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1
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Zhou G, Zheng S, Xu Y. Molecular Insights into Propofol's Neurotoxic Effects: Targeting the HTR1A/cAMP Signaling Pathway. Chem Res Toxicol 2025; 38:561-572. [PMID: 40168001 DOI: 10.1021/acs.chemrestox.4c00339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Propofol, a commonly used anesthetic in clinical practice, is favored for its rapid onset and short duration of action. Despite its widespread use, the potential neurotoxic effects of propofol remain insufficiently understood. This study utilized high-throughput transcriptome sequencing and network pharmacology to investigate the mechanisms by which propofol induces neurotoxicity in rat hippocampal neural progenitor cells (NPCs), focusing on the HTR1A/cAMP signaling pathway. Our findings reveal that propofol significantly inhibits the HTR1A/cAMP pathway, leading to altered expression of key genes that affect neuronal activity, inflammatory responses, and apoptosis. In vivo experiments further demonstrate that propofol impairs spatial learning and memory in rats, an effect that is partially reversed by overexpression of HTR1A. These results not only elucidate the molecular mechanisms underlying propofol-induced neuronal damage but also provide critical insights into the safe application of propofol in clinical settings.
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Affiliation(s)
- Gongrui Zhou
- Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu 610083, China
| | - Shubin Zheng
- Department of Anesthesiology, Air Force Medical Center, Beijing 100142, China
| | - Yuhai Xu
- Department of Anesthesiology, Air Force Medical Center, Beijing 100142, China
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2
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Cătană CS, Marta MM, Ungureanu D, Crișan CA. MicroRNAs: A Novel Approach for Monitoring Treatment Response in Major Depressive Disorder? Noncoding RNA 2025; 11:21. [PMID: 40126345 PMCID: PMC11932203 DOI: 10.3390/ncrna11020021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/14/2025] [Accepted: 03/02/2025] [Indexed: 03/25/2025] Open
Abstract
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders, with an increasing incidence each year and an important socioeconomic burden. Although new treatments are continuously being developed, there is no effective monitoring method to determine the suitability of treatment and ensure positive outcomes. Therefore, patients often struggle with ineffective antidepressants and their potential adverse effects, which halts any future progress in managing the disorder. Considering the potential of microRNAs (miRNAs) as biomarkers for various pathologies and the increasing evidence of the modulation of several genes involved in MDD, this minireview aimed to evaluate the literature data on the impact of miRNAs in MDD and their usefulness in monitoring treatment response. The correlations between antidepressants and the expression of several miRNAs support the existence of a common epigenetic mechanism of antidepressants and explain the epigenetic differences influencing treatment efficacy in MDD.
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Affiliation(s)
- Cristina-Sorina Cătană
- Department of Medical Biochemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Monica Mihaela Marta
- Department of Medical Education, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
| | - Daniel Ungureanu
- Department of Pharmaceutical Chemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania
- “Prof. Dr. Ion Chiricuță” Institute of Oncology, 34–36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Cătălina-Angela Crișan
- Department of Psychiatry and Pediatric Psychiatry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania;
- First Psychiatric Clinic, Cluj County Emergency Hospital, 43 Victor Babeș Street, 400012 Cluj-Napoca, Romania
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Chen CY, Wang YF, Lei L, Zhang Y. MicroRNA-specific targets for neuronal plasticity, neurotransmitters, neurotrophic factors, and gut microbes in the pathogenesis and therapeutics of depression. Prog Neuropsychopharmacol Biol Psychiatry 2025; 136:111186. [PMID: 39521033 DOI: 10.1016/j.pnpbp.2024.111186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/11/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
Depression is of great concern because of the huge burden, and it is impacted by various epigenetic modifications, e.g., histone modification, covalent modifications in DNA, and silencing mechanisms of non-coding protein genes, e.g., microRNAs (miRNAs). MiRNAs are a class of endogenous non-coding RNAs. Alternations in specific miRNAs have been observed both in depressive patients and experimental animals. Also, miRNAs are highly expressed in the central nervous system and can be delivered to different tissues via tissue-specific exosomes. However, the mechanism of miRNAs' involvement in the pathological process of depression is not well understood. Therefore, we summarized and discussed the role of miRNAs in depression. Conclusively, miRNAs are involved in the pathology of depression by causing structural and functional changes in synapses, mediating neuronal regeneration, differentiation, and apoptosis, regulating the gut microbes and the expression of various neurotransmitters and BDNF, and mediating inflammatory and immune responses. Moreover, miRNAs can predict the efficacy of antidepressant medications and explain the mechanism of action of antidepressant drugs and aerobic exercise to prevent and assist in treating depression.
