeniería Informática, 32004, Ourense, Spain; SING Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Spain.
| | - Roberto C Agís-Balboa
- Translational Neuroscience Group-CIBERSAM, Galicia Sur Health Research Institute (IIS Galicia Sur), Área Sanitaria de Vigo-Hospital Álvaro Cunqueiro, SERGAS-UVIGO, 36213, Vigo, Spain; NeuroEpigenetics Lab. University Hospital Complex of Vigo, SERGAS-UVIGO, 36213, Vigo, Spain.
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26
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MicroRNAs hsa-mir-34a and hsa-mir-124 as biomarkers for predicting and monitoring the lithium treatment in bipolar disorder: in silico analysis. UKRAINIAN BIOCHEMICAL JOURNAL 2021. [DOI: 10.15407/ubj93.01.082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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27
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Segaran RC, Chan LY, Wang H, Sethi G, Tang FR. Neuronal Development-Related miRNAs as Biomarkers for Alzheimer's Disease, Depression, Schizophrenia and Ionizing Radiation Exposure. Curr Med Chem 2021; 28:19-52. [PMID: 31965936 DOI: 10.2174/0929867327666200121122910] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/30/2019] [Accepted: 10/22/2019] [Indexed: 11/22/2022]
Abstract
Radiation exposure may induce Alzheimer's disease (AD), depression or schizophrenia. A number of experimental and clinical studies suggest the involvement of miRNA in the development of these diseases, and also in the neuropathological changes after brain radiation exposure. The current literature review indicated the involvement of 65 miRNAs in neuronal development in the brain. In the brain tissue, blood, or cerebral spinal fluid (CSF), 11, 55, or 28 miRNAs are involved in the development of AD respectively, 89, 50, 19 miRNAs in depression, and 102, 35, 8 miRNAs in schizophrenia. We compared miRNAs regulating neuronal development to those involved in the genesis of AD, depression and schizophrenia and also those driving radiation-induced brain neuropathological changes by reviewing the available data. We found that 3, 11, or 8 neuronal developmentrelated miRNAs from the brain tissue, 13, 16 or 14 miRNAs from the blood of patient with AD, depression and schizophrenia respectively were also involved in radiation-induced brain pathological changes, suggesting a possibly specific involvement of these miRNAs in radiation-induced development of AD, depression and schizophrenia respectively. On the other hand, we noted that radiationinduced changes of two miRNAs, i.e., miR-132, miR-29 in the brain tissue, three miRNAs, i.e., miR- 29c-5p, miR-106b-5p, miR-34a-5p in the blood were also involved in the development of AD, depression and schizophrenia, thereby suggesting that these miRNAs may be involved in the common brain neuropathological changes, such as impairment of neurogenesis and reduced learning memory ability observed in these three diseases and also after radiation exposure.
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Affiliation(s)
- Renu Chandra Segaran
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
| | - Li Yun Chan
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
| | - Hong Wang
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Feng Ru Tang
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
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28
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Mirabella F, Gulisano M, Capelli M, Lauretta G, Cirnigliaro M, Palmucci S, Stella M, Barbagallo D, Di Pietro C, Purrello M, Ragusa M, Rizzo R. Enrichment and Correlation Analysis of Serum miRNAs in Comorbidity Between Arnold-Chiari and Tourette Syndrome Contribute to Clarify Their Molecular Bases. Front Mol Neurosci 2021; 13:608355. [PMID: 33469418 PMCID: PMC7813987 DOI: 10.3389/fnmol.2020.608355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 12/04/2020] [Indexed: 12/27/2022] Open
Abstract
Due to its rarity, coupled to a multifactorial and very heterogeneous nature, the molecular etiology of Arnold-Chiari (AC) syndrome remains almost totally unknown. Its relationship with other neuropsychiatric disorders such as Tourette syndrome (TS) is also undetermined. The rare comorbid status between both disorders (ACTS) complicates the framework of diagnosis and negatively affects the patients' quality of life. In this exploratory study, we aimed to identify serum microRNA expression profiles as molecular fingerprints for AC, TS, and ACTS, by using a high-throughput approach. For this aim, 10 AC patients, 11 ACTS patients, 6 TS patients, and 8 unaffected controls (NC) were recruited. Nine miRNAs resulted significantly differentially expressed (DE): let-7b-5p (upregulated in ACTS vs. TS); miR-21-5p (upregulated in ACTS vs. AC; downregulated in AC vs. TS); miR-23a-3p (upregulated in TS vs. NCs; downregulated in AC vs. TS); miR-25-3p (upregulated in AC vs. TS and NCs; downregulated in ACTS vs. AC); miR-93-5p (upregulated in AC vs. TS); miR-130a-3p (downregulated in ACTS and TS vs. NCs); miR-144-3p (downregulated in ACTS vs. AC; upregulated in AC vs. TS); miR-222-3p (upregulated in ACTS vs. NCs); miR-451a (upregulated in AC vs. TS and NCs; in ACTS vs. NCs). Altered expression of miRNAs was statistically correlated to neuroimaging and neuropsychological anomalies. Furthermore, computational analyses indicated that DE miRNAs are involved in AC and TS pathomechanisms. Finally, we propose the dysregulation of the miRNA set as a potential molecular tool for supporting the current diagnosis of AC, TS, and ACTS by using liquid biopsies, in an unbiased and non-invasive way.
