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Fettahoğlu İ, Akşahin İC, Yeşiloğlu B, Çelik HEA, Kaymakçı EÇ, Kendirlioğlu BK, Frye M, Özerdem A, Ceylan D. Downregulated mitochondria-encoded long non-coding RNAs in mood disorders. J Affect Disord 2025; 389:119653. [PMID: 40516619 DOI: 10.1016/j.jad.2025.119653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 06/02/2025] [Accepted: 06/07/2025] [Indexed: 06/16/2025]
Abstract
BACKGROUND Mitochondrial genome-encoded long non-coding RNAs (mt-LncRNAs) that play roles in regulation of energy metabolism and mitochondrial function, both crucial in mood disorder pathogenesis, yet remain poorly explored despite growing interest. This study examines their expression levels in individuals with major depressive disorder (MDD), bipolar disorder (BD), siblings of individuals with BD (SIB), and healthy controls (HC). METHODS Blood samples from 153 participants (31 MDD, 40 BD, 39 SIB, 43 HC) were analyzed for 10 mt-LncRNAs via RT-qPCR. Samples from a subgroup of 15 remitted MDD (MDDREM) patients following 8-week treatment were included for exploratory analysis. A composite score for all LncRNAs, global factor, was derived using principal component analysis. All comparisons were adjusted for age, sex, smoking, BMI, and multiple comparisons. RESULTS Global scores showed overall downregulation in MDD, BD, and SIB compared to HCs, with BD exhibiting the lowest levels (p < 0.01). All mt-LncRNAs were downregulated in BD and SIB, while 8 (excluding ASncmtRNA-2 and 7S RNA) were downregulated in MDD (p < 0.05). Mt-LncRNA levels were lower in BD than in SIB and MDD (p < 0.05), with 6 also lower in SIB compared to MDD (p < 0.05). Exploratory analysis revealed a significant increase in 8 mt-LncRNAs (excluding LIPCAR and 7S RNA) in MDDREM compared to baseline MDD (p < 0.05). CONCLUSION Findings show a significant mt-LncRNA downregulation in mood disorders and suggest genetic transmission as well as a capacity to change with treatment. Further research is needed to explore the genetics and modifiability of mt-LncRNAs in mood disorders.
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Affiliation(s)
- İbrahim Fettahoğlu
- Koç University Research Center for Translational Medicine, İstanbul, Türkiye
| | - İzel Cemre Akşahin
- Koç University Research Center for Translational Medicine, İstanbul, Türkiye; Department of Neuroscience, Graduate School of Health Sciences, Koç University, İstanbul, Türkiye
| | - Buket Yeşiloğlu
- Koç University Research Center for Translational Medicine, İstanbul, Türkiye; Department of Neuroscience, Graduate School of Health Sciences, Koç University, İstanbul, Türkiye
| | | | | | | | - Mark Frye
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA
| | - Ayşegül Özerdem
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA
| | - Deniz Ceylan
- Koç University Research Center for Translational Medicine, İstanbul, Türkiye; Department of Neuroscience, Graduate School of Health Sciences, Koç University, İstanbul, Türkiye; Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry, School of Medicine, Koç University, İstanbul, Türkiye.
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Kong L, Zhang L. An Alternative Approach to Future Diagnosis: Can Generalized Anxiety Disorder Be Distinguished From Major Depressive Disorder, Healthy People by Differentially Expressed lncRNAs in Peripheral Blood. Neuropsychiatr Dis Treat 2025; 21:729-739. [PMID: 40200939 PMCID: PMC11977568 DOI: 10.2147/ndt.s511375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/15/2025] [Indexed: 04/10/2025] Open
Abstract
Purpose Symptomatic diagnosis combined with unclear pathological mechanism and diverse etiology may increase misdiagnosis risk for generalized anxiety disorder (GAD) in the clinical setting. This study aimed to confirm the diagnostic value of aberrantly expressed long non-coding RNAs (lncRNAs) for GAD. Patients and Methods Eighty sex- and age-matched patients with GAD and major depressive disorder (MDD) and healthy controls (HCs) were enrolled using a convenient sampling method. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify lncRNA expression levels in all participants, and a receiver operating characteristic (ROC) curve was used to test the accuracy of aberrantly expressed lncRNAs in differentiating health conditions. Results ΔCt values of ENST00000505825, NONHSAG017299, NONHSAT078768, NONHSAT029028, NONHSAT101077, NONHSAT031726, TCONS_l2_00010607 in GAD patients were less than in HCs (P<0.05 or 0.01). The total severity score of HAMA-14 and somatic anxiety scores were negatively correlated with ΔCt values of ENST00000505825, NONHSAG017299, NONHSAT078768, NONHSAT029028, NONHSAT101077, NONHSAT031726, ENST00000505825, TCONS_l2_00010607, and NONHSAT131696, and psychic anxiety scores were negatively associated with the ΔCt value of ENST00000505825 (P<0.05 or 0.01). The AUC of the combined ROC curve between patients with GAD and healthy people was 0.810, with sensitivity and specificity of 0.825 and 0.762, respectively (P<0.05 or 0.01). The AUC of the combined ROC curve between patients with GAD and MDD patients was 0.938, with sensitivity and specificity of 0.850 and 0.900, respectively (P<0.05 or 0.01). Conclusion ENST00000505825, NONHSAG017299, NONHSAT078768, NONHSAT029028, NONHSAT101077, NONHSAT031726, TCONS_l2_00010607, which may serve as biomarkers for the GAD diagnosis and differentiation between GAD and MDD, can improve the diagnostic accuracy and avoid misdiagnosis to a certain extent. It is also beneficial for personalized treatment of GAD.
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Affiliation(s)
- Lingming Kong
- Treatment & Prevention Center for Mental Disorder, No. 904th Hospital, Changzhou, Jiangsu, 213003, People’s Republic of China
| | - Liang Zhang
- Psychiatry Department, The 5th People’s Hospital of Luoyang, Luoyang, Henan, 471027, People’s Republic of China
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Wang L, Mao L, Huang Z, Switzer JA, Hess DC, Zhang Q. Photobiomodulation: shining a light on depression. Theranostics 2025; 15:362-383. [PMID: 39744683 PMCID: PMC11671386 DOI: 10.7150/thno.104502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/08/2024] [Indexed: 01/11/2025] Open
Abstract
Depression is a prevalent public health issue, characterized by persistent low mood, impaired concentration, and diminished motivation. Photobiomodulation (PBM), which involves the application of red or near-infrared light, modulates physiological processes by enhancing cerebral blood flow, reducing inflammation, inhibiting apoptosis, and promoting neurogenesis. PBM can be administered transcranially or through systemic approaches, offering a potentially effective intervention for depression. This review discusses the characteristics of PBM, its underlying neurobiological mechanisms, and relevant physical parameters. Recent progress in both animal and clinical research underscores PBM's therapeutic potential for depression and emphasizes the need for further studies to establish a robust theoretical basis for standardized treatment protocols.
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Affiliation(s)
- Lian Wang
- Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Liwei Mao
- Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Zhihai Huang
- Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71103, USA
| | - Jeffrey A. Switzer
- Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - David C. Hess
- Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Quanguang Zhang
- Department of Neurology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
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Javidi Aghdam K, Baradaran B, Rahmani S, Manafzadeh F, Noor Azar SG, Aghayan S, Shayannia A, Ghafouri-Fard S. Expression pattern of long non-coding RNAs in treatment-naïve and medicated schizophrenia patients. Sci Rep 2024; 14:27654. [PMID: 39532914 PMCID: PMC11557838 DOI: 10.1038/s41598-024-78220-w] [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: 07/10/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Schizophrenia is a disabling mental disorder that affects 1% of people over their lifetime. The etiology and mechanism of schizophrenia are very complex, and many genes are involved in many different signaling pathways in the etiology of this disease. According to recent studies, one of the important mechanisms altered in this disorder is the regulation of immune system and the inflammation mechanism. In the present study, we evaluated the peripheral blood expression pattern of four lncRNAs and three protein-coding genes in the treatment- naïve patients, and medicated patients compared with sex and age-matched controls. In the medicated-patients, expression levels of IFNG, IL18RAP, AC007278.2 were significantly up-regulated (P < 0.05); and the expression level of IFNG-AS1-001 was significantly down-regulated compared to healthy controls (P < 0.05). However, levels of IL18R1, AC007278.3 and IFNG-AS1-003 were not different between these groups. In the treatment-naïve patients, IFNG, IL18R1, IL18RAP, IFNG-AS1-001, AC007278.2, and AC007278.3 were significantly up-regulated compared to controls. On the other hand, IFNG-AS1-003 was significantly down-regulated in the treatment-naïve patients compared to controls. Based on the Spearman correlation matrix, there was a significant correlation between genes in the treatment-naïve patients. We also showed the high sensitivity and specificity of IFNG-AS1-003, IFNG, IL18R1, and AC007278.3 in the identification of treatment-naïve patients from controls. The current study contributes further evidence to the understanding of the role of lncRNAs in the pathogenesis of schizophrenia. Future research is necessary to establish the validity of lncRNAs as peripheral markers for this condition.
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Affiliation(s)
- Kamran Javidi Aghdam
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shima Rahmani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Manafzadeh
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Seyed Gholamreza Noor Azar
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahrokh Aghayan
- Sexual Health and Fertility Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Asghar Shayannia
- Department of Medical Biotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wang Q, Wang H, Dwivedi Y. Integrated Long Noncoding RNA and Messenger RNA Expression Analysis Identifies Molecules Specifically Associated With Resiliency and Susceptibility to Depression and Antidepressant Response. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100365. [PMID: 39257693 PMCID: PMC11385423 DOI: 10.1016/j.bpsgos.2024.100365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/18/2024] [Accepted: 07/02/2024] [Indexed: 09/12/2024] Open
Abstract
Background Depression involves maladaptive processes impairing an individual's ability to interface with the environment appropriately. Long noncoding RNAs (lncRNAs) are gaining traction for their role in higher-order brain functioning. Recently, we reported that lncRNA coexpression modules may underlie abnormal responses to stress in rats showing depression-like behavior. The current study explored the global expression regulation of lncRNAs and messenger RNAs (mRNAs) in the hippocampus of rats showing susceptibility (learned helplessness [LH]) or resiliency (non-LH) to depression and fluoxetine response to LH (LH+FLX). Methods Multiple comparison analysis was performed with an analysis of variance via the aov and summary function in the R platform to identify the differential expression of mRNAs and lncRNAs among LH, non-LH, tested control, and LH+FLX groups. Weighted gene coexpression network analysis was used to identify distinctive modules and pathways associated with each phenotype. A machine learning analysis was conducted to screen the critical target genes. Based on the combined analysis, the regulatory effects of lncRNAs on mRNA expression were explored. Results Multiple comparison analyses revealed differentially expressed mRNAs and lncRNAs with each phenotype. Integrated bioinformatics analysis identified novel transcripts, specific modules, and regulatory pairs of mRNA-lncRNA in each phenotype. In addition, the machine learning approach predicted lncRNA-regulated Spp2 and Olr25 genes in developing LH behavior, whereas joint analysis of mRNA-lncRNA pairs identified Mboat7, Lmod1, I l 18, and Rfx5 genes in depression-like behavior and Adam6 and Tpra1 in antidepressant response. Conclusions The study shows a novel role for lncRNAs in the development of specific depression phenotypes and in identifying newer targets for therapeutic development.