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Affiliation(s)
- Cong-Ya Chen
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu-Fei Wang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Lan Lei
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
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4
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Wang Y, Gu L, Zhang H, Wang J, Wang X, Li Y, Chai S, Xu C. Therapeutic potential of mackerel-derived peptides and the synthetic tetrapeptide TVGF for sleep disorders in a light-induced anxiety zebrafish model. Front Pharmacol 2024; 15:1475432. [PMID: 39600360 PMCID: PMC11589825 DOI: 10.3389/fphar.2024.1475432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
Introduction Anxiety-like insomnia is a known risk factor for the onset and worsening of certain neurological diseases, including Alzheimer's disease. Due to the adverse effects of current anti-insomnia medications, such as drug dependence and limited safety, researchers are actively exploring natural bioactive compounds to mitigate anxiety-like insomnia with fewer side effects. Mackerel (Pneumatophorus japonicus), a traditional Chinese medicine, is known for its tonic effects and is commonly used to treat neurasthenia. The use of mackerel protein extract has been shown to effectively improve symptoms of light-induced anxiety-like insomnia in a zebrafish model. Methods This study examines the effects of mackerel bone peptides (MW < 1 kDa, MBP1) and the synthetic peptide Thr-Val-Gly-Phe (TVGF) on light-induced anxiety-like insomnia in zebrafish. The evaluation is conducted through behavioral observation, biochemical marker analysis, and gene transcriptome profiling. Results MBP1 significantly alleviated abnormal hyperactivity and restored neurotransmitter levels (dopamine and γ-aminobutyric acid) to normal. Moreover, it mitigated oxidative stress by reducing reactive oxygen species production and malonaldehyde levels, while enhancing antioxidant enzyme activities (superoxide dismutase and catalase). This was further attributed to the regulation of lipid accumulation and protein homeostasis. Furthermore, MBP1 ameliorated sleep disturbances primarily by restoring normal expression levels of genes involved in circadian rhythm (per2 and sik1) and visual function (opn1mw2, zgc:73075, and arr3b). Molecular docking analysis indicated that TVGF exhibited good affinity for receptors linked to sleep disturbances, including IL6, HTR1A, and MAOA. TVGF exhibited sedative effects in behavioral assays, mainly mediated by regulating the normal expression of genes associated with circadian rhythm (cry1bb, cry1ba, per2, per1b and sik1), visual function (opn1mw1, gnb3b, arr3b, gnat2), purine metabolism (pnp5a), and stress recovery (fkbp5). Discussion These findings suggest that MBP1 and TVGF could be promising therapies for light-induced anxiety-like insomnia in humans, offering safer alternatives to current medications. Additionally, the regulation of genes related to circadian rhythm and visual perception may be a key mechanism by which MBP1 and TVGF effectively relieve anxiety-like insomnia.
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Affiliation(s)
- Yang Wang
- Department of Pharmacy, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Lei Gu
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Haijing Zhang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Junbao Wang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Xichang Wang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
- R&D department, Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai, China
- R&D department, Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation, Ministry of Agriculture, Shanghai, China
- R&D department, National R&D Branch Center for Freshwater Aquatic Products Processing Technology, Shanghai, China
| | - Yu Li
- Department of Pharmacy, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shiwei Chai
- Department of Pharmacy, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Changhua Xu
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
- R&D department, Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai, China
- R&D department, Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation, Ministry of Agriculture, Shanghai, China
- R&D department, National R&D Branch Center for Freshwater Aquatic Products Processing Technology, Shanghai, China
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Luan X, Xing H, Guo F, Liu W, Jiao Y, Liu Z, Wang X, Gao S. The role of ncRNAs in depression. Heliyon 2024; 10:e27307. [PMID: 38496863 PMCID: PMC10944209 DOI: 10.1016/j.heliyon.2024.e27307] [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: 06/29/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/19/2024] Open
Abstract
Depressive disorders have a significant impact on public health, and depression have an unsatisfactory recurrence rate and are challenging to treat. Non-coding RNAs (ncRNAs) are RNAs that do not code protein, which have been shown to be crucial for transcriptional regulation. NcRNAs are important to the onset, progress and treatment of depression because they regulate various physiological functions. This makes them distinctively useful as biomarkers for diagnosing and tracking responses to therapy among individuals with depression. It is important to seek out and summarize the research findings on the impact of ncRNAs on depression since significant advancements have been made in this area recently. Hence, we methodically outlined the findings of published researches on ncRNAs and depression, focusing on microRNAs. Above all, this review aims to improve our understanding of ncRNAs and provide new insights of the diagnosis and treatment of depression.