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Affiliation(s)
- Federica Mirabella
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Mariangela Gulisano
- Section of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Mara Capelli
- Section of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giovanni Lauretta
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Matilde Cirnigliaro
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Stefano Palmucci
- Radiology Unit 1, Department of Medical Surgical Sciences and Advanced Technologies, University Hospital “Policlinico-Vittorio Emanuele”, University of Catania, Catania, Italy
| | - Michele Stella
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Davide Barbagallo
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Cinzia Di Pietro
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Michele Purrello
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Marco Ragusa
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Oasi Research Institute–IRCCS, Troina, Italy
| | - Renata Rizzo
- Section of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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29
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Widespread transcriptional disruption of the microRNA biogenesis machinery in brain and peripheral tissues of individuals with schizophrenia. Transl Psychiatry 2020; 10:376. [PMID: 33149139 PMCID: PMC7642431 DOI: 10.1038/s41398-020-01052-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 09/16/2020] [Accepted: 10/01/2020] [Indexed: 12/17/2022] Open
Abstract
In schizophrenia, altered transcription in brain and peripheral tissues may be due to altered expression of the microRNA biogenesis machinery genes. In this study, we explore the expression of these genes both at the cerebral and peripheral levels. We used shinyGEO application to analyze gene expression from ten Gene Expression Omnibus datasets, in order to perform differential expression analyses for eight genes encoding the microRNA biogenesis machinery. First, we compared expression of the candidate genes between control subjects and individuals with schizophrenia in postmortem cerebral samples from seven different brain regions. Then, we compared the expression of the candidate genes between control subjects and individuals with schizophrenia in three peripheral tissues. In brain and peripheral tissues of individuals with schizophrenia, we report distinct altered expression patterns of the microRNA biogenesis machinery genes. In the dorsolateral prefrontal cortex, associative striatum and cerebellum of individuals with schizophrenia, we observed an overexpression pattern of some candidate genes suggesting a heightened miRNA production in these brain regions. Additionally, mixed transcriptional abnormalities were identified in the hippocampus. Moreover, in the blood and olfactory epithelium of individuals with schizophrenia, we observed distinct aberrant transcription patterns of the candidate genes. Remarkably, in individuals with schizophrenia, we report DICER1 overexpression in the dorsolateral prefrontal cortex, hippocampus and cerebellum as well as a congruent DICER1 upregulation in the blood compartment suggesting that it may represent a peripheral marker. Transcriptional disruption of the miRNA biogenesis machinery may contribute to schizophrenia pathogenesis both in brain and peripheral tissues.
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30
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Soto-Angona Ó, Anmella G, Valdés-Florido MJ, De Uribe-Viloria N, Carvalho AF, Penninx BWJH, Berk M. Non-alcoholic fatty liver disease (NAFLD) as a neglected metabolic companion of psychiatric disorders: common pathways and future approaches. BMC Med 2020; 18:261. [PMID: 32998725 PMCID: PMC7528270 DOI: 10.1186/s12916-020-01713-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in over 5% of the parenchyma in the absence of excessive alcohol consumption. It is more prevalent in patients with diverse mental disorders, being part of the comorbidity driving loss of life expectancy and quality of life, yet remains a neglected entity. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and increases the risk for cirrhosis and hepatic carcinoma. Both NAFLD and mental disorders share pathophysiological pathways, and also present a complex, bidirectional relationship with the metabolic syndrome (MetS) and related cardiometabolic diseases. MAIN TEXT This review compares the demographic data on NAFLD and NASH among the global population and the psychiatric population, finding differences that suggest a higher incidence of this disease among the latter. It also analyzes the link between NAFLD and psychiatric disorders, looking into common pathophysiological pathways, such as metabolic, genetic, and lifestyle factors. Finally, possible treatments, tailored approaches, and future research directions are suggested. CONCLUSION NAFLD is part of a complex system of mental and non-communicable somatic disorders with a common pathogenesis, based on shared lifestyle and environmental risks, mediated by dysregulation of inflammation, oxidative stress pathways, and mitochondrial function. The recognition of the prevalent comorbidity between NAFLD and mental disorders is required to inform clinical practice and develop novel interventions to prevent and treat these complex and interacting disorders.
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Affiliation(s)
- Óscar Soto-Angona
- Department of Psychiatry, Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Catalonia, Spain.
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.
| | - Gerard Anmella
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain
| | | | - Nieves De Uribe-Viloria
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Department of Psychiatry, Hospital Clínico Universitario de Valladolid, Castilla y León, Spain
| | - Andre F Carvalho
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - Brenda W J H Penninx
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam University Medical Center/Vrije Universiteit & GGZinGeest, Amsterdam, the Netherlands
| | - Michael Berk
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry, and the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
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Peedicayil J. Pharmacoepigenetics and Pharmacoepigenomics: An Overview. Curr Drug Discov Technol 2020; 16:392-399. [PMID: 29676232 DOI: 10.2174/1570163815666180419154633] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The rapid and major advances being made in epigenetics are impacting pharmacology, giving rise to new sub-disciplines in pharmacology, pharmacoepigenetics, the study of the epigenetic basis of variation in response to drugs; and pharmacoepigenomics, the application of pharmacoepigenetics on a genome-wide scale. METHODS This article highlights the following aspects of pharmacoepigenetics and pharmacoepigenomics: epigenetic therapy, the role of epigenetics in pharmacokinetics, the relevance of epigenetics to adverse drug reactions, personalized medicine, drug addiction, and drug resistance, and the use of epigenetic biomarkers in drug therapy. RESULTS Epigenetics is having an increasing impact on several areas of pharmacology. CONCLUSION Pharmacoepigenetics and pharmacoepigenomics are new sub-disciplines in pharmacology and are likely to have an increasing impact on the use of drugs in clinical practice.
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Affiliation(s)
- Jacob Peedicayil
- Department of Pharmacology & Clinical Pharmacology, Christian Medical College, Vellore, India
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32
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Gibbons A, Sundram S, Dean B. Changes in Non-Coding RNA in Depression and Bipolar Disorder: Can They Be Used as Diagnostic or Theranostic Biomarkers? Noncoding RNA 2020; 6:E33. [PMID: 32846922 PMCID: PMC7549354 DOI: 10.3390/ncrna6030033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/20/2020] [Accepted: 08/20/2020] [Indexed: 12/14/2022] Open
Abstract
The similarities between the depressive symptoms of Major Depressive Disorders (MDD) and Bipolar Disorders (BD) suggest these disorders have some commonality in their molecular pathophysiologies, which is not apparent from the risk genes shared between MDD and BD. This is significant, given the growing literature suggesting that changes in non-coding RNA may be important in both MDD and BD, because they are causing dysfunctions in the control of biochemical pathways that are affected in both disorders. Therefore, understanding the changes in non-coding RNA in MDD and BD will lead to a better understanding of how and why these disorders develop. Furthermore, as a significant number of individuals suffering with MDD and BD do not respond to medication, identifying non-coding RNA that are altered by the drugs used to treat these disorders offer the potential to identify biomarkers that could predict medication response. Such biomarkers offer the potential to quickly identify patients who are unlikely to respond to traditional medications so clinicians can refocus treatment strategies to ensure more effective outcomes for the patient. This review will focus on the evidence supporting the involvement of non-coding RNA in MDD and BD and their potential use as biomarkers for treatment response.