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Affiliation(s)
- Qingzhong Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huizhen Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
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Hosseini M, Mokhtari MJ. Up-regulation of HOXA-AS2 and MEG3 long non-coding RNAs acts as a potential peripheral biomarker for bipolar disorder. J Cell Mol Med 2024; 28:e70150. [PMID: 39482996 PMCID: PMC11528130 DOI: 10.1111/jcmm.70150] [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: 05/25/2024] [Revised: 09/21/2024] [Accepted: 10/01/2024] [Indexed: 11/03/2024] Open
Abstract
Bipolar disorder (BD) is a psychiatric condition that is frequently misdiagnosed and linked to inadequate treatment. Long non-coding RNAs (lncRNAs) have lately gained recognition as crucial genetic elements and are now regarded as regulatory mechanisms in the neurological system. Our objective was to measure the quantities of HOXA-AS2 and MEG3 ncRNA transcripts. HOXA-AS2 and MEG3 ncRNA levels were checked in the peripheral blood of 50 type I BD and 50 control samples by real-time PCR. Furthermore, we conducted ROC curve analysis and correlation analysis to examine the association between gene expression and specific clinical characteristics in instances with BD. Additionally, a computational study was performed to investigate the binding sites of miRNAs on the HOXA-AS2 and MEG3 lncRNAs. BD subjects showed a significant increase in the expression of HOXA-AS2 and MEG3 compared to controls. The lncRNAs HOXA-AS2 and MEG3 have an area under the ROC curve (AUC) values of 0.70 and 0.71, respectively. There was a significant correlation between the expression levels of ncRNAs HOXA-AS2 and MEG3 in the peripheral blood of patients with BD and occupation scores. The data presented indicate a potential correlation between the expression of HOXA-AS2 and MEG3 lncRNAs with an elevated risk of BD. Furthermore, these lncRNAs may be linked to several molecular pathways. Our findings indicate that the amounts of lncRNAs HOXA-AS2 and MEG3 in transcripts might be a promising potential biomarker for patients with BD.
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Affiliation(s)
- Maryam Hosseini
- Department of Biology, Zarghan BranchIslamic Azad UniversityZarghanIran
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Zhu L, Guo M, Li K, Guo C, He K. The Association and Prognostic Implications of Long Non-Coding RNAs in Major Psychiatric Disorders, Alzheimer's Diseases and Parkinson's Diseases: A Systematic Review. Int J Mol Sci 2024; 25:10995. [PMID: 39456775 PMCID: PMC11507000 DOI: 10.3390/ijms252010995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/09/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
The prevalence of psychiatric disorders and neurodegenerative diseases is steadily increasing, placing a significant burden on both society and individuals. Given the intricate and multifaceted nature of these diseases, the precise underlying mechanisms remain elusive. Consequently, there is an increasing imperative to investigate the mechanisms, identify specific target sites for effective treatment, and provide for accurate diagnosis of patients with these diseases. Numerous studies have revealed significant alterations in the expression of long non-coding RNAs (lncRNAs) in psychiatric disorders and neurodegenerative diseases, suggesting their potential to increase the probability of these diseases. Moreover, these findings propose that lncRNAs could be used as highly valuable biomarkers in diagnosing and treating these diseases, thereby offering novel insights for future clinical interventions. The review presents a comprehensive summary of the origin, biological functions, and action mechanisms of lncRNAs, while exploring their implications in the pathogenesis of psychiatric disorders and neurodegenerative diseases and their potential utility as biomarkers.
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Affiliation(s)
- Lin Zhu
- College of Life Sciences and Food Engineering, Inner Mongolia Minzu University, Tongliao 028000, China; (L.Z.); (K.L.); (C.G.)
| | - Meng Guo
- Finance Office, Inner Mongolia Minzu University, Tongliao 028000, China;
| | - Ke Li
- College of Life Sciences and Food Engineering, Inner Mongolia Minzu University, Tongliao 028000, China; (L.Z.); (K.L.); (C.G.)
| | - Chuang Guo
- College of Life Sciences and Food Engineering, Inner Mongolia Minzu University, Tongliao 028000, China; (L.Z.); (K.L.); (C.G.)
| | - Kuanjun He
- College of Life Sciences and Food Engineering, Inner Mongolia Minzu University, Tongliao 028000, China; (L.Z.); (K.L.); (C.G.)
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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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Wang H, Deng S, Bi J. LncRNA SNHG14 Served as a Biomarker of Depression Disorder Patients and Regulated Depression-Like Behaviors via MiR-200a-3p. TOHOKU J EXP MED 2024; 263:55-62. [PMID: 38296487 DOI: 10.1620/tjem.2024.j007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
Depression disorder has become a major mental disease and has attracted special attention globally. Identifying specific biomarkers for the diagnosis and severity of depression disorder would benefit its clinical management. This study focused on the significance of lncRNA SNHG14 in depression disorder and investigated its effect on depression-like behaviors, aiming to explore a potential biomarker for depression disorder occurrence and development. This study included 147 patients with depression disorder and 98 healthy individuals. The serum SNHG14 in all participants was analyzed by PCR, and its diagnostic value was evaluated by receiver operatorating characteristic curve (ROC) analysis. The depression-like behaviors were induced via chronic social defeat stress (CSDS) and evaluated by sucrose preference, forced swimming, and open field tests. SNHG14 was significantly upregulated in depression disorder patients relative to healthy individuals, which discriminated depression disorder patients with a relatively high efficiency. Depression disorder patients with severe conditions showed higher serum SNHG14 levels, and a significantly positive correlation of SNHG14 with PHQ9 score was demonstrated. In CSDS mice, increasing SNHG14 and decreasing miR-200a-3p were observed. Silencing SNHG14 and overexpressing miR-200a-3p could alleviate reduced sucrose preference, increased swimming immobility time, decreased standing times, and decreased traveling distance induced by CSDS. The knockdown of SNHG14 promoted the expression of miR-200a-3p, and silencing miR-200a-3p could reverse the protective effect of SNHG14 silencing on depression-like behaviors. SNHG14 served as a biomarker for the occurrence and severity of depression disorder. Silencing SNHG14could alleviate depression-like behaviors via modulating miR-200a-3p.
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Affiliation(s)
- HongLi Wang
- Department of Neurology, People's Hospital of Dongxihu District
| | - SiWen Deng
- Department of Urology, People's Hospital of Dongxihu District
| | - Juan Bi
- Department of Neurology, People's Hospital of Dongxihu District
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Dean B, Scarr E. Common changes in rat cortical gene expression after antidepressant drug treatment: Impacts on metabolism of polyamines, mRNA splicing, regulation of RAS by GAPs, neddylation and GPCR ligand binding. World J Biol Psychiatry 2024; 25:200-213. [PMID: 38349617 DOI: 10.1080/15622975.2024.2312475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/27/2024] [Indexed: 03/02/2024]
Abstract
OBJECTIVES This study sought to identify pathways affected by rat cortical RNA that were changed after treatment with fluoxetine or imipramine. METHODS We measured levels of cortical RNA in male rats using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (0.9% NaCl), fluoxetine (10 mg/kg/day) or imipramine (20 mg/kg/day) for 28 days. Levels of coding and non-coding RNA in vehicle treated rats were compared to those in treated rats using ANOVA in JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify pathways involving the changed RNAs. RESULTS 18,876 transcripts were detected; there were highly correlated changes in 1010 levels of RNA after both drug treatments that would principally affect the metabolism of polyamines, mRNA splicing, regulation of RAS by GAPs, neddylation and GPCR ligand binding. Using our previously published data, we compared changes in transcripts after treatment with antipsychotic and mood stabilising drugs. CONCLUSIONS Our study shows there are common, correlated, changes in coding and non-coding RNA in the rat cortex after treatment with fluoxetine or imipramine; we propose the pathways affected by these changes are involved in the therapeutic mechanisms of action of antidepressant drugs.
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Affiliation(s)
- Brian Dean
- The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
| | - Elizabeth Scarr
- The Department of Psychiatry, The University of Melbourne, Parkville, Australia
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Ceylan D, Arat-Çelik HE, Aksahin IC. Integrating mitoepigenetics into research in mood disorders: a state-of-the-art review. Front Physiol 2024; 15:1338544. [PMID: 38410811 PMCID: PMC10895490 DOI: 10.3389/fphys.2024.1338544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/24/2024] [Indexed: 02/28/2024] Open
Abstract
Mood disorders, including major depressive disorder and bipolar disorder, are highly prevalent and stand among the leading causes of disability. Despite the largely elusive nature of the molecular mechanisms underpinning these disorders, two pivotal contributors-mitochondrial dysfunctions and epigenetic alterations-have emerged as significant players in their pathogenesis. This state-of-the-art review aims to present existing data on epigenetic alterations in the mitochondrial genome in mood disorders, laying the groundwork for future research into their pathogenesis. Associations between abnormalities in mitochondrial function and mood disorders have been observed, with evidence pointing to notable changes in mitochondrial DNA (mtDNA). These changes encompass variations in copy number and oxidative damage. However, information on additional epigenetic alterations in the mitochondrial genome remains limited. Recent studies have delved into alterations in mtDNA and regulations in the mitochondrial genome, giving rise to the burgeoning field of mitochondrial epigenetics. Mitochondrial epigenetics encompasses three main categories of modifications: mtDNA methylation/hydroxymethylation, modifications of mitochondrial nucleoids, and mitochondrial RNA alterations. The epigenetic modulation of mitochondrial nucleoids, lacking histones, may impact mtDNA function. Additionally, mitochondrial RNAs, including non-coding RNAs, present a complex landscape influencing interactions between the mitochondria and the nucleus. The exploration of mitochondrial epigenetics offers valuable perspectives on how these alterations impact neurodegenerative diseases, presenting an intriguing avenue for research on mood disorders. Investigations into post-translational modifications and the role of mitochondrial non-coding RNAs hold promise to unravel the dynamics of mitoepigenetics in mood disorders, providing crucial insights for future therapeutic interventions.