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Affiliation(s)
- Xinchi Luan
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Han Xing
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Feifei Guo
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Weiyi Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Yang Jiao
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Zhenyu Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Xuezhe Wang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Shengli Gao
- Biomedical Center, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
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Kaurani L. Clinical Insights into MicroRNAs in Depression: Bridging Molecular Discoveries and Therapeutic Potential. Int J Mol Sci 2024; 25:2866. [PMID: 38474112 PMCID: PMC10931847 DOI: 10.3390/ijms25052866] [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: 01/31/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Depression is a major contributor to the overall global burden of disease. The discovery of biomarkers for diagnosis or prediction of treatment responses and as therapeutic agents is a current priority. Previous studies have demonstrated the importance of short RNA molecules in the etiology of depression. The most extensively researched of these are microRNAs, a major component of cellular gene regulation and function. MicroRNAs function in a temporal and tissue-specific manner to regulate and modify the post-transcriptional expression of target mRNAs. They can also be shuttled as cargo of extracellular vesicles between the brain and the blood, thus informing about relevant mechanisms in the CNS through the periphery. In fact, studies have already shown that microRNAs identified peripherally are dysregulated in the pathological phenotypes seen in depression. Our article aims to review the existing evidence on microRNA dysregulation in depression and to summarize and evaluate the growing body of evidence for the use of microRNAs as a target for diagnostics and RNA-based therapies.
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Affiliation(s)
- Lalit Kaurani
- Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany
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Carneiro BA, Franco Guerreiro-Costa LN, Lins-Silva D, Faria Guimaraes D, Souza LS, Leal GC, Caliman-Fontes AT, Beanes G, Costa RDS, Quarantini LC. MicroRNAs as Diagnostic Biomarkers and Predictors of Antidepressant Response in Major Depressive Disorder: A Systematic Review. Cureus 2024; 16:e56910. [PMID: 38665721 PMCID: PMC11043793 DOI: 10.7759/cureus.56910] [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] [Accepted: 03/16/2024] [Indexed: 04/28/2024] Open
Abstract
Despite the hardships of major depressive disorder (MDD), biomarkers for the diagnosis and pharmacological management of this condition are lacking. MicroRNAs are epigenetic mechanisms that could provide promising MDD biomarkers. Our aim was to summarize the findings and provide validation for the selection and use of specific microRNAs as biomarkers in the diagnosis and treatment of MDD. A systematic review was conducted using the PubMed/Medline, Cochrane, PsycINFO, Embase, and LILACS databases from March 2022 to November 2023, with clusters of terms based on "microRNA" and "antidepressant". Studies involving human subjects, animal models, and cell cultures were included, whereas those that evaluated herbal medicines, non-pharmacological therapies, or epigenetic mechanisms other than miRNA were excluded. The review revealed differences in the expression of various microRNAs when considering the time of assessment (before or after antidepressant treatment) and the population studied. However, due to the heterogeneity of the microRNAs investigated, the limited size of the samples, and the wide variety of antidepressants used, few conclusions could be made. Despite the observed heterogeneity, the following microRNAs were determined to be important factors in MDD and the antidepressant response: mir-1202, mir-135, mir-124, and mir-16. The findings indicate the potential for the use of microRNAs as biomarkers for the diagnosis and treatment of MDD; however, more homogeneous studies are needed.