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Affiliation(s)
- Andrew Gibbons
- The Florey Institute for Neuroscience and Mental Health, Parkville, The University of Melbourne, Melbourne, Victoria 3052, Australia; (S.S.); (B.D.)
- The Department of Psychiatry, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia
| | - Suresh Sundram
- The Florey Institute for Neuroscience and Mental Health, Parkville, The University of Melbourne, Melbourne, Victoria 3052, Australia; (S.S.); (B.D.)
- The Department of Psychiatry, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia
| | - Brian Dean
- The Florey Institute for Neuroscience and Mental Health, Parkville, The University of Melbourne, Melbourne, Victoria 3052, Australia; (S.S.); (B.D.)
- The Centre for Mental Health, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia
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Xu Q, Ou J, Zhang Q, Tang R, Wang J, Hong Q, Guo X, Tong M, Yang L, Chi X. Effects of Aberrant miR-384-5p Expression on Learning and Memory in a Rat Model of Attention Deficit Hyperactivity Disorder. Front Neurol 2020; 10:1414. [PMID: 32116987 PMCID: PMC7026368 DOI: 10.3389/fneur.2019.01414] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/27/2019] [Indexed: 11/30/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterized by inattention, hyperactivity, and impulsivity. It may be accompanied by learning difficulties and working memory deficits. Few studies have examined the role of miRNAs in cognitive dysfunction in ADHD. This study investigated the effects of aberrant miR-384-5p expression on learning and memory in a widely used ADHD rat model. Lentiviral vectors were injected into the lateral ventricles of the rats to increase or decrease miR-384-5p level. To determine whether aberrant miR-384-5p expression affects learning and memory, spontaneous activity and cognitive function were assessed with the open field and Morris water maze tests. In the place navigation experiment of the Morris water maze test, time, and total swimming distance to reach the platform decreased compared to the control group when miR-384-5p was overexpressed, whereas down-regulation of miR-384-5p had the opposite effect. There were no obvious changes in brain tissue morphology following miR-384-5p overexpression or inhibition; however, dopamine (DA) receptor D1 (DRD1) level has decreased and increased, respectively, in the prefrontal cortex (PFC). The luciferase activity of the wild-type DRD1 group has decreased in luciferase reporter assay. Cyclic AMP response element-binding protein (CREB) phosphorylation has increased, and DA transporter (DAT) level has decreased in the PFC of spontaneously hypertensive rats (SHR) by miR-384-5p overexpression. On the other hand, miR-384-5p suppression increased DRD1 and decreased DAT and CREB protein levels relative to control rats. These findings suggest that miR-384-5p may play a critical role in learning and memory impairment in ADHD.
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Affiliation(s)
- Qu Xu
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jiaxin Ou
- Department of Pediatrics, First People's Hospital of Foshan, Affiliated Foshan Hospital of Sun Yat-sen University, Foshan, China
| | - Qingyu Zhang
- Jiangsu Key Laboratory of Pediatrics, Institute of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Ranran Tang
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jing Wang
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Qin Hong
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Xirong Guo
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meiling Tong
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Lei Yang
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Xia Chi
- Department of Child Health Care, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Institute of Pediatrics, Nanjing Medical University, Nanjing, China
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Ceylan D, Tufekci KU, Keskinoglu P, Genc S, Özerdem A. Circulating exosomal microRNAs in bipolar disorder. J Affect Disord 2020; 262:99-107. [PMID: 31726266 DOI: 10.1016/j.jad.2019.10.038] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/23/2019] [Accepted: 10/27/2019] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Emerging evidence suggests central roles of miRNAs in the pathogenesis of bipolar disorder (BD). Exosomes are membrane-bound vesicles acting as "biological cargo carriers" of various types of molecules including microRNAs. In this study, we aimed to investigate circulating exosomal microRNAs as potential diagnostic biomarkers for BD. METHODS The exosomes were precipitated from plasma samples of patients with BD (n = 69; 15 depressed, 27 manic, 27 euthymic) and healthy controls (n = 41). Total RNA was extracted from the exosomes and the levels of miRNAs were assayed by qPCR. Dysregulated miRNAs were subjected to Kyoto Encyclopedia of Genes and Genomes" (KEGG) pathway analysis by DIANA-miRPath v3.0 to identify the predicted targets and the related pathways. RESULTS Thirteen miRNAs showed significant differences between patients with BD and healthy individuals; among these, MiR-484, -652-3p, -142-3p remained significantly downregulated and miR-185-5p remained significantly upregulated after accounting for multiple comparisons and adjustments for potential confounders. There were no significant alterations among different states of BD. The KEEG analysis of four dysregulated miRNAs highlighted several target pathways including PI3K/Akt signaling, fatty acid biosynthesis/metabolism, extracellular matrix and adhesion pathways. CONCLUSION Our findings suggest that dysregulation of miRNAs might be involved in the underlying pathophysiology of BD through several biological pathways; and highlight the importance of the exosomal miRNAs for biomarker research in BD. Further longitudinal studies may clarify the roles of exosomal miRNAs and their targets in the neurobiology of BD.
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Affiliation(s)
- Deniz Ceylan
- Izmir University of Economics, Faculty of Medicine, Department of Psychiatry, Izmir, Turkey
| | - Kemal Ugur Tufekci
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey
| | - Pembe Keskinoglu
- Department of Biostatistics and Medical Informatics, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Sermin Genc
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Department of Neuroscience, Institute of Health Sciences, Dokuz Eylul University Health Campus, Izmir, Turkey
| | - Ayşegül Özerdem
- Department of Neuroscience, Institute of Health Sciences, Dokuz Eylul University Health Campus, Izmir, Turkey; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey.