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Affiliation(s)
- Deniz Ceylan
- Department of Psychiatry, School of Medicine, Koç University, Istanbul, Türkiye
- Koç University Research Center for Translational Medicine (KUTTAM), Affective Laboratory, Istanbul, Türkiye
| | | | - Izel Cemre Aksahin
- Koç University Research Center for Translational Medicine (KUTTAM), Affective Laboratory, Istanbul, Türkiye
- Graduate School of Health Sciences, Koç University, Istanbul, Türkiye
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Vyas A, Doshi G. A cross talk on the role of contemporary biomarkers in depression. Biomarkers 2024; 29:18-29. [PMID: 38261718 DOI: 10.1080/1354750x.2024.2308834] [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: 08/23/2023] [Accepted: 01/14/2024] [Indexed: 01/25/2024]
Abstract
Introduction: Biomarkers can be used to identify determinants of response to various treatments of mental disorders. Evidence to date demonstrates that markers of inflammatory, neurotransmitter, neurotrophic, neuroendocrine, and metabolic function can predict the psychological and physical consequences of depression in individuals, allowing for the development of new therapeutic targets with fewer side effects. Extensive research has included hundreds of potential biomarkers of depression, but their roles in depression, abnormal patients, and how bioinformatics can be used to improve diagnosis, treatment, and prognosis have not been determined or defined. To determine which biomarkers can and cannot be used to predict treatment response, classify patients for specific treatments, and develop targets for new interventions, proprietary strategies, and current research projects need to be tailored.Material and Methods: This review article focuses on - biomarker systems that would help in the further development and expansion of newer targets - which holds great promise for reducing the burden of depression.Results and Discussion: Further, this review point to the inflammatory response, metabolic marker, and microribonucleic acids, long non-coding RNAs, HPA axis which are - related to depression and can serve as future targets.
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Affiliation(s)
- Aditi Vyas
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Gaurav Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
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13
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Yuan D, Meng Y, Ai Z, Zhou S. Research trend of epigenetics and depression: adolescents' research needs to strengthen. Front Neurosci 2024; 17:1289019. [PMID: 38249586 PMCID: PMC10799345 DOI: 10.3389/fnins.2023.1289019] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/30/2023] [Indexed: 01/23/2024] Open
Abstract
Objective With its high prevalence, depression's pathogenesis remains unclear. Recent attention has turned to the interplay between depression and epigenetic modifications. However, quantitative bibliometric analyses are lacking. This study aims to visually analyze depression epigenetics trends, utilizing bibliometric tools, while comprehensively reviewing its epigenetic mechanisms. Methods Utilizing the Web of Science core dataset, we collected depression and epigenetics-related studies. Employing VOSViewer software, we visualized data on authors, countries, journals, and keywords. A ranking table highlighted field leaders. Results Analysis encompassed 3,469 depression epigenetics studies published from January 2002 to June 2023. Key findings include: (1) Gradual publication growth, peaking in 2021; (2) The United States and its research institutions leading contributions; (3) Need for enhanced collaborations, spanning international and interdisciplinary efforts; (4) Keyword clustering revealed five main themes-early-life stress, microRNA, genetics, DNA methylation, and histone acetylation-highlighting research hotspots; (5) Limited focus on adolescent depression epigenetics, warranting increased attention. Conclusion Taken together, this study revealed trends and hotspots in depression epigenetics research, underscoring global collaboration, interdisciplinary fusion, and multi-omics data's importance. It discussed in detail the potential of epigenetic mechanisms in depression diagnosis and treatment, advocating increased focus on adolescent research in this field. Insights aid researchers in shaping their investigative paths toward understanding depression's epigenetic mechanisms and antidepressant interventions.
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Affiliation(s)
- Dongfeng Yuan
- Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Yitong Meng
- Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Zhongzhu Ai
- Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
- Hubei Shizhen Laboratory, Wuhan, China
- Modern Engineering Research Center of Traditional Chinese Medicine and Ethnic Medicine of Hubei Province, Wuhan, China
| | - Shiquan Zhou
- Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
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14
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Li Y, Wang YX, Tang XM, Liang P, Chen JJ, Jiang F, Yang Q, Liang YD. Haplotype analysis of long-chain non-coding RNA NONHSAT102891 promoter polymorphisms and depression in Chinese individuals: A case-control association study. World J Psychiatry 2023; 13:1005-1015. [PMID: 38186730 PMCID: PMC10768487 DOI: 10.5498/wjp.v13.i12.1005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 11/09/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Our previous study reported that the single-nucleotide polymorphism (SNP) rs155979 GC in the promoter region of long-chain non-coding RNA (lncRNA) NONHSAT102891 affects depression susceptibility in a Chinese population. AIM To explored associations of two SNPs and haplotypes in the lncRNA NONHSAT102891 promoter region with depression susceptibility in Chinese population. METHODS This this case-control association study was approved by the Ethics Committee of Chengdu Medical College (approval number: 201815). Patient diagnosis was based on DSM-IV criteria. We selected a total of 480 patients with depression and 329 healthy controls with no history of psychopathology, and performed genotyping of two SNPs by extracting peripheral venous blood samples from the subjects. The function of the two lncRNA NONHSAT102891 promoter G/C and A/T haplotypes was detected by dual-luciferase reporter assays of human embryonic kidney 293T transfected cells. RESULTS Stratified analysis of clinical and genotypic characteristics of our cohort showed that the degree of mild depressive episodes associated with the rs6230 TC/CC genotype increased by 1.59 times [TC/CC vs TT: odds ratio (OR) = 1.59, 95% confidence interval (CI): 1.08-2.35, P = 0.019]. The haploid analysis revealed linkage disequilibrium between rs3792747 and rs6230, and the double SNP CG haplotype was more common in the control group compared to case group, indicating that this haplotype significantly reduced the risk of depression (C/G vs T/A: OR = 0.42, 95%CI: 0.21-0.83, P = 0.01). There was no significant difference in the dual-luciferase reporter activity of the G/C and A/T haplotypes compared with the control group (P > 0.05), indicating that the double SNP haplotype has no transcriptional activity. CONCLUSION The rs3792747 and rs6230 CG haplotypes of the lncRNA NONHSA T102891 promoter may be related to a reduced risk of depression in the Han Chinese population.
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Affiliation(s)
- Yue Li
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Yi-Xi Wang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Xing-Ming Tang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Peng Liang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jing-Jie Chen
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Feng Jiang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Qiang Yang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Yun-Dan Liang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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15
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Cui X, Xu Y, Zhu H, Wang L, Zhou J. Long noncoding RNA NONHSAG045500 regulates serotonin transporter to ameliorate depressive-like behavior via the cAMP-PKA-CREB signaling pathway in a model of perinatal depression. J Matern Fetal Neonatal Med 2023; 36:2183468. [PMID: 36997170 DOI: 10.1080/14767058.2023.2183468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2023]
Abstract
OBJECTIVE Perinatal depression (PND) is the most common complication of childbirth and negatively affects the mother. Long noncoding RNA (lncRNA) NONHSAG045500 inhibits the expression of 5-hydroxytryptamine (5-HT) transporter (i.e. serotonin transporter [SERT]) and produces an antidepressant effect. This study aimed to identify a link between the lncRNA NONHSAG045500 and the pathogenesis of PND. METHODS Female C57BL/6 J mice were divided into normal control group (control group, n = 15), chronic unpredictable stress (CUS) model group (PND group, n = 15), lncRNA NONHSAG045500-overexpressed group (LNC group, sublingual intravenous injection of NONHSAG045500 overexpression cells for 7 days, n = 15), and escitalopram treatment group (i.e. the selective serotonin reuptake inhibitor [SSRI] group, with escitalopram administered from the 10th day after pregnancy to the 10th day after delivery, n = 15). Control group mice were conceived normally, whereas, in the other groups, a CUS model was established before mice were conceived. Depressive-like behaviour was assessed via sucrose preference, forced swimming, and open-field tests. The expression levels of 5-HT, SERT, and cAMP-PKA-CREB pathway-related proteins in the prefrontal cortex were detected on the 10th day after delivery. RESULTS Mice in the PND group exhibited significant depressive-like behaviours compared with those in the control group, indicating that the PND model was successfully established. The expression of lncRNA NONHSAG045500 was markedly decreased in the PND group compared with that in the control group. After treatment, both LNC and SSRI groups showed a significant improvement in depression-like behaviour, and the expression of 5-HT in the prefrontal cortex was increased in these groups compared with that in the PND group. In addition, the LNC group displayed lower expression of SERT and higher expression of cAMP, PKA, and CREB when in comparison to PND group. CONCLUSION NONHSAG045500 mediates the development of PND mainly by activating the cAMP-PKA-CREB pathway, increasing the level of 5-HT, and decreasing the expression of SERT.
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Affiliation(s)
- Xuelian Cui
- Department of Psychology, Changzhou Maternity and Child Health Care Hospital, Changzhou, P.R. China
| | - Yongjuan Xu
- Department of Cervical, Changzhou Maternity and Child Health Care Hospital, Changzhou, P.R. China
| | - Haiyan Zhu
- Department of Psychology, Changzhou Maternity and Child Health Care Hospital, Changzhou, P.R. China
| | - Li Wang
- Department of Psychology, Changzhou Maternity and Child Health Care Hospital, Changzhou, P.R. China
| | - Jun Zhou
- Department of Respiratory, Changzhou Maternity and Child Health Care Hospital, Changzhou, P.R. China
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16
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Teng P, Li Y, Ku L, Wang F, Goldsmith DR, Wen Z, Yao B, Feng Y. The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases. Brain Behav Immun 2023; 112:175-187. [PMID: 37301236 PMCID: PMC10527610 DOI: 10.1016/j.bbi.2023.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 05/26/2023] [Accepted: 06/04/2023] [Indexed: 06/12/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.
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Affiliation(s)
- Peng Teng
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States
| | - Yangping Li
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, United States
| | - Li Ku
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States
| | - Feng Wang
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, United States
| | - David R Goldsmith
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States; Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
| | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, United States.
| | - Yue Feng
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States.
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Zhong XL, Du Y, Chen L, Cheng Y. The emerging role of long noncoding RNA in depression and its implications in diagnostics and therapeutic responses. J Psychiatr Res 2023; 164:251-258. [PMID: 37385004 DOI: 10.1016/j.jpsychires.2023.06.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/18/2023] [Accepted: 06/15/2023] [Indexed: 07/01/2023]
Abstract
Depression is one of the most common mental illnesses, affecting more than 350 million people worldwide. However, the occurrence of depression is a complex process involving genetic, physiological, psychological, and social factors, and the underlying mechanisms of its pathogenesis remain unclear. With advances in sequencing technology and epigenetic studies, increasing research evidence suggests that long noncoding RNAs (lncRNAs) play nonnegligible roles in the development of depression and may be involved in the pathogenesis of depression through multiple pathways, including regulating neurotrophic factors and other growth factors and affecting synaptic function. In addition, significant alterations in lncRNA expression profiles in peripheral blood and different brain regions of patients and model animals with depression suggest that lncRNAs may function as biomarkers for the differential diagnosis of depression and other psychiatric disorders and may also be potential therapeutic targets. In this paper, the biological functions of lncRNAs are briefly described, and the functional roles and abnormal expression of lncRNAs in the development, diagnosis and treatment of depression are reviewed.
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Affiliation(s)
- Xiao-Lin Zhong
- Center on Translational Neuroscience, College of Life and Environmental Sciences, 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
| | - Lei Chen
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Yong Cheng
- Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China; Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China; Institute of National Security, Minzu University of China, Beijing, China.