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Affiliation(s)
- Beatriz A Carneiro
- Medicine, Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BRA
| | | | - Daniel Lins-Silva
- Medicine, Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BRA
| | - Daniela Faria Guimaraes
- Medicine, Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BRA
| | - Lucca S Souza
- Medicine, Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BRA
| | - Gustavo C Leal
- Medicine, Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, BRA
| | - Ana Teresa Caliman-Fontes
- Medicine, Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, BRA
| | - Graziele Beanes
- Medicine, Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria do Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BRA
| | - Ryan Dos S Costa
- Medicine, Laboratório de Imunofarmacologia e Biologia Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BRA
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Azargoonjahromi A. The role of epigenetics in anxiety disorders. Mol Biol Rep 2023; 50:9625-9636. [PMID: 37804465 DOI: 10.1007/s11033-023-08787-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/30/2023] [Indexed: 10/09/2023]
Abstract
Anxiety disorders (ADs) are extremely common psychiatric conditions that frequently co-occur with other physical and mental disorders. The pathophysiology of ADs is multifaceted and involves intricate connections among biological elements, environmental stimuli, and psychological mechanisms. Recent discoveries have highlighted the significance of epigenetics in bridging the gap between multiple risk factors that contribute to ADs and expanding our understanding of the pathomechanisms underlying ADs. Epigenetics is the study of how changes in the environment and behavior can have an impact on gene function. Indeed, researchers have found that epigenetic mechanisms can affect how genes are activated or inactivated, as well as whether they are expressed. Such mechanisms may also affect how ADs form and are protected. That is, the bulk of pharmacological trials evaluating epigenetic treatments for the treatment of ADs have used histone deacetylase inhibitors (HDACi), yielding promising outcomes in both preclinical and clinical studies. This review will provide an outline of how epigenetic pathways can be used to treat ADs or lessen their risk. It will also present the findings from preclinical and clinical trials that are currently available on the use of epigenetic drugs to treat ADs.
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9
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Li S, Huang Q, Yang Q, Peng X, Wu Q. MicroRNAs as promising therapeutic agents: A perspective from acupuncture. Pathol Res Pract 2023; 248:154652. [PMID: 37406378 DOI: 10.1016/j.prp.2023.154652] [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: 06/02/2023] [Revised: 06/24/2023] [Accepted: 06/25/2023] [Indexed: 07/07/2023]
Abstract
MicroRNAs (miRNAs) are gaining recognition as potential therapeutic agents due to their small size, ability to target a wide range of genes, and significant role in disease progression. However, despite their promising potential, nearly half of the miRNA drugs developed for therapeutic purposes have been discontinued or put on hold, and none have advanced to phase III clinical trials. The development of miRNA therapeutics has faced obstacles such as difficulties in validating miRNA targets, conflicting evidence regarding competition and saturation effects, challenges in miRNA delivery, and determining appropriate dosages. These hurdles primarily arise from the intricate functional complexity of miRNAs. Acupuncture, a distinct, complementary therapy, offers a promising avenue to overcome these barriers, particularly by addressing the fundamental issue of preserving functional complexity through acupuncture regulatory networks. The acupuncture regulatory network consists of three main components: the acupoint network, the neuro-endocrine-immune (NEI) network, and the disease network. These networks represent the processes of information transformation, amplification, and conduction that occur during acupuncture. Notably, miRNAs serve as essential mediators and shared biological language within these interconnected networks. Harnessing the therapeutic potential of acupuncture-derived miRNAs can help reduce the time and economic resources required for miRNA drug development and alleviate the current developmental challenges miRNA therapeutics face. This review provides an interdisciplinary perspective by summarizing the interactions between miRNAs, their targets, and the three acupuncture regulatory networks mentioned earlier. The aim is to illuminate the challenges and opportunities in developing miRNA therapeutics. This review paper presents a comprehensive overview of miRNAs, their interactions with acupuncture regulatory networks, and their potential as therapeutic agents. By bridging the miRNA research and acupuncture fields, we aim to offer valuable insights into the obstacles and prospects of developing miRNA therapeutics.
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Affiliation(s)
- Sihui Li
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China
| | - Qianhui Huang
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China
| | - Qingqing Yang
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China
| | - Xiaohua Peng
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China
| | - Qiaofeng Wu
- Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China; Acupuncture & Chronobiology Key Laboratory of Sichuan Province, Chengdu, Sichuan 610075, China; Institute of Acupuncture and Homeostasis Regulation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China.
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10
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Favoretto CA, Pagliusi M, Morais-Silva G. Involvement of brain cell phenotypes in stress-vulnerability and resilience. Front Neurosci 2023; 17:1175514. [PMID: 37476833 PMCID: PMC10354562 DOI: 10.3389/fnins.2023.1175514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/19/2023] [Indexed: 07/22/2023] Open
Abstract
Stress-related disorders' prevalence is epidemically increasing in modern society, leading to a severe impact on individuals' well-being and a great economic burden on public resources. Based on this, it is critical to understand the mechanisms by which stress induces these disorders. The study of stress made great progress in the past decades, from deeper into the hypothalamic-pituitary-adrenal axis to the understanding of the involvement of a single cell subtype on stress outcomes. In fact, many studies have used state-of-the-art tools such as chemogenetic, optogenetic, genetic manipulation, electrophysiology, pharmacology, and immunohistochemistry to investigate the role of specific cell subtypes in the stress response. In this review, we aim to gather studies addressing the involvement of specific brain cell subtypes in stress-related responses, exploring possible mechanisms associated with stress vulnerability versus resilience in preclinical models. We particularly focus on the involvement of the astrocytes, microglia, medium spiny neurons, parvalbumin neurons, pyramidal neurons, serotonergic neurons, and interneurons of different brain areas in stress-induced outcomes, resilience, and vulnerability to stress. We believe that this review can shed light on how diverse molecular mechanisms, involving specific receptors, neurotrophic factors, epigenetic enzymes, and miRNAs, among others, within these brain cell subtypes, are associated with the expression of a stress-susceptible or resilient phenotype, advancing the understanding/knowledge on the specific machinery implicate in those events.