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Sharma S, Akundi RS. Mitochondria: A Connecting Link in the Major Depressive Disorder Jigsaw. Curr Neuropharmacol 2019; 17:550-562. [PMID: 29512466 PMCID: PMC6712299 DOI: 10.2174/1570159x16666180302120322] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 02/02/2018] [Accepted: 02/27/2018] [Indexed: 12/19/2022] Open
Abstract
Background Depression is a widespread phenomenon with varying degrees of pathology in different patients. Various hypotheses have been proposed for the cause and continuance of depression. Some of these include, but not limited to, the monoamine hypothesis, the neuroendocrine hypothesis, and the more recent epigenetic and inflammatory hypotheses. Objective In this article, we review all the above hypotheses with a focus on the role of mitochondria as the connecting link. Oxidative stress, respiratory activity, mitochondrial dynamics and metabolism are some of the mitochondria-dependent factors which are affected during depression. We also propose exogenous ATP as a contributing factor to depression. Result Literature review shows that pro-inflammatory markers are elevated in depressive individuals. The cause for elevated levels of cytokines in depression is not completely understood. We propose exogenous ATP activates purinergic receptors which in turn increase the levels of various pro-inflammatory factors in the pathophysiology of depression. Conclusion Mitochondria are integral to the function of neurons and undergo dysfunction in major depressive disorder patients. This dysfunction is reflected in all the various hypotheses that have been proposed for depression. Among the newer targets identified, which also involve mitochondria, includes the role of exogenous ATP. The diversity of purinergic receptors, and their differential expression among various individuals in the population, due to genetic and environmental (prenatal) influences, may influence the susceptibility and severity of depression. Identifying specific receptors involved and using patient-specific purinergic receptor antagonist may be an appropriate therapeutic course in the future.
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Affiliation(s)
- Shilpa Sharma
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Ravi S Akundi
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
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36
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Tovo-Rodrigues L, Quinte GC, Brum CB, Ghisleni G, Bastos CR, Oliveira IOD, Barros FC, Barros AJD, Santos IS, Rohde LA, Hutz MH, Matijasevich A. The Role of MIR9-2 in Shared Susceptibility of Psychiatric Disorders during Childhood: A Population-Based Birth Cohort Study. Genes (Basel) 2019; 10:E626. [PMID: 31434288 PMCID: PMC6723948 DOI: 10.3390/genes10080626] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 07/23/2019] [Accepted: 08/13/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND It has been suggested that microRNAs (miRNAs; short non-protein-coding RNA molecules that mediate post-transcriptional regulation), including mir-9 and mir-34 families, are important for brain development. Current data suggest that mir-9 and mir-34 may have shared effects across psychiatric disorders. This study aims to explore the role of genetic polymorphisms in the MIR9-2 (rs4916723) and MIR34B/C (rs4938723) genes on the susceptibility of psychiatric disorders in children from the 2004 Pelotas Birth Cohort. METHODS Psychiatric disorders were assessed in 3585 individuals using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria through the application of standard semi-structured interviews (using the Development and Well-Being Assessment, DAWBA) at the six-years-of-age follow-up. The outcome was defined as the presence of any mental disorder. We also considered two broad groups of internalizing and externalizing disorders to further investigate the role of these variants in mental health. RESULTS We observed an association between rs4916723 (MIR9-2) and the presence of any psychiatric disorder (odds ratios (OR) = 0.820; 95% CI = 0.7130-0.944; p = 0.006) and a suggestive effect on internalizing disorders (OR = 0.830; 95% CI = 0.698-0.987; p = 0.035). rs4938723 (MIR34B/C) was not associated with any evaluated outcome. CONCLUSION The study suggests that MIR9-2 may have an important role on a broad susceptibility for psychiatric disorders and may be important mainly for internalization problems.
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Affiliation(s)
- Luciana Tovo-Rodrigues
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil.
| | - Gabriela Callo Quinte
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Clarice Brinck Brum
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Gabriele Ghisleni
- Laboratory of Clinical Neuroscience, Post-Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Clarissa Ribeiro Bastos
- Laboratory of Clinical Neuroscience, Post-Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Isabel Oliveira de Oliveira
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Fernando C Barros
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Aluisio J D Barros
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil
| | - Iná S Santos
- Postgraduate Program In Health and Behavior, Catholic University of Pelotas., Pelotas, Rio Grande do Sul 96015-560, Brazil
- Post-graduate Program Pediatrics Child Health, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90619-900, Brazil
| | - Luis A Rohde
- Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-007, Brazil
- National Institute of Developmental Psychiatry for Children and Adolescents, São Paulo, São Paulo 05403-900, Brazil
| | - Mara H Hutz
- Program in Genetics and Molecular Biology Universidade Federal do Rio Grande Do Sul, Porto Alegre, Rio Grande do Sul 91501-970, Brazil
| | - Alicia Matijasevich
- Departamento de Medicina Preventiva, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brasil
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Altered microRNA 5692b and microRNA let-7d expression levels in children and adolescents with attention deficit hyperactivity disorder. J Psychiatr Res 2019; 115:158-164. [PMID: 31146084 DOI: 10.1016/j.jpsychires.2019.05.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/19/2019] [Accepted: 05/20/2019] [Indexed: 11/22/2022]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Its etiology is not clearly understood yet, but neurobiological, genetic and environmental factors are shown to play a role. The relationship between ADHD and miRNAs has been studied quite recently, and few studies have been conducted up to now. In this study, peripheral blood expression levels of miR-5692b, miR-let-7d, miR-124-3p, miR-4447 and miR-107 of 30 children and adolescents with combined type ADHD were compared to 30 healthy controls to understand the roles of these miRNAs in the ADHD etiopathogenesis. Compared to controls, levels of miR-5692b (p = 0.006) were found higher and levels of miR-let-7d (p = 0.017) were found lower in the ADHD group. There was no significant difference in terms of miR-124-3p, miR-4447, and miR-107 levels between the groups. In conclusion, our findings support other studies suggesting the importance of miRNAs in the pathogenesis of ADHD. Regarding the regulatory role of miRNAs in gene regulation, their contribution to etiopathogenesis and heterogeneity of ADHD should be investigated further.