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18
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Zhu J, Guo S, Hu S, Chen Q. The 2210408F21Rik/miR-1968-5p/Hras axis regulates synapse-related proteins in a mouse model of depressive-like behaviors through a ceRNA mechanism. Behav Brain Res 2023; 447:114440. [PMID: 37075955 DOI: 10.1016/j.bbr.2023.114440] [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: 12/13/2022] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/21/2023]
Abstract
Abnormal expression of long non-coding RNAs (lncRNAs) has been correlated with depressive disorders, but limited data are available on the lncRNA-microRNA (miRNA/miR)-messenger RNA (mRNA) competitive endogenous RNA (ceRNA) mechanism in depression. Herein, we address this issue based on transcriptome sequencing and in vitro experiments. Mouse hippocampus tissues were obtained from chronic unpredictable mild stress (CUMS)-induced mice to screen out differentially expressed mRNAs and lncRNAs based on the transcriptome sequencing. Next, the depression-related differentially expressed genes (DEGs) were obtained, followed by Gene Ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) enrichment analysis. A total of 1018 differentially expressed mRNAs, 239 differentially expressed lncRNAs, and 58 DEGs related to depression were acquired. The miRNAs targeting Harvey rat sarcoma virus oncogene (Hras) and miRNAs sponged by Hras-related lncRNA were intersected to identify the ceRNA regulatory network. In addition, the synapse-related genes related to depression were acquired by bioinformatics analysis. Hras was identified as the core gene related to depression, mainly related to neuronal excitation. We also found that 2210408F21Rik competitively bound to miR-1968-5p that targeted Hras. The effects of 2210408F21Rik/miR-1968-5p/Hras axis on neuronal excitation were verified in primary hippocampal neurons. The experimental data indicated that the downregulation of 2210408F21Rik increased the level of miR-1968-5p to diminish Hras expression, thereby affecting neuronal excitation in CUMS mice. In conclusion, the 2210408F21Rik/miR-1968-5p/Hras ceRNA network can potentially affect the expression of synapsia-related proteins and is a promising target for preventing and treating depression.
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Affiliation(s)
- Jiang Zhu
- Department of Neurology, Affiliated Hospital of Chengde Medical College, Chengde 067000, China.
| | - Sen Guo
- Hebei Key Laboratory of Nerve Injury and Repair, Chengde Medical College, Chengde 067000, China; Department of Spinal Cord Injury and Rehabilitation, Chengde Medical College, Chengde 067000, China
| | - Shaofu Hu
- Department of Neurology, Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - Qihang Chen
- Department of Neurology, Affiliated Hospital of Chengde Medical College, Chengde 067000, China
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19
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Sun M, Zhang M, Yin H, Tu H, Wen Y, Wei X, Shen W, Huang R, Xiong W, Li G, Gao Y. Long non-coding RNA MSTRG.81401 short hairpin RNA relieves diabetic neuropathic pain and behaviors of depression by inhibiting P2X4 receptor expression in type 2 diabetic rats. Purinergic Signal 2023; 19:123-133. [PMID: 35022948 PMCID: PMC9984665 DOI: 10.1007/s11302-021-09828-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/02/2021] [Indexed: 11/26/2022] Open
Abstract
Patients with diabetic neuropathic pain (DNP) experience immense physical and mental suffering, which is comorbid with other mental disorders, including major depressive disorder (MDD). P2X4 receptor, one of the purinergic receptors, is a significant mediator of DNP and MDD. The present study aimed to identify the roles and mechanisms of MSTRG.81401, a long non-coding RNA (lncRNA), in alleviating DNP and MDD-like behaviors in type 2 diabetic rats. After administration with MSTRG.81401 short hairpin RNA (shRNA), the model + MSTRG.81401 shRNA group demonstrated increased mechanical withdrawal threshold, thermal withdrawal latency, open-field test, and sucrose preference test; however, immobility time on the forced swimming test decreased. MSTRG.81401 shRNA administration significantly decreased the expression of the P2X4 receptor, tumor necrosis factor-α, and interleukin-1β in the hippocampus and spinal cord in the model + MSTRG.81401 shRNA group. Simultaneously, MSTRG.81401 shRNA administration downregulated phosphorylation of ERK1/2 in the hippocampus and spinal cord. Thus, lncRNA MSTRG.81401 shRNA can alleviate DNP and MDD-like behaviors in type 2 diabetic rats and may downregulate the expression of P2X4 receptors in the hippocampus and spinal cord of rats.
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Affiliation(s)
- Mengyun Sun
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Road, Nanchang, Jiangxi, People's Republic of China
| | - Mingming Zhang
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Road, Nanchang, Jiangxi, People's Republic of China
| | - Haoming Yin
- Medical College of Grade 2017, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Hongcheng Tu
- Basic Medical College of Grade 2018, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Yuqing Wen
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Road, Nanchang, Jiangxi, People's Republic of China
| | - Xingyu Wei
- Basic Medical College of Grade 2017, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Wenhao Shen
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Ruoyu Huang
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Wei Xiong
- Affiliated Stomatological Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Guodong Li
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Road, Nanchang, Jiangxi, People's Republic of China
| | - Yun Gao
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Road, Nanchang, Jiangxi, People's Republic of China.
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, People's Republic of China.
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Jiao X, Wang R, Ding X, Yan B, Lin Y, Liu Q, Wu Y, Zhou C. LncRNA-84277 is involved in chronic pain-related depressive behaviors through miR-128-3p/SIRT1 axis in central amygdala. Front Mol Neurosci 2022; 15:920216. [PMID: 35959106 PMCID: PMC9362774 DOI: 10.3389/fnmol.2022.920216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Long-term chronic pain can lead to depression. However, the mechanism underlying chronic pain-related depression remains unclear. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC). Our previous studies have demonstrated that SIRT1 in the central nucleus of the amygdala (CeA) is involved in the development of chronic pain-related depression. In addition, increasing studies have indicated that long non-coding RNAs (lncRNAs) play a vital role in the pathogenesis of pain or depression. However, whether lncRNAs are involved in SIRT1-mediated chronic pain-related depression remains largely unknown. In this study, we identified that a novel lncRNA-84277 in CeA was the upstream molecule to regulate SIRT1 expression. Functionally, lncRNA-84277 overexpression in CeA significantly alleviated the depression-like behaviors in spared nerve injury (SNI)-induced chronic pain rats, whereas lncRNA-84277 knockdown in CeA induced the depression-like behaviors in naïve rats. Mechanically, lncRNA-84277 acted as a competing endogenous RNA (ceRNA) to upregulate SIRT1 expression by competitively sponging miR-128-3p, and therefore improved chronic pain-related depression-like behaviors. Our findings reveal the critical role of lncRNA-84277 in CeA specifically in guarding against chronic pain-related depression via a ceRNA mechanism and provide a potential therapeutic target for chronic pain-related depression.
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Affiliation(s)
- Xiaowei Jiao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Ruiyao Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Xiaobao Ding
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Binbin Yan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yuwen Lin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qiang Liu
- Jiangsu Province Key Laboratory of Anesthesiology, National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China
| | - Yuqing Wu
- Jiangsu Province Key Laboratory of Anesthesiology, National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China
- Yuqing Wu,
| | - Chenghua Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- *Correspondence: Chenghua Zhou,
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21
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The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders. Int J Mol Sci 2022; 23:ijms23116118. [PMID: 35682796 PMCID: PMC9181295 DOI: 10.3390/ijms23116118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology of neurodevelopmental disorders (NDD). Bypassing the classic protein-centric conception of disease mechanisms, some studies have been conducted to identify and characterize the putative roles of non-coding sequences in the genetic pathogenesis and diagnosis of complex diseases. However, their involvement in NDD, and more specifically in intellectual disability (ID), is still poorly documented and only a few genomic alterations affecting the lncRNAs function and/or expression have been causally linked to the disease endophenotype. Considering that a significant fraction of patients still lacks a genetic or molecular explanation, we expect that a deeper investigation of the non-coding genome will unravel novel pathogenic mechanisms, opening new translational opportunities. Here, we present evidence of the possible involvement of many lncRNAs in the etiology of different forms of ID and NDD, grouping the candidate disease-genes in the most frequently affected cellular processes in which ID-risk genes were previously collected. We also illustrate new approaches for the identification and prioritization of NDD-risk lncRNAs, together with the current strategies to exploit them in diagnosis.
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22
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Hao WZ, Chen Q, Wang L, Tao G, Gan H, Deng LJ, Huang JQ, Chen JX. Emerging roles of long non-coding RNA in depression. Prog Neuropsychopharmacol Biol Psychiatry 2022; 115:110515. [PMID: 35077841 DOI: 10.1016/j.pnpbp.2022.110515] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 12/31/2022]
Abstract
Depression is the second most common psychiatric disorder, affecting more than 340 million people of all ages worldwide. However, the mechanisms underlying the development of depression remain unclear, and existing antidepressants may cause clinical dependence and toxic side effects. Recently, emerging evidence from the fields of neuroscience, genetics, and genomics supports the modulatory role of long non-coding RNA (lncRNA) in depression. LncRNAs may mediate the pathogenesis of depression through multiple pathways, including regulating neurotransmitters and neurotrophic factors, affecting synaptic conduction, and regulating the ventriculo-olfactory neurogenic system. In addition, relying on genome-wide association study and molecular biological experiment, the possibility of lncRNA as a potential biomarker for the differential diagnosis of depression and other mental illnesses, including schizophrenia and anxiety disorders, is gradually being revealed. Thus, it is important to explore whether lncRNAs are potential therapeutic targets and diagnostic biomarkers for depression. Here, we summarize the genesis and function of lncRNAs and discuss the aberrant expression and functional roles of lncRNAs in the development, diagnosis, and therapy of depression, as well as the deficiencies and limitations of these studies. Moreover, we established a lncRNA-miRNA-mRNA-pathway-drug network of depression through bioinformatics analysis methods to deepen our understanding of the relationship between lncRNA and depression, promoting the clinical application of epigenetic research.
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Affiliation(s)
- Wen-Zhi Hao
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Qian Chen
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Lu Wang
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Gabriel Tao
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, United States
| | - Hua Gan
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Li-Juan Deng
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Jun-Qing Huang
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Jia-Xu Chen
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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23
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Zhang C, Owen LA, Lillvis JH, Zhang SX, Kim IK, DeAngelis MM. AMD Genomics: Non-Coding RNAs as Biomarkers and Therapeutic Targets. J Clin Med 2022; 11:jcm11061484. [PMID: 35329812 PMCID: PMC8954267 DOI: 10.3390/jcm11061484] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/22/2022] [Accepted: 03/01/2022] [Indexed: 12/04/2022] Open
Abstract
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world’s leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets.
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Affiliation(s)
- Charles Zhang
- Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA; (C.Z.); (L.A.O.); (J.H.L.); (S.X.Z.)
| | - Leah A. Owen
- Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA; (C.Z.); (L.A.O.); (J.H.L.); (S.X.Z.)
- Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
- Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
- Department of Obstetrics and Gynecology, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
| | - John H. Lillvis
- Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA; (C.Z.); (L.A.O.); (J.H.L.); (S.X.Z.)
- Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA
| | - Sarah X. Zhang
- Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA; (C.Z.); (L.A.O.); (J.H.L.); (S.X.Z.)
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
- Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
| | - Ivana K. Kim
- Retina Service, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
- Correspondence: (I.K.K.); (M.M.D.)
| | - Margaret M. DeAngelis
- Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA; (C.Z.); (L.A.O.); (J.H.L.); (S.X.Z.)
- Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
- Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
- Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
- Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
- Genetics, Genomics and Bioinformatics Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
- Correspondence: (I.K.K.); (M.M.D.)
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24
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Pisanu C, Severino G, De Toma I, Dierssen M, Fusar-Poli P, Gennarelli M, Lio P, Maffioletti E, Maron E, Mehta D, Minelli A, Potier MC, Serretti A, Stacey D, van Westrhenen R, Xicota L, Baune BT, Squassina A. Transcriptional biomarkers of response to pharmacological treatments in severe mental disorders: A systematic review. Eur Neuropsychopharmacol 2022; 55:112-157. [PMID: 35016057 DOI: 10.1016/j.euroneuro.2021.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/18/2021] [Accepted: 12/16/2021] [Indexed: 11/04/2022]
Abstract
Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.
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Affiliation(s)
- Claudia Pisanu
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Giovanni Severino
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Ilario De Toma
- Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Mara Dierssen
- Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Paolo Fusar-Poli
- Early Psychosis: Intervention and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, King's College London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - Massimo Gennarelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Pietro Lio
- Department of Computer Science and Technology, University of Cambridge, Cambridge, UK
| | - Elisabetta Maffioletti
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Eduard Maron
- Department of Psychiatry, University of Tartu, Tartu, Estonia; Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK
| | - Divya Mehta
- Queensland University of Technology, Centre for Genomics and Personalised Health, Faculty of Health, Kelvin Grove, Queensland, Australia
| | - Alessandra Minelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | | | - Alessandro Serretti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy
| | - David Stacey
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Roos van Westrhenen
- Parnassia Psychiatric Institute, Amsterdam, The Netherlands; Department of Psychiatry and Neuropsychology, Faculty of Health and Sciences, Maastricht University, Maastricht, The Netherlands; Institute of Psychiatry, Psychology&Neuroscience (IoPPN) King's College London, UK
| | - Laura Xicota
- Paris Brain Institute ICM, Salpetriere Hospital, Paris, France
| | | | - Bernhard T Baune
- Department of Psychiatry, University of Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Alessio Squassina
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
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25
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Tamaddon M, Azimzadeh M, Tavangar SM. microRNAs and long non-coding RNAs as biomarkers for polycystic ovary syndrome. J Cell Mol Med 2022; 26:654-670. [PMID: 34989136 PMCID: PMC8817139 DOI: 10.1111/jcmm.17139] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 11/05/2021] [Accepted: 11/29/2021] [Indexed: 12/18/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is known as the most common metabolic/endocrine disorder among women of reproductive age. Its complicated causality assessment and diagnostic emphasized the role of non‐coding regulatory RNAs as molecular biomarkers in studying, diagnosing and even as therapeutics of PCOS. This review discusses a comparative summary of research into microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs) that are molecularly or statistically related to PCOS. We categorize the literature in terms of centering on either miRNAs or lncRNAs and discuss the combinatory studies and promising ideas as well. Additionally, we compare the pros and cons of the prominent research methodologies used for each of the abovementioned research themes and discuss how errors can be stopped from propagation by selecting correct methodologies for future research. Finally, it can be concluded that research into miRNAs and lncRNAs has the potential for identifying functional networks of regulation with multiple mRNAs (and hence, functional proteins). This new understanding may eventually afford clinicians to control the molecular course of the pathogenesis better. With further research, RNA (with statistical significance and present in the blood) may be used as biomarkers for the disease, and more possibilities for RNA therapy agents can be identified.
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Affiliation(s)
- Mona Tamaddon
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Azimzadeh
- Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Medical Nanotechnology & Tissue Engineering Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Mohammad Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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26
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Wang Y, Wei J, Chen T, Yang X, Zhao L, Wang M, Dou Y, Du Y, Ni R, Li T, Ma X. A Whole Transcriptome Analysis in Peripheral Blood Suggests That Energy Metabolism and Inflammation Are Involved in Major Depressive Disorder. Front Psychiatry 2022; 13:907034. [PMID: 35633815 PMCID: PMC9136012 DOI: 10.3389/fpsyt.2022.907034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Previous studies on transcriptional profiles suggested dysregulation of multiple RNA species in major depressive disorder (MDD). However, the interaction between different types of RNA was neglected. Therefore, integration of different RNA species in transcriptome analysis would be helpful for interpreting the functional readout of the transcriptome in MDD. METHODS A whole transcriptome sequencing were performed on the peripheral blood of 15 patients with MDD and 15 matched healthy controls (HCs). The differential expression of miRNAs, lncRNAs, circRNAs, and mRNAs was examined between MDD and HCs using empirical analysis of digital gene expression data in R (edgeR). Weighted correlation network analysis (WGCNA) was used to identify RNA co-expression modules associated with MDD. A ceRNA network was constructed for interpretation of interactions between different RNA species. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to explore potential biological mechanisms associated with MDD. RESULTS Multiple RNAs and co-expression modules were identified to be significantly dysregulated in MDD compared to HCs. Based on the differential RNAs, a ceRNA network that were dysregulated in MDD were constructed. The pathway networks that related to oxidative phosphorylation and the chemokine signaling were found to be associated with MDD. CONCLUSION Our results suggested that the processes of energy metabolism and inflammation may be involved in the pathophysiology of MDD.
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Affiliation(s)
- Yu Wang
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Jinxue Wei
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China.,Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Ting Chen
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao Yang
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Liansheng Zhao
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China.,Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Min Wang
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yikai Dou
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yue Du
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Rongjun Ni
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Tao Li
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaohong Ma
- Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, China
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27
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Sun J, Wang R, Chao T, Wang C. Long Noncoding RNAs Involved in Cardiomyocyte Apoptosis Triggered by Different Stressors. J Cardiovasc Transl Res 2021; 15:588-603. [PMID: 34855148 DOI: 10.1007/s12265-021-10186-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/04/2021] [Indexed: 12/26/2022]
Abstract
Cardiomyocytes are essential to maintain the normal cardiac function. Ischemia, hypoxia, and drug stimulation can induce pathological apoptosis of cardiomyocytes which eventually leads to heart failure, arrhythmia, and other cardiovascular diseases. Understanding the molecular mechanisms that regulate cardiomyocyte apoptosis is of great significance for the prevention and treatment of cardiovascular diseases. In recent years, more and more evidences reveal that long noncoding RNAs (lncRNAs) play important regulatory roles in myocardial cell apoptosis. They can modulate the expression of apoptosis-related genes at post-transcriptional level by altering the translation efficacy of target mRNAs or functioning as a precursor for miRNAs or competing for miRNA-mediated inhibition. Moreover, reversing the abnormal expression of lncRNAs can attenuate and even reverse the pathological apoptosis of cardiomyocytes. Therefore, apoptosis-related lncRNAs may become a potential new field for studying cardiomyocyte apoptosis and provide new ideas for the treatment of cardiovascular diseases.
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Affiliation(s)
- Jinghui Sun
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ru Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tiantian Chao
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chenglong Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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28
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Shi Y, Wang Q, Song R, Kong Y, Zhang Z. Non-coding RNAs in depression: Promising diagnostic and therapeutic biomarkers. EBioMedicine 2021; 71:103569. [PMID: 34521053 PMCID: PMC8441067 DOI: 10.1016/j.ebiom.2021.103569] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/04/2021] [Accepted: 08/18/2021] [Indexed: 01/18/2023] Open
Abstract
Non-coding RNAs (ncRNAs), including microRNAs, circular RNAs, and long non-coding RNAs, are important regulators of normal biological processes and their abnormal expression may be involved in the pathogenesis of human diseases including depression. Multiple studies have demonstrated a significantly increased or reduced ncRNAs expression in depressed patients compared with healthy subjects and that antidepressant therapy can alter the aberrant expression of ncRNAs in depressed patients. Although the existing evidence is important, it is also mixed and a comprehensive review to guide an effective clinical translation is lacking. Focused on human research, this review summarizes clinical findings of ncRNAs in depression, including those in brain tissues and peripheral samples. We outlined the characteristics and functions of ncRNAs and highlighted their performance in the diagnosis and treatment of depression. Although their precise roles in depression remain uncertain, ncRNAs have shown potential value as biomarkers for diagnosis and therapy in depressed patients.
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Affiliation(s)
- Yachen Shi
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, Jiangsu 210009, China
| | - Qingyun Wang
- College of Agricultural and Environmental Sciences, University of California, Davis, California 95616, United States
| | - Ruize Song
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, Jiangsu 210009, China
| | - Yan Kong
- Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, Jiangsu 210009, China.
| | - Zhijun Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, Jiangsu 210009, China; School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210096, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, Guangdong 510330, China.
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29
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Bhattacharyya N, Pandey V, Bhattacharyya M, Dey A. Regulatory role of long non coding RNAs (lncRNAs) in neurological disorders: From novel biomarkers to promising therapeutic strategies. Asian J Pharm Sci 2021; 16:533-550. [PMID: 34849161 PMCID: PMC8609388 DOI: 10.1016/j.ajps.2021.02.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/28/2021] [Accepted: 02/18/2021] [Indexed: 01/12/2023] Open
Abstract
Long non coding RNAs (lncRNAs) are non-protein or low-protein coding transcripts that contain more than 200 nucleotides. They representing a large share of the cell's transcriptional output, demonstrate functional attributes viz. tissue-specific expression, determination of cell fate, controlled expression, RNA processing and editing, dosage compensation, genomic imprinting, conserved evolutionary traits etc. These long non coding variants are well associated with pathogenicity of various diseases including the neurological disorders like Alzheimer's disease, schizophrenia, Huntington's disease, Parkinson's disease etc. Neurological disorders are widespread and there knowing the underlying mechanisms become crucial. The lncRNAs take part in the pathogenesis by a plethora of mechanisms like decoy, scaffold, mi-RNA sequestrator, histone modifiers and in transcriptional interference. Detailed knowledge of the role of lncRNAs can help to use them further as novel biomarkers for therapeutic aspects. Here, in this review we discuss regulation and functional roles of lncRNAs in eight neurological diseases and psychiatric disorders, and the mechanisms by which they act. With these, we try to establish their roles as potential markers and viable diagnostic tools in these disorders.