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Affiliation(s)
- Cristiane Aparecida Favoretto
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil
| | - Marco Pagliusi
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Gessynger Morais-Silva
- Laboratory of Pharmacology, Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
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Amini J, Beyer C, Zendedel A, Sanadgol N. MAPK Is a Mutual Pathway Targeted by Anxiety-Related miRNAs, and E2F5 Is a Putative Target for Anxiolytic miRNAs. Biomolecules 2023; 13:biom13030544. [PMID: 36979479 PMCID: PMC10046777 DOI: 10.3390/biom13030544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/07/2023] [Accepted: 03/12/2023] [Indexed: 03/19/2023] Open
Abstract
Anxiety-related disorders (ARDs) are chronic neuropsychological diseases and the sixth leading cause of disability in the world. As dysregulation of microRNAs (miRs) are observed in the pathological course of neuropsychiatric disorders, the present study aimed to introduce miRs that underlie anxiety processing in the brain. First, we collected the experimentally confirmed anxiety-related miRNAs (ARmiRs), predicted their target transcripts, and introduced critical cellular pathways with key commune hub genes. As a result, we have found nine anxiolytic and ten anxiogenic ARmiRs. The anxiolytic miRs frequently target the mRNA of Acyl-CoA synthetase long-chain family member 4 (Acsl4), AFF4-AF4/FMR2 family member 4 (Aff4), and Krüppel like transcription factor 4 (Klf4) genes, where miR-34b-5p and miR-34c-5p interact with all of them. Moreover, the anxiogenic miRs frequently target the mRNA of nine genes; among them, only two miR (miR-142-5p and miR-218-5p) have no interaction with the mRNA of trinucleotide repeat-containing adaptor 6B (Tnrc6b), and miR-124-3p interacts with all of them where MAPK is the main signaling pathway affected by both anxiolytic and anxiogenic miR. In addition, the anxiolytic miR commonly target E2F transcription factor 5 (E2F5) in the TGF-β signaling pathway, and the anxiogenic miR commonly target Ataxin 1 (Atxn1), WASP-like actin nucleation promoting factor (Wasl), and Solute Carrier Family 17 Member 6 (Slc17a6) genes in the notch signaling, adherence junction, and synaptic vesicle cycle pathways, respectively. Taken together, we conclude that the most important anxiolytic (miR-34c, Let-7d, and miR-17) and anxiogenic (miR-19b, miR-92a, and 218) miR, as hub epigenetic modulators, potentially influence the pathophysiology of anxiety, primarily via interaction with the MAPK signaling pathway. Moreover, the role of E2F5 as a novel putative target for anxiolytic miRNAs in ARDs disorders deserves further exploration.