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Gruzdev SK, Yakovlev AA, Druzhkova TA, Guekht AB, Gulyaeva NV. The Missing Link: How Exosomes and miRNAs can Help in Bridging Psychiatry and Molecular Biology in the Context of Depression, Bipolar Disorder and Schizophrenia. Cell Mol Neurobiol 2019; 39:729-750. [PMID: 31089834 PMCID: PMC11462851 DOI: 10.1007/s10571-019-00684-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/03/2019] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs) only recently have been recognized as promising molecules for both fundamental and clinical neuroscience. We provide a literature review of miRNA biomarker studies in three most prominent psychiatric disorders (depression, bipolar disorder and schizophrenia) with the particular focus on depression due to its social and healthcare importance. Our search resulted in 191 unique miRNAs across 35 human studies measuring miRNA levels in blood, serum or plasma. 30 miRNAs replicated in more than one study. Most miRNAs targeted neuroplasticity and neurodevelopment pathways. Various limitations do not allow us to make firm conclusions on clinical potential of studied miRNAs. Based on our results we discuss the rationale for future research investigations of exosomal mechanisms to overcome methodological caveats both in studying etiology and pathogenesis, and providing an objective back-up for clinical decisions.
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Affiliation(s)
- S K Gruzdev
- Institute of Medicine, RUDN University, Miklukho-Maklaya Str. 6, Moscow, Russia, 117198.
| | - A A Yakovlev
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Butlerova Str., 5A, Moscow, Russia, 117485
- Moscow Research & Clinical Center for Neuropsychiatry, Moscow Healthcare Department, Donskaya Str., 43, Moscow, Russia, 115419
| | - T A Druzhkova
- Moscow Research & Clinical Center for Neuropsychiatry, Moscow Healthcare Department, Donskaya Str., 43, Moscow, Russia, 115419
| | - A B Guekht
- Moscow Research & Clinical Center for Neuropsychiatry, Moscow Healthcare Department, Donskaya Str., 43, Moscow, Russia, 115419
- Russian National Research Medical University, Ostrovitianov Str. 1, Moscow, Russia, 117997
| | - N V Gulyaeva
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Butlerova Str., 5A, Moscow, Russia, 117485
- Moscow Research & Clinical Center for Neuropsychiatry, Moscow Healthcare Department, Donskaya Str., 43, Moscow, Russia, 115419
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Changes in serum miRNA-let-7 level in children with attention deficit hyperactivity disorder treated by repetitive transcranial magnetic stimulation or atomoxetine: An exploratory trial. Psychiatry Res 2019; 274:189-194. [PMID: 30807970 DOI: 10.1016/j.psychres.2019.02.037] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 02/15/2019] [Accepted: 02/15/2019] [Indexed: 12/18/2022]
Abstract
We aimed to investigate whether microRNA-let-7d (miRNA-let-7d) and miRNA-107 may serve as diagnostic and therapeutic biomarkers of attention deficit hyperactivity disorder (ADHD). The relative expression level of miRNA-let-7d and miRNA-107 in patients with ADHD and in a healthy control group was detected by real-time polymerase chain reaction. The blood samples were collected at 6 weeks after repetitive transcranial magnetic stimulation (rTMS) or atomoxetine (ATX) in ADHD patients, and the relative expression levels of the two miRNAs before and after treatments were compared. There were significant differences in the expression level of miRNA-let-7d between ADHD patients and healthy children, as well as before and after rTMS or ATX treatment in ADHD patients. However, the expression of miRNA-107 showed no significant difference between ADHD patients and healthy children or before and after rTMS (or ATX treatment). These results suggest that serum miRNA-let-7d may serve as a potential diagnostic and therapeutic biomarker for children with ADHD.
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Sánchez-Mora C, Soler Artigas M, Garcia-Martínez I, Pagerols M, Rovira P, Richarte V, Corrales M, Fadeuilhe C, Padilla N, de la Cruz X, Franke B, Arias-Vásquez A, Casas M, Ramos-Quiroga JA, Ribasés M. Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells. Neuropsychopharmacology 2019; 44:890-897. [PMID: 30568281 PMCID: PMC6461896 DOI: 10.1038/s41386-018-0297-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 11/21/2018] [Accepted: 12/07/2018] [Indexed: 01/01/2023]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40-65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA-mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.
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Affiliation(s)
- Cristina Sánchez-Mora
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain.
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
| | - María Soler Artigas
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Iris Garcia-Martínez
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
| | - Mireia Pagerols
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
| | - Paula Rovira
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
| | - Vanesa Richarte
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Montse Corrales
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Christian Fadeuilhe
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
| | - Natàlia Padilla
- Research Unit in Clinical and Translational Bioinformatics, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Xavier de la Cruz
- Research Unit in Clinical and Translational Bioinformatics, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- ICREA, Barcelona, Spain
| | - Barbara Franke
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Alejandro Arias-Vásquez
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Miguel Casas
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Josep-Antoni Ramos-Quiroga
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Marta Ribasés
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain.
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
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41
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Kahl KG, Stapel B, Frieling H. Link between depression and cardiovascular diseases due to epigenomics and proteomics: Focus on energy metabolism. Prog Neuropsychopharmacol Biol Psychiatry 2019; 89:146-157. [PMID: 30194950 DOI: 10.1016/j.pnpbp.2018.09.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/13/2018] [Accepted: 09/05/2018] [Indexed: 12/11/2022]
Abstract
Major depression is the most common mental disorder and a leading cause of years lived with disability. In addition to the burden attributed to depressive symptoms and reduced daily life functioning, people with major depression are at increased risk of premature mortality, particularly due to cardiovascular diseases. Several studies point to a bi-directional relation between major depression and cardiovascular diseases, thereby indicating that both diseases may share common pathophysiological pathways. These include lifestyle factors (e.g. physical activity, smoking behavior), dysfunctions of endocrine systems (e.g. hypothalamus-pituitary adrenal axis), and a dysbalance of pro- and anti-inflammatory factors. Furthermore, recent research point to the role of epigenomic and proteomic factors, that are reviewed here with a particular focus on the mitochondrial energy metabolism.