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Affiliation(s)
| | - Vedansh Pandey
- Department of Life Sciences, Presidency University, Kolkata, India
| | | | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, India
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30
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Kim HK, Zai G, Hennings JM, Müller DJ, Kloiber S. Changes in RNA expression levels during antidepressant treatment: a systematic review. J Neural Transm (Vienna) 2021; 128:1461-1477. [PMID: 34415438 DOI: 10.1007/s00702-021-02394-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/26/2021] [Indexed: 12/28/2022]
Abstract
More than a third of patients treated with antidepressants experience treatment resistance. Furthermore, molecular pathways involved in antidepressant effect have yet to be fully understood. Therefore, we performed a systematic review of clinical studies that examined changes in RNA expression levels produced by antidepressant treatment. Literature search was performed through April 2021 for peer-reviewed studies measuring changes in mRNA or non-coding RNA levels before and after antidepressant treatment in human participants following PRISMA guidelines. Thirty-one studies were included in qualitative synthesis. We identified a large amount of heterogeneity between the studies for genes/RNAs measured, antidepressants used, and treatment duration. Of the six RNAs examined by more than one study, expression of the brain-derived neurotrophic factor (BDNF) gene and genes in the inflammation pathway, particularly IL-1β, were consistently reported to be altered by antidepressant treatment. Limitations of this review include heterogeneity of the studies, possibility of positive publication bias, and risk of false-negative findings secondary to small sample sizes. In conclusion, our systematic review provides an updated synthesis of RNA expression changes produced by antidepressant treatment in human participants, where genes in the BDNF and inflammatory pathways were identified as potential targets of antidepressant effect. Importantly, these findings also highlight the need for replication of the included studies in multiple strong, placebo-controlled studies for the identification of evidence-based markers that can be targeted to improve treatment outcomes.
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Affiliation(s)
| | - Gwyneth Zai
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, ON, M6H 1J4, Canada.,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - Daniel J Müller
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, ON, M6H 1J4, Canada.,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Stefan Kloiber
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada. .,Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, ON, M6H 1J4, Canada. .,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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31
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Wang L, Zhang M, Zhu H, Sun L, Yu B, Cui X. Combined identification of lncRNA NONHSAG004550 and NONHSAT125420 as a potential diagnostic biomarker of perinatal depression. J Clin Lab Anal 2021; 35:e23890. [PMID: 34263944 PMCID: PMC8373316 DOI: 10.1002/jcla.23890] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/05/2021] [Accepted: 06/15/2021] [Indexed: 12/14/2022] Open
Abstract
Background Perinatal depression (PD) is one of the most common complications of pregnancy, and timely diagnosis and treatment are still challenging in China due to the scarcity of psychiatrists. This study aimed to investigate whether long noncoding RNAs (lncRNAs) are potential diagnostic biomarkers of PD. Methods Using RT‐PCR, six downregulated major depressive disorder (MDD)‐associated lncRNAs (NONSUSG010267, NONHSAT140386, NONHSAG004550, NONHSAT125420, NONHSAG013606, and NONMMUG014361) were assessed in 39 pregnant women with PD (PD group), 20 PD patients undergoing mindfulness‐integrated cognitive behavior therapy (MiCBT) (treatment group (TG)), and 51 normal pregnant women (normal control (NC) group) to identify significantly differentially expressed lncRNAs during the second trimester and at 42 days postpartum. Results Compared with the NC group, the six lncRNAs were significantly downregulated in the PD group during the second trimester and at 42 days postpartum (p<0.01~0.001). Expression of NONHSAG004550 and NONHSAT125420 was significantly upregulated after MiCBT therapy in TG (p<0.01~0.001), and no significant differences were observed between TG and the NC group at 42 days postpartum (p>0.05). NONHSAG004550 and NONHSAT125420 were significantly differentially expressed in the PD group, and this expression was altered according to the amelioration of depressive symptoms. Receiver operating characteristic (ROC) curve analysis revealed that the two lncRNAs combined had a good value in predicting PD, with an area under the curve (AUC) of 0.764 (95% confidence interval (CI): 0.639–0.888). Conclusion The combination of lncRNAs NONHSAG004550 and NONHSAT125420 is a novel potential diagnostic biomarker of PD.
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Affiliation(s)
- Li Wang
- Department of Healthcare, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, China
| | - Ming Zhang
- Department of Clinical Laboratory, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, China
| | - Haiyan Zhu
- Department of Healthcare, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, China
| | - Liying Sun
- Department of Healthcare, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, China
| | - Bin Yu
- Department of Genetic Laboratory, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, China
| | - Xuelian Cui
- Department of Healthcare, Changzhou Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Changzhou, China
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The Potential Use of Peripheral Blood Mononuclear Cells as Biomarkers for Treatment Response and Outcome Prediction in Psychiatry: A Systematic Review. Mol Diagn Ther 2021; 25:283-299. [PMID: 33978935 DOI: 10.1007/s40291-021-00516-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Psychiatric disorders have a major impact on the global burden of disease while therapeutic interventions remain insufficient to adequately treat a large number of patients. Regrettably, the efficacy of several psychopharmacological treatment regimens becomes apparent only after 4-6 weeks, and at this point, a significant number of patients present as non-responsive. As such, many patients go weeks/months without appropriate treatment or symptom management. Adequate biomarkers for treatment success and outcome prediction are thus urgently needed. OBJECTIVE With this systematic review, we provide an overview of the use of peripheral blood mononuclear cells (PBMCs) and their signaling pathways in evaluating and/or predicting the effectiveness of different treatment regimens in the course of psychiatric illnesses. We highlight PBMC characteristics that (i) reflect treatment presence, (ii) allow differentiation of responders from non-responders, and (iii) prove predictive at baseline with regard to treatment outcome for a broad range of psychiatric intervention strategies. REVIEW METHODS A PubMed database search was performed to extract papers investigating the relation between any type of PBMC characteristic and treatment presence and/or outcome in patients suffering from severe mental illness. Criteria for eligibility were: written in English; psychiatric diagnosis based on DSM-III-R or newer; PBMC isolation via gradient centrifugation; comparison between treated and untreated patients via PBMC features; sample size ≥ n = 5 per experimental group. Papers not researching in vivo treatment effects between patients and healthy controls, non-clinical trials, and non-hypothesis-/data-driven (e.g., -omics designs) approaches were excluded. DATA SYNTHESIS Twenty-nine original articles were included and qualitatively summarized. Antidepressant and antipsychotic treatments were mostly reflected by intracellular inflammatory markers while intervention with mood stabilizers was evidenced through cell maturation pathways. Lastly, cell viability parameters mirrored predominantly non-pharmacological therapeutic strategies. As for response prediction, PBMC (subtype) counts and telomerase activity seemed most promising for antidepressant treatment outcome determination; full length brain-derived neurotrophic factor (BDNF)/truncated BDNF were shown to be most apt to prognosticate antipsychotic treatment. CONCLUSIONS We conclude that, although inherent limitations to and heterogeneity in study designs in combination with the scarce number of original studies hamper unambiguous identification, several PBMC characteristics-mostly related to inflammatory pathways and cell viability-indeed show promise towards establishment as clinically relevant treatment biomarkers.
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LncRNA Gm14205 induces astrocytic NLRP3 inflammasome activation via inhibiting oxytocin receptor in postpartum depression. Biosci Rep 2021; 40:225881. [PMID: 32706026 PMCID: PMC7414522 DOI: 10.1042/bsr20200672] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/04/2020] [Accepted: 07/14/2020] [Indexed: 12/18/2022] Open
Abstract
Postpartum depression (PPD) is a kind of mental disorder characterized by persistent low emotions in puerperium. The most significant physiological change in postpartum is lactation which is regulated by oxytocin receptor (OXTR). However, whether OXTR is related to pathological process of PPD and the potential mechanism still remain unclear. In the present study, we prepared hormone-simulated pregnancy (HSP)-induced PPD mouse model and found that the protein level of OXTR in hippocampus of PPD model mice was down-regulated and Nod-like receptor protein 3 (NLRP3) inflammasome was activated. We identified five long non-coding RNAs (lncRNAs) related to PPD by transcriptome sequencing, including three up-regulated and two down-regulated. The five lncRNAs were associated with the signaling pathway of OXTR according to the bioinformatics analysis. Furthermore, we focused on one of the five lncRNAs, Gm14205, and found that it targeted OXTR which inhibited astrocytic NLRP3 inflammasome activation in hippocampal primary astrocytes. These findings illustrate that OXTR has protective effects in PPD by inhibiting NLRP3 inflammasome activation and provides a new strategy for targeting lncRNA Gm14205 in the pathogenesis of PPD.
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Zhang CL, Li YJ, Lu S, Zhang T, Xiao R, Luo HR. Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus. Zool Res 2021; 42:28-42. [PMID: 33420763 PMCID: PMC7840451 DOI: 10.24272/j.issn.2095-8137.2020.294] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Depression is a prevalent mental disorder that is associated with aging and contributes to increased mortality and morbidity. The overall prevalence of geriatric depression with clinically significant symptoms is currently on the rise. Recent studies have demonstrated that altered expressions of long non-coding RNAs (lncRNAs) in the brain affect neurodevelopment and manifest modulating functions during the depression. However, most lncRNAs have not yet been studied. Herein, we analyzed the transcriptome of dysregulated lncRNAs to reveal their expressions in a mouse model exhibiting depressive-like behaviors, as well as their corresponding response following antidepressant fluoxetine treatment. A chronic unpredictable mild stress (CUMS) mouse model was applied. A six-week fluoxetine intervention in CUMS-induced mice attenuated depressive-like behaviors. In addition, differential expression analysis of lncRNAs was performed following RNA-sequencing. A total of 282 lncRNAs (134 up-regulated and 148 down-regulated) were differentially expressed in CUMS-induced mice relative to non-stressed counterparts ( P<0.05). Moreover, 370 differentially expressed lncRNAs were identified in CUMS-induced mice after fluoxetine intervention. Gene Ontology (GO) analyses showed an association between significantly dysregulated lncRNAs and protein binding, oxygen binding, and transport activity, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these dysregulated lncRNAs might be involved in inflammatory response pathways. Fluoxetine effectively ameliorated the symptoms of depression in CUMS-induced mice by regulating the expression of lncRNAs in the hippocampus. The findings herein provide valuable insights into the potential mechanism underlying depression in elderly people.