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Affiliation(s)
- Kai G Kahl
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Germany.
| | - Britta Stapel
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Germany
| | - Helge Frieling
- Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Germany
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42
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Jyonouchi H, Geng L, Rose S, Bennuri SC, Frye RE. Variations in Mitochondrial Respiration Differ in IL-1ß/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders. Front Psychiatry 2019; 10:71. [PMID: 30842746 PMCID: PMC6391925 DOI: 10.3389/fpsyt.2019.00071] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 01/30/2019] [Indexed: 12/31/2022] Open
Abstract
Autism spectrum disorder (ASD)7 is associated with multiple physiological abnormalities, including immune dysregulation, and mitochondrial dysfunction. However, an association between these two commonly reported abnormalities in ASD has not been studied in depth. This study assessed the association between previously identified alterations in cytokine profiles by ASD peripheral blood monocytes (PBMo) and mitochondrial dysfunction. In 112 ASD and 38 non-ASD subjects, cytokine production was assessed by culturing purified PBMo overnight with stimuli of innate immunity. Parameters of mitochondrial respiration including proton-leak respiration (PLR), ATP-linked respiration (ALR), maximal respiratory capacity (MRC), and reserve capacity (RC) were measured in peripheral blood mononuclear cells (PBMCs). The ASD samples were analyzed by subgrouping them into high, normal, and low IL-1ß/IL-10 ratio groups, which was previously shown to be associated with changes in behaviors and PBMo miRNA expression. MRC, RC, and RC/PLR, a marker of electron transport chain (ETC) efficiency, were higher in ASD PBMCs than controls. The expected positive associations between PLR and ALR were found in control non-ASD PBMCs, but not in ASD PBMCs. Higher MRC, RC, RC/PLR in ASD PBMCs were secondary to higher levels of these parameters in the high and normal IL-1ß/IL-10 ratio ASD subgroups than controls. Associations between mitochondrial parameters and monocyte cytokine profiles differed markedly across the IL-1ß/IL-10 ratio based ASD subgroups, rendering such associations less evident when ASD samples as a whole were compared to non-ASD controls. Our results indicate for the first time, an association between PBMC mitochondrial function and PBMo cytokine profiles in ASD subjects. This relationship differs across the IL-1ß/IL-10 ratio based ASD subgroups. Changes in mitochondrial function are likely due to adaptive changes or mitochondrial dysfunction, resulting from chronic oxidative stress. These results may indicate alteration in molecular pathways affecting both the immune system and mitochondrial function in some ASD subjects.
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Affiliation(s)
- Harumi Jyonouchi
- Department of Pediatrics, Saint Peter's University Hospital, New Brunswick, NJ, United States.,Robert Wood Johnson Medical School-Rutgers, New Brunswick, NJ, United States
| | - Lee Geng
- Department of Pediatrics, Saint Peter's University Hospital, New Brunswick, NJ, United States
| | - Shannon Rose
- Arkansas Children's Research Institute, Little Rock, AR, United States.,Department of Pediatrics, University of Arkansas of Medical Sciences, Little Rock, AR, United States
| | - Sirish C Bennuri
- Arkansas Children's Research Institute, Little Rock, AR, United States.,Department of Pediatrics, University of Arkansas of Medical Sciences, Little Rock, AR, United States
| | - Richard E Frye
- Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.,Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, United States
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43
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The critical role of microRNAs in stress response: Therapeutic prospect and limitation. Pharmacol Res 2018; 142:294-302. [PMID: 30553824 DOI: 10.1016/j.phrs.2018.12.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/07/2018] [Accepted: 12/10/2018] [Indexed: 12/22/2022]
Abstract
Stress response refers to the systemic nonspecific response upon exposure to strong stimulation or chronic stress, such as severe trauma, shock, infection, burn, major surgery or improper environment, which disturb organisms and damage their physical and psychological health. However, the pathogenesis of stress induced disorder remains complicated and diverse under different stress exposure. Recently, studies have revealed a specific role of microRNAs (miRNAs) in regulating cellular function under different types of stress, suggesting a significant role in the treatment and prevention of stress-related diseases, such as stress ulcer, posttraumatic stress disorder, stress-induced cardiomyopathy and so on. This paper have reviewed the literature on microRNA related stress diseases in different databases including PubMed, Web of Science, and the MiRbase. It considers only peer-reviewed papers published in English between 2004 and 2018. This review summarizes new advances in principles and mechanisms of miRNAs regulating stress signalling pathway and the role of miRNAs in human stress diseases. This comprehensive review is to provide an integrated account of how different stresses affect miRNAs and how stress-miRNA pathways may, in turn, be linked with disease, which offers some potential strategies for stress disorder treatment. Furthermore, the limitation of current studies and challenges for clinical use are discussed.