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Affiliation(s)
- Chuan-Ling Zhang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medical Chemistry, Kunming Institute of Botany, the Chinese Academy of Sciences, Kunming, Yunnan 650201, China.,School of Pharmacy, Inner Mongolia Medical University, Huhhot, Inner Mongolia 010110, China.,University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Yi-Jia Li
- Key Laboratory of Molecular Pathology, Inner Mongolia Medical University, Huhhot, Inner Mongolia 010059, China
| | - Shuang Lu
- Key Laboratory of Molecular Pathology, Inner Mongolia Medical University, Huhhot, Inner Mongolia 010059, China
| | - Ting Zhang
- Key Laboratory of Molecular Pathology, Inner Mongolia Medical University, Huhhot, Inner Mongolia 010059, China
| | - Rui Xiao
- Key Laboratory of Molecular Pathology, Inner Mongolia Medical University, Huhhot, Inner Mongolia 010059, China. E-mail:
| | - Huai-Rong Luo
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medical Chemistry, Kunming Institute of Botany, the Chinese Academy of Sciences, Kunming, Yunnan 650201, China.,Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology, School of Pharmacy, Southwestern Medical University, Luzhou, Sichuan 646000, China. E-mail:
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35
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The Importance of Epigenetics in Diagnostics and Treatment of Major Depressive Disorder. J Pers Med 2021; 11:jpm11030167. [PMID: 33804455 PMCID: PMC7999864 DOI: 10.3390/jpm11030167] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/09/2021] [Accepted: 02/17/2021] [Indexed: 12/15/2022] Open
Abstract
Recent studies imply that there is a tight association between epigenetics and a molecular mechanism of major depressive disorder (MDD). Epigenetic modifications, i.e., DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA), are able to influence the severity of the disease and the outcome of the therapy. This article summarizes the most recent literature data on this topic, i.e., usage of histone deacetylases as therapeutic agents with an antidepressant effect and miRNAs or lncRNAs as markers of depression. Due to the noteworthy potential of the role of epigenetics in MDD diagnostics and therapy, we have gathered the most relevant data in this area.
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36
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Wu Y, Rong W, Jiang Q, Wang R, Huang H. Downregulation of lncRNA GAS5 Alleviates Hippocampal Neuronal Damage in Mice with Depression-Like Behaviors Via Modulation of MicroRNA-26a/EGR1 Axis. J Stroke Cerebrovasc Dis 2021; 30:105550. [PMID: 33341564 DOI: 10.1016/j.jstrokecerebrovasdis.2020.105550] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Accumulating evidences have demonstrated the roles of several long non-coding RNAs (lncRNAs) in depression. We aim to examine the capabilities of lncRNA growth arrest-specific transcript 5 (GAS5) on mice with depression-like behaviors and the mechanism of action. METHODS Fifty-six healthy mice were selected for model establishment. Morris water maze test and trapeze test were performed for evaluating learning and memory ability. The binding relationship between lncRNA GAS5 and microRNA-26a (miR-26a) and the target relationship between miR-26a and EGR1 were verified by dual-luciferase reporter gene assay. The apoptosis of neurons in the hippocampal CA1 region of mice was detected by TUNEL staining. The expression of inflammatory factors, lncRNA GAS5, miR-26a, early growth response gene 1 (EGR1), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway- and apoptosis-related factors in hippocampal tissues was tested by RT-qPCR and western blot analysis. RESULTS miR-26a expression was down-regulated while EGR1 and lncRNA GAS5 expression were up-regulated in hippocampal tissues of mice with depression-like behaviors. LncRNA GAS5 specifically bound to miR-26a and miR-26a targeted EGR1. Silencing of lncRNA GAS5 curtailed the release of inflammatory factors and the apoptosis of hippocampal neuron of mice with depression-like behaviors. EGR1 suppressed PI3K/AKT pathway activation to promote the release of inflammatory factors and the apoptosis of hippocampal neurons in mice with depression-like behaviors. CONCLUSION Our study provides evidence that silencing of lncRNA GAS5 could activate PI3K/AKT pathway to protect hippocampal neurons against damage in mice with depression-like behaviors by regulating the miR-26a/EGR1 axis.
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Affiliation(s)
- Yigao Wu
- Department of Medical Psychology, The First Affiliated Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu 241001, Anhui, PR China.
| | - Wei Rong
- Department of Clinical Medical Psychology, The Second People's Hospital of Wuhu, Wuhu 241001, Anhui, PR China.
| | - Qin Jiang
- Department of Medical Psychology, The First Affiliated Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu 241001, Anhui, PR China.
| | - Ruiquan Wang
- Department of Medical Psychology, The First Affiliated Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu 241001, Anhui, PR China.
| | - Huilan Huang
- Department of Medical Psychology, The First Affiliated Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu 241001, Anhui, PR China.
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37
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Blokhin IO, Khorkova O, Saveanu RV, Wahlestedt C. Molecular mechanisms of psychiatric diseases. Neurobiol Dis 2020; 146:105136. [PMID: 33080337 DOI: 10.1016/j.nbd.2020.105136] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 09/24/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022] Open
Abstract
For most psychiatric diseases, pathogenetic concepts as well as paradigms underlying neuropsychopharmacologic approaches currently revolve around neurotransmitters such as dopamine, serotonin, and norepinephrine. However, despite the fact that several generations of neurotransmitter-based psychotropics including atypical antipsychotics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors are available, the effectiveness of these medications is limited, and relapse rates in psychiatric diseases are relatively high, indicating potential involvement of other pathogenetic pathways. Indeed, recent high-throughput studies in genetics and molecular biology have shown that pathogenesis of major psychiatric illnesses involves hundreds of genes and numerous pathways via such fundamental processes as DNA methylation, transcription, and splicing. Current review summarizes these and other molecular mechanisms of such psychiatric illnesses as schizophrenia, major depressive disorder, and alcohol use disorder and suggests a conceptual framework for future studies.
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Affiliation(s)
- Ilya O Blokhin
- Center for Therapeutic Innovation, University of Miami, Miami, FL, United States of America; Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States of America; Jackson Memorial Hospital, Miami, FL, United States of America
| | - Olga Khorkova
- OPKO Health Inc., Miami, FL, United States of America
| | - Radu V Saveanu
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States of America
| | - Claes Wahlestedt
- Center for Therapeutic Innovation, University of Miami, Miami, FL, United States of America; Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States of America.
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38
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Erabi H, Okada G, Shibasaki C, Setoyama D, Kang D, Takamura M, Yoshino A, Fuchikami M, Kurata A, Kato TA, Yamawaki S, Okamoto Y. Kynurenic acid is a potential overlapped biomarker between diagnosis and treatment response for depression from metabolome analysis. Sci Rep 2020; 10:16822. [PMID: 33033336 PMCID: PMC7545168 DOI: 10.1038/s41598-020-73918-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Since optimal treatment at an early stage leads to remission of symptoms and recovery of function, putative biomarkers leading to early diagnosis and prediction of therapeutic responses are desired. The current study aimed to use a metabolomic approach to extract metabolites involved in both the diagnosis of major depressive disorder (MDD) and the prediction of therapeutic response for escitalopram. We compared plasma metabolites of MDD patients (n = 88) with those in healthy participants (n = 88) and found significant differences in the concentrations of 20 metabolites. We measured the Hamilton Rating Scale for Depression (HRSD) on 62 patients who completed approximately six-week treatment with escitalopram before and after treatment and found that kynurenic acid and kynurenine were significantly and negatively associated with HRSD reduction. Only one metabolite, kynurenic acid, was detected among 73 metabolites for overlapped biomarkers. Kynurenic acid was lower in MDD, and lower levels showed a better therapeutic response to escitalopram. Kynurenic acid is a metabolite in the kynurenine pathway that has been widely accepted as being a major mechanism in MDD. Overlapping biomarkers that facilitate diagnosis and prediction of the treatment response may help to improve disease classification and reduce the exposure of patients to less effective treatments in MDD.
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Affiliation(s)
- Hisayuki Erabi
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Go Okada
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Chiyo Shibasaki
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Daiki Setoyama
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Dongchon Kang
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Masahiro Takamura
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Atsuo Yoshino
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Manabu Fuchikami
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Akiko Kurata
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takahiro A Kato
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Shigeto Yamawaki
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yasumasa Okamoto
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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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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40
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Gu XH, Xu LJ, Zheng LL, Yang YJ, Tang ZY, Wu HJ, Chen ZZ, Wang W. Long non-coding RNA uc.80- overexpression promotes M2 polarization of microglias to ameliorate depression in rats. IUBMB Life 2020; 72:2194-2203. [PMID: 32780551 DOI: 10.1002/iub.2353] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 12/19/2022]
Abstract
Microglia polarization is associated with the pathogenesis of depression. A previous study shows that long non-coding RNA uc.80- is down-regulated in the hippocampus of depressed rats. Thus, this article aims to investigate the role of uc.80- in microglia polarization in depression. We first established depression model rats by chronic unpredictable mild stress (CUMS) regiment. We found that hippocampus of depressed rats exhibited an increase of M1 microglias and a decrease of M2 microglias. uc.80- was down-regulated in hippocampus of depressed rats. Furthermore, the detection of behaviouristics of depressed rats showed that uc.80- overexpression alleviated depression of rats. In addition, uc.80- overexpression promoted M2 polarization of microglias in vivo and in vitro. uc.80- overexpression led to a decrease in apoptosis of hippocampal neurons in vivo and in vitro. In conclusion, our study confirms that lncRNA uc.80- overexpression ameliorates depression in rats by promoting M2 polarization of microglias. Thus, our work suggests that uc.80- may be a target gene for depression treatment.
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Affiliation(s)
- Xun-Hu Gu
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Li-Jun Xu
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Li-Li Zheng
- Department of Pharmacy, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Yuan-Jian Yang
- Department of Medical Experimental Center, Jiangxi Mental Hospital, Nanchang, Jiangxi, China
| | - Zhen-Yu Tang
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Han-Jun Wu
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhen-Zhen Chen
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Wang
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Marie-Claire C, Lejeune FX, Mundwiller E, Ulveling D, Moszer I, Bellivier F, Etain B. A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1. Sci Rep 2020; 10:12239. [PMID: 32699220 PMCID: PMC7376060 DOI: 10.1038/s41598-020-69073-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 07/03/2020] [Indexed: 12/15/2022] Open
Abstract
Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand Factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.