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44
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Cong L, Zhao Y, Pogue AI, Lukiw WJ. Role of microRNA (miRNA) and Viroids in Lethal Diseases of Plants and Animals. Potential Contribution to Human Neurodegenerative Disorders. BIOCHEMISTRY (MOSCOW) 2018; 83:1018-1029. [PMID: 30472940 DOI: 10.1134/s0006297918090031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Both plants and animals have adopted a common strategy of using ~18-25-nucleotide small non-coding RNAs (sncRNAs), known as microRNAs (miRNAs), to transmit DNA-based epigenetic information. miRNAs (i) shape the total transcriptional output of individual cells; (ii) regulate and fine-tune gene expression profiles of cell clusters, and (iii) modulate cell phenotype in response to environmental stimuli and stressors. These miRNAs, the smallest known carriers of gene-encoded post-transcriptional regulatory information, not only regulate cellular function in healthy cells but also act as important mediators in the development of plant and animal diseases. Plants possess their own specific miRNAs; at least 32 plant species have been found to carry infectious sncRNAs called viroids, whose mechanisms of generation and functions are strikingly similar to those of miRNAs. This review highlights recent remarkable and sometimes controversial findings in miRNA signaling in plants and animals. Special attention is given to the intriguing possibility that dietary miRNAs and/or sncRNAs can function as mobile epigenetic and/or evolutionary linkers between different species and contribute to both intra- and interkingdom signaling. Wherever possible, emphasis has been placed on the relevance of these miRNAs to the development of human neurodegenerative diseases, such as Alzheimer's disease. Based on the current available data, we suggest that such xeno-miRNAs may (i) contribute to the beneficial properties of medicinal plants, (ii) contribute to the negative properties of disease-causing or poisonous plants, and (iii) provide cross-species communication between kingdoms of living organisms involving multiple epigenetic and/or potentially pathogenic mechanisms associated with the onset and pathogenesis of various diseases.
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Affiliation(s)
- L Cong
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112-2272, USA.,Department of Neurology, Shengjing Hospital, China Medical University, Heping District, Shenyang, Liaoning Province, China
| | - Y Zhao
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112-2272, USA.,Department of Anatomy and Cell Biology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112-2272, USA
| | - A I Pogue
- Alchem Biotech Research, Toronto, ON M5S 1A8, Canada
| | - W J Lukiw
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112-2272, USA. .,Department Neurology, Louisiana State University School of Medicine, New Orleans, LA 70112-2272, USA.,Department Ophthalmology, Louisiana State University School of Medicine, New Orleans, LA 70112-2272, USA
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45
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The microbiome regulates amygdala-dependent fear recall. Mol Psychiatry 2018; 23:1134-1144. [PMID: 28507320 PMCID: PMC5984090 DOI: 10.1038/mp.2017.100] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 02/20/2017] [Accepted: 03/16/2017] [Indexed: 12/25/2022]
Abstract
The amygdala is a key brain region that is critically involved in the processing and expression of anxiety and fear-related signals. In parallel, a growing number of preclinical and human studies have implicated the microbiome-gut-brain in regulating anxiety and stress-related responses. However, the role of the microbiome in fear-related behaviours is unclear. To this end we investigated the importance of the host microbiome on amygdala-dependent behavioural readouts using the cued fear conditioning paradigm. We also assessed changes in neuronal transcription and post-transcriptional regulation in the amygdala of naive and stimulated germ-free (GF) mice, using a genome-wide transcriptome profiling approach. Our results reveal that GF mice display reduced freezing during the cued memory retention test. Moreover, we demonstrate that under baseline conditions, GF mice display altered transcriptional profile with a marked increase in immediate-early genes (for example, Fos, Egr2, Fosb, Arc) as well as genes implicated in neural activity, synaptic transmission and nervous system development. We also found a predicted interaction between mRNA and specific microRNAs that are differentially regulated in GF mice. Interestingly, colonized GF mice (ex-GF) were behaviourally comparable to conventionally raised (CON) mice. Together, our data demonstrates a unique transcriptional response in GF animals, likely because of already elevated levels of immediate-early gene expression and the potentially underlying neuronal hyperactivity that in turn primes the amygdala for a different transcriptional response. Thus, we demonstrate for what is to our knowledge the first time that the presence of the host microbiome is crucial for the appropriate behavioural response during amygdala-dependent memory retention.
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46
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Cao T, Zhen XC. Dysregulation of miRNA and its potential therapeutic application in schizophrenia. CNS Neurosci Ther 2018. [PMID: 29529357 DOI: 10.1111/cns.12840] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Although it is generally believed that genetic and developmental factors play critical roles in pathogenesis of schizophrenia, however, the precise etiological mechanism of schizophrenia remains largely unknown. Over past decades, miRNAs have emerged as an essential post-transcriptional regulator in gene expression regulation. The importance of miRNA in brain development and neuroplasticity has been well-established. Abnormal expression and dysfunction of miRNAs are known to involve in the pathophysiology of many neuropsychiatric diseases including schizophrenia. In this review, we summarized the recent findings in the schizophrenia-associated dysregulation of miRNA and functional roles in the development and pathogenesis of schizophrenia. We also discussed the potential therapeutic implications of miRNA regulation in the illness.
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Affiliation(s)
- Ting Cao
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.,The Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China
| | - Xue-Chu Zhen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.,The Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China
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47
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Flores Saiffe Farías A, Mendizabal AP, Morales JA. An Ontology Systems Approach on Human Brain Expression and Metaproteomics. Front Microbiol 2018; 9:406. [PMID: 29568289 PMCID: PMC5852110 DOI: 10.3389/fmicb.2018.00406] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 02/21/2018] [Indexed: 12/21/2022] Open
Abstract
Research in the last decade has shown growing evidence of the gut microbiota influence on brain physiology. While many mechanisms of this influence have been proposed in animal models, most studies in humans are the result of a pathology-dysbiosis association and very few have related the presence of certain taxa with brain substructures or molecular pathways. In this paper, we associated the functional ontologies in the differential expression of brain substructures from the Allen Brain Atlas database, with those of the metaproteome from the Human Microbiome Project. Our results showed several coherent clustered ontologies where many taxa could influence brain expression and physiology. A detailed analysis of psychobiotics showed specific slim ontologies functionally associated with substructures in the basal ganglia and cerebellar cortex. Some of the most relevant slim ontology groups are related to Ion transport, Membrane potential, Synapse, DNA and RNA metabolism, and Antigen processing, while the most relevant neuropathology found was Parkinson disease. In some of these cases, new hypothetical gut microbiota-brain interaction pathways are proposed.