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Affiliation(s)
- C Marie-Claire
- Optimisation thérapeutique en Neurospsychopharmacologie, INSERM U1144, Université de Paris, Paris, France.
| | - F X Lejeune
- Bioinformatics and Biostatistics Core Facility iCONICS, Inserm U 1127, CNRS UMR 7225, Sorbonne Université UMR S 1127, Institut du Cerveau Et de La Moelle Épinière, Paris, France
| | - E Mundwiller
- IGenSeq, Institut du Cerveau Et de La Moelle Épinière, Paris, France
| | - D Ulveling
- Bioinformatics and Biostatistics Core Facility iCONICS, Inserm U 1127, CNRS UMR 7225, Sorbonne Université UMR S 1127, Institut du Cerveau Et de La Moelle Épinière, Paris, France
| | - I Moszer
- Bioinformatics and Biostatistics Core Facility iCONICS, Inserm U 1127, CNRS UMR 7225, Sorbonne Université UMR S 1127, Institut du Cerveau Et de La Moelle Épinière, Paris, France
| | - F Bellivier
- Optimisation thérapeutique en Neurospsychopharmacologie, INSERM U1144, Université de Paris, Paris, France.,AP-HP, GH Saint-Louis-Lariboisière-F. Widal, Pole de Psychiatrie Et de Médecine Addictologique, Paris, France.,Fondation FondaMental, Créteil, France.,Faculté de Médecine, Université de Paris, Paris, France
| | - B Etain
- Optimisation thérapeutique en Neurospsychopharmacologie, INSERM U1144, Université de Paris, Paris, France.,AP-HP, GH Saint-Louis-Lariboisière-F. Widal, Pole de Psychiatrie Et de Médecine Addictologique, Paris, France.,Fondation FondaMental, Créteil, France.,Faculté de Médecine, Université de Paris, Paris, France
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Seki T, Yamagata H, Uchida S, Chen C, Kobayashi A, Kobayashi M, Harada K, Matsuo K, Watanabe Y, Nakagawa S. Altered expression of long noncoding RNAs in patients with major depressive disorder. J Psychiatr Res 2019; 117:92-99. [PMID: 31351391 DOI: 10.1016/j.jpsychires.2019.07.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 07/10/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
Although major depressive disorder (MDD) is a leading cause of disability worldwide, its pathophysiology is poorly understood. Increasing evidence suggests that aberrant regulation of transcription plays a key role in the pathophysiology of MDD. Recently, long noncoding RNAs (lncRNAs) have been recognized for their important functions in chromatin structure, gene expression, and the subsequent manifestation of various biological processes in the central nervous system. However, it is unclear whether the aberrant expression and function of lncRNAs are associated with the pathophysiology of MDD. In this study, we sought to evaluate the expression of lncRNAs in peripheral blood leukocytes as potential biomarkers for MDD. We measured the expression levels of 83 lncRNAs in the peripheral blood leukocytes of 29 MDD patients and 29 age- and gender-matched healthy controls using quantitative reverse transcription PCR (RT-qPCR) analysis. We found that MDD patients exhibited distinct expression signatures. Specifically, the expression level of one lncRNA (RMRP) was lower while the levels of four (Y5, MER11C, PCAT1, and PCAT29) were higher in MDD patients compared to healthy controls. The expression level of RMRP was correlated with depression severity as measured by the Hamilton Depression Rating Scale (HAM-D). Moreover, RMRP expression was lower in a mouse model of depression, corroborating the observation from MDD patients. Taken together, our data suggest that lower RMRP levels may serve as a potential biomarker for MDD.
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Affiliation(s)
- Tomoe Seki
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
| | - Hirotaka Yamagata
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
| | - Shusaku Uchida
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
| | - Chong Chen
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Ayumi Kobayashi
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Masaaki Kobayashi
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Kenichiro Harada
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Koji Matsuo
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Yoshifumi Watanabe
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shin Nakagawa
- Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan
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Grinman E, Espadas I, Puthanveettil SV. Emerging roles for long noncoding RNAs in learning, memory and associated disorders. Neurobiol Learn Mem 2019; 163:107034. [DOI: 10.1016/j.nlm.2019.107034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 05/03/2019] [Accepted: 06/05/2019] [Indexed: 12/13/2022]
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Antoniuk S, Bijata M, Ponimaskin E, Wlodarczyk J. Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neurosci Biobehav Rev 2019; 99:101-116. [DOI: 10.1016/j.neubiorev.2018.12.002] [Citation(s) in RCA: 466] [Impact Index Per Article: 77.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 12/03/2018] [Accepted: 12/03/2018] [Indexed: 01/01/2023]
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RNA-Sequencing and Bioinformatics Analysis of Long Noncoding RNAs and mRNAs in the Prefrontal Cortex of Mice Following Repeated Social Defeat Stress. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7505260. [PMID: 31032362 PMCID: PMC6457290 DOI: 10.1155/2019/7505260] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/01/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023]
Abstract
Background Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. Main Methods RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. Key Findings In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. Significance Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.
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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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Schurz H, Kinnear CJ, Gignoux C, Wojcik G, van Helden PD, Tromp G, Henn B, Hoal EG, Möller M. A Sex-Stratified Genome-Wide Association Study of Tuberculosis Using a Multi-Ethnic Genotyping Array. Front Genet 2019; 9:678. [PMID: 30713548 PMCID: PMC6346682 DOI: 10.3389/fgene.2018.00678] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 12/06/2018] [Indexed: 11/13/2022] Open
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males than in females. While socio-economic status, behavior and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. A total of 810 individuals (410 cases and 405 controls) from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome (8,27,386 variants) and X chromosome (20,939 variants) in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.
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Affiliation(s)
- Haiko Schurz
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Tuberculosis Bioinformatics Initiative, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Craig J. Kinnear
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Chris Gignoux
- Colorado Center for Personalized Medicine, Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Genevieve Wojcik
- Department of Genetics, Stanford University, Stanford, CA, United States
| | - Paul D. van Helden
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Gerard Tromp
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Tuberculosis Bioinformatics Initiative, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Centre for Bioinformatics and Computational Biology, Stellenbosch University, Cape Town, South Africa
| | - Brenna Henn
- Department of Anthropology, UC Davis Genome Center, University of California, Davis, Davis, CA, United States
| | - Eileen G. Hoal
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Marlo Möller
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Menezes IC, von Werne Baes C, Lacchini R, Juruena MF. Genetic biomarkers for differential diagnosis of major depressive disorder and bipolar disorder: A systematic and critical review. Behav Brain Res 2019; 357-358:29-38. [PMID: 29331712 DOI: 10.1016/j.bbr.2018.01.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 09/20/2017] [Accepted: 01/08/2018] [Indexed: 02/05/2023]
Abstract
Depressive symptoms are present in the depressive mood state of bipolar disorder (BPD) and major depression disorder (MDD). Often, in clinical practice, BPD patients are misdiagnosed with MDD. Therefore, genetic biomarkers could contribute to the improvement of differential diagnosis between BPD and MDD. This systematic and critical review aimed to find in literature reliable genetic biomarkers that may show differences between BPD and MDD. This systematic review followed the PRISMA-P method. The terms used to search PubMed, Scopus, PsycINFO, and Web of Science were depress*, bipolar, diagnos*, genetic*, biomark*. After applying the selection criteria, N = 27 studies were selected, being n = 9 about biomarkers for BPD; n = 15, about MDD; and n = 3 for distinguishing MDD from BPD. A total of N = 3086 subjects were assessed in the selected studies (n = 486 in BPD group; n = 1212 in MDD group; and n = 1388, healthy control group). The articles were dated up to June 2017. Of the N = 27 studies, n = 16 assessed gene, n = 1 miRNA, n = 2 lcnRNA and n = 3 protein expressions, n = 4 methylation, and n = 4 polymorphisms. Some studies applied more than one of these genetic analyses. To find reliable genetic biomarkers we have taken into account the methodological care during the studies development and their validity. The genetic biomarkers selected are related to genes that play a fundamental role in synaptic plasticity, neurogenesis, mood control, brain ageing, immune-inflammatory processes and mitochondrial respiratory chain. BDNF gene expression was one of the genetic biomarkers that highlighted because of its capacity of distinguishing BPD and MDD groups, and being adequately reproduced by more than one selected study.
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Affiliation(s)
- Itiana Castro Menezes
- Stress and Affective Disorders (SAD) Programme, Department of Neurosciences and Behavior, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil
| | - Cristiane von Werne Baes
- Stress and Affective Disorders (SAD) Programme, Department of Neurosciences and Behavior, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil
| | - Riccardo Lacchini
- Departament of Psychiatric Nursing and Human Sciences, College of Nursing of Ribeirão Preto, University of Sao Paulo, Brazil
| | - Mario Francisco Juruena
- Stress and Affective Disorders (SAD) Programme, Department of Neurosciences and Behavior, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil; Centre for Affective Disorders, Psychological Medicine, King's College London, UK.
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Azizi Z, Mirtavoos-Mahyari H, Karimi R, Noroozi Z, Motevaseli E. Long non-coding RNAs: Diverse roles in various disorders. Hum Antibodies 2019; 27:221-225. [PMID: 30909207 DOI: 10.3233/hab-190374] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are a group of transcripts larger than 200 nucleotides that are not translated to proteins. These transcripts regulate expression of numerous genes at different levels by acting as decoys, scaffolds, and enhancers. Thus they regulate cell development, differentiation and fate. OBJECTIVE To find the role of lncRNAs in various diseases. METHODS We searched PubMed and google scholar and summarized the data regarding the role of lncRNAs in cancer and neurologic disorders. RESULTS Several recent studies have shown that their expressions are up-/down-regulated in malignant tissues. Consequently, they have suggested that lncRNAs can differentiate cancer samples from normal samples. Their application as biomarker is not limited to cancers. In several neurologic or psychiatric disorders researchers have found aberrant expression of lncRNAs. CONCLUSIONS Taken together, lncRNAs constitute a novel vast area of research to find answer to fundamental biologic questions.
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Affiliation(s)
- Zahra Azizi
- Department of Molecular Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanifeh Mirtavoos-Mahyari
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Roya Karimi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Noroozi
- Department of Molecular Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Naghavi-Gargari B, Zahirodin A, Ghaderian SMH, Shirvani-Farsani Z. Significant increasing of DISC2 long non-coding RNA expression as a potential biomarker in bipolar disorder. Neurosci Lett 2018; 696:206-211. [PMID: 30599263 DOI: 10.1016/j.neulet.2018.12.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 12/07/2018] [Accepted: 12/28/2018] [Indexed: 11/18/2022]
Abstract
Bipolar disorder (BD) is a mental disorder that is often misdiagnosed with ineffective treatment. It has strong genetic component but unknown pathophysiology. Long non-coding RNAs (lncRNAs) have been recently recognized as one of the important genetic factors and are considered as one of the regulatory mechanisms of nervous system. Given that lncRNAs may be diagnostic biomarkers for BD, we aimed to quantify the levels of DISC1 and DISC2 lncRNA transcripts. The levels of DISC1 and DISC2 lncRNA were tested in peripheral blood mononuclear cells (PBMCs) of 50 BD and 50 controls by real-time PCR. In addition, we performed ROC curve analysis as well as correlation analysis between the gene expression and some clinical features of BD cases. Computational analysis of miRNAs binding sites and CpG Islands on DISC1 and DISC2 lncRNA was performed as well. Significant down-regulation of DISC1 and up-regulation of DISC2 were observed in BD cases compared with controls. The areas under the ROC curve (AUC) for DISC1 and DISC2 lncRNA were 0.76 and 0.68 respectively. There was no significant correlation between the levels of mRNA expression in PBMCs of BD patients and clinical features. These data demonstrated that DISC1 and DISC2 lncRNA expression was potentially associated with an increased risk of bipolar disorder and might involve several molecular mechanisms. Our results revealed that the transcript levels of DISC1 and DISC2 lncRNA could be considered as a good putative biomarker for individuals with bipolar disorder.
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Affiliation(s)
- Bahar Naghavi-Gargari
- Department of Basic Science, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Alireza Zahirodin
- Behavioral Science Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | | | - Zeinab Shirvani-Farsani
- Department of Cellular and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G.C., Tehran, Islamic Republic of Iran.
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