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48
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Arslan A. Mapping the Schizophrenia Genes by Neuroimaging: The Opportunities and the Challenges. Int J Mol Sci 2018; 19:ijms19010219. [PMID: 29324666 PMCID: PMC5796168 DOI: 10.3390/ijms19010219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/05/2018] [Accepted: 01/07/2018] [Indexed: 12/18/2022] Open
Abstract
Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic and environmental factors. The genes underpinning the neurobiology of SZ are largely unknown but recent data suggest strong evidence for genetic variations, such as single nucleotide polymorphisms, making the brain vulnerable to the risk of SZ. Structural and functional brain mapping of these genetic variations are essential for the development of agents and tools for better diagnosis, treatment and prevention of SZ. Addressing this, neuroimaging methods in combination with genetic analysis have been increasingly used for almost 20 years. So-called imaging genetics, the opportunities of this approach along with its limitations for SZ research will be outlined in this invited paper. While the problems such as reproducibility, genetic effect size, specificity and sensitivity exist, opportunities such as multivariate analysis, development of multisite consortia for large-scale data collection, emergence of non-candidate gene (hypothesis-free) approach of neuroimaging genetics are likely to contribute to a rapid progress for gene discovery besides to gene validation studies that are related to SZ.
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Affiliation(s)
- Ayla Arslan
- Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnica cesta, 15 Ilidza, Sarajevo 71210, Bosnia and Herzegovina.
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul 34662, Turkey.
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49
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Zhao Y, Cong L, Lukiw WJ. Plant and Animal microRNAs (miRNAs) and Their Potential for Inter-kingdom Communication. Cell Mol Neurobiol 2018; 38:133-140. [PMID: 28879580 PMCID: PMC11482019 DOI: 10.1007/s10571-017-0547-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/31/2017] [Indexed: 12/22/2022]
Abstract
microRNAs (miRNAs) comprise a class of ~18-25 nucleotide (nt) single-stranded non-coding RNAs (sncRNAs) that are the smallest known carriers of gene-encoded, post-transcriptional regulatory information in both plants and animals. There are many fundamental similarities between plant and animal miRNAs-the miRNAs of both kingdoms play essential roles in development, aging and disease, and the shaping of the transcriptome of many cell types. Both plant and animal miRNAs appear to predominantly exert their genetic and transcriptomic influences by regulating gene expression at the level of messenger RNA (mRNA) stability and/or translational inhibition. Certain miRNA species, such as miRNA-155, miRNA-168, and members of the miRNA-854 family may be expressed in both plants and animals, suggesting a common origin and functional selection of specific miRNAs over vast periods of evolution (for example, Arabidopsis thaliana-Homo sapiens divergence ~1.5 billion years). Although there is emerging evidence for cross-kingdom miRNA communication-that plant-enriched miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease-some research reports repudiate this possibility. This research paper highlights some recent, controversial, and remarkable findings in plant- and animal-based miRNA signaling research with emphasis on the intriguing possibility that dietary miRNAs and/or sncRNAs may have potential to contribute to both intra- and inter-kingdom signaling, and in doing so modulate molecular-genetic mechanisms associated with human health and disease.
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Affiliation(s)
- Yuhai Zhao
- LSU Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112-2272, USA
- Department of Anatomy and Cell Biology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272, USA
| | - Lin Cong
- LSU Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112-2272, USA
- Department of Neurology, Shengjing Hospital, China Medical University, 36 No. 3 Street, Heping District, Shenyang, Liaoning, China
| | - Walter J Lukiw
- LSU Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112-2272, USA.
- Department of Neurology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272, USA.
- Department of Ophthalmology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272, USA.
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50
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Hoban AE, Stilling RM, M Moloney G, Moloney RD, Shanahan F, Dinan TG, Cryan JF, Clarke G. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. MICROBIOME 2017; 5:102. [PMID: 28838324 PMCID: PMC5571609 DOI: 10.1186/s40168-017-0321-3] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 08/01/2017] [Indexed: 05/20/2023]
Abstract
BACKGROUND There is growing evidence for a role of the gut microbiome in shaping behaviour relevant to many psychiatric and neurological disorders. Preclinical studies using germ-free (GF) animals have been essential in contributing to our current understanding of the potential importance of the host microbiome for neurodevelopment and behaviour. In particular, it has been repeatedly demonstrated that manipulation of the gut microbiome modulates anxiety-like behaviours. The neural circuits that underlie anxiety- and fear-related behaviours are complex and heavily depend on functional communication between the amygdala and prefrontal cortex (PFC). Previously, we have shown that the transcriptional networks within the amygdala and PFC of GF mice are altered. MicroRNAs (miRNAs) act through translational repression to control gene translation and have also been implicated in anxiety-like behaviours. However, it is unknown whether these features of host post-transcriptional machinery are also recruited by the gut microbiome to exert control over CNS transcriptional networks. RESULTS We conducted Illumina® next-generation sequencing (NGS) in the amygdala and PFC of conventional, GF and germ-free colonized mice (exGF). We found a large proportion of miRNAs to be dysregulated in GF animals in both brain regions (103 in the amygdala and 31 in the PFC). Additionally, colonization of GF mice normalized some of the noted alterations. Next, we used a complementary approach to GF by manipulating the adult rat microbiome with an antibiotic cocktail to deplete the gut microbiota and found that this strategy also impacted the expression of relevant miRNAs. CONCLUSION These results suggest that the microbiome is necessary for appropriate regulation of miRNA expression in brain regions implicated in anxiety-like behaviours.
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Affiliation(s)
- Alan E Hoban
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Roman M Stilling
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Gerard M Moloney
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Rachel D Moloney
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Psychiatry and Neurobehavioural Science, Biosciences Institute, University College Cork, Room 1.15, College Road, Cork City, Ireland
| | - Fergus Shanahan
- APC Microbiome Institute, University College Cork, Cork City, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Psychiatry and Neurobehavioural Science, Biosciences Institute, University College Cork, Room 1.15, College Road, Cork City, Ireland
| | - John F Cryan
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Gerard Clarke
- APC Microbiome Institute, University College Cork, Cork City, Ireland.
- Department of Psychiatry and Neurobehavioural Science, Biosciences Institute, University College Cork, Room 1.15, College Road, Cork City, Ireland.
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