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Affiliation(s)
- Javad Amini
- Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Cordian Beyer
- Institute of Neuroanatomy, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Adib Zendedel
- Institute of Neuroanatomy, RWTH University Hospital Aachen, 52074 Aachen, Germany
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Nima Sanadgol
- Institute of Neuroanatomy, RWTH University Hospital Aachen, 52074 Aachen, Germany
- Correspondence:
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Hu L, Wang J, Wu N, Zhao X, Cai D. Utilizing network pharmacology and experimental validation to investigate the underlying mechanism of phellodendrine on inflammation. PeerJ 2022; 10:e13852. [PMID: 36172495 PMCID: PMC9512003 DOI: 10.7717/peerj.13852] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/16/2022] [Indexed: 01/18/2023] Open
Abstract
Background Phellodendrine, one of the characteristic and important active components of Cortex phellodendri, has been proven to show anti-inflammatory effects. However, the underlying mechanism of phellodendrine on inflammation remains largely unclear. Aim of the study In this study, network pharmacology and experimental validation were used to explore the underlying mechanism of phellodendrine on inflammation. Materials and Methods PubChem and SwissADME database were used to evaluate the drug-likeness and other characteristics of phellodendrine. The targets of phellodendrine for the treatment of inflammation were analyzed with multiple databases. Other extensive analyses including protein-protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were accomplished with the STRING database, Cytoscape software, and DAVID database. Moreover, the effect of phellodendrine on anti-inflammation was proven in RAW264.7. Results The network pharmacology results indicated that phellodendrine had drug potential. Phellodendrine acted directly on 12 targets, including PTGS1, PTGS2, HTR1A, and PIK3CA, and then regulated cAMP, estrogen, TNF, serotonergic synapse, and other signaling pathways to exert anti-inflammatory effects. The experimental results showed that phellodendrine reduced the levels of IL-6 compared with the LPS group in 24 h and changed the mRNA expression of PTGS1, PTGS2, HSP90ab1, AKT1, HTR1A, PI3CA, and F10. Conclusion Our research preliminarily uncovered the therapeutic mechanisms of phellodendrine on inflammation with multiple targets and pathways. Phellodendrine may be a potential treatment for inflammation-related diseases related to the cAMP and TNF signaling pathways.
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Affiliation(s)
- Lili Hu
- Shanxi University of Chinese Medicine, Jinzhong, China
| | - Jue Wang
- Shanxi University of Chinese Medicine, Jinzhong, China
| | - Na Wu
- Shanxi University of Chinese Medicine, Jinzhong, China
| | | | - Donghui Cai
- Shanxi University of Chinese Medicine, Jinzhong, China
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13
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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14
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Ortega MA, Alvarez-Mon MA, García-Montero C, Fraile-Martinez O, Lahera G, Monserrat J, Muñoz-Merida L, Mora F, Rodríguez-Jiménez R, Fernandez-Rojo S, Quintero J, Álvarez-Mon M. MicroRNAs as Critical Biomarkers of Major Depressive Disorder: A Comprehensive Perspective. Biomedicines 2021; 9:biomedicines9111659. [PMID: 34829888 PMCID: PMC8615526 DOI: 10.3390/biomedicines9111659] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/23/2022] Open
Abstract
Major Depressive Disorder (MDD) represents a major global health concern, a body-mind malady of rising prevalence worldwide nowadays. The complex network of mechanisms involved in MDD pathophysiology is subjected to epigenetic changes modulated by microRNAs (miRNAs). Serum free or vesicles loaded miRNAs have starred numerous publications, denoting a key role in cell-cell communication, systematically and in brain structure and neuronal morphogenesis, activity and plasticity. Upregulated or downregulated expression of these signaling molecules may imply the impairment of genes implicated in pathways of MDD etiopathogenesis (neuroinflammation, brain-derived neurotrophic factor (BDNF), neurotransmitters, hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, circadian rhythms...). In addition, these miRNAs could serve as potential biomarkers with diagnostic, prognostic and predictive value, allowing to classify severity of the disease or to make decisions in clinical management. They have been considered as promising therapy targets as well and may interfere with available antidepressant treatments. As epigenetic malleable regulators, we also conclude emphasizing lifestyle interventions with physical activity, mindfulness and diet, opening the door to new clinical management considerations.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain; (F.M.); (S.F.-R.); (J.Q.)
| | - Miguel Angel Alvarez-Mon
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Department of Psychiatry and Mental Health, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain
- Correspondence:
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Guillermo Lahera
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Psychiatry Service, Center for Biomedical Research in the Mental Health Network, University Hospital Príncipe de Asturias, 28806 Alcalá de Henares, Spain
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Luis Muñoz-Merida
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
| | - Fernando Mora
- Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain; (F.M.); (S.F.-R.); (J.Q.)
- Department of Legal Medicine and Psychiatry, Complutense University, 28040 Madrid, Spain;
| | - Roberto Rodríguez-Jiménez
- Department of Legal Medicine and Psychiatry, Complutense University, 28040 Madrid, Spain;
- Institute for Health Research Hospital 12 de Octubre (imas 12), CIBERSAM, 28041 Madrid, Spain
| | - Sonia Fernandez-Rojo
- Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain; (F.M.); (S.F.-R.); (J.Q.)
- Department of Legal Medicine and Psychiatry, Complutense University, 28040 Madrid, Spain;
| | - Javier Quintero
- Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain; (F.M.); (S.F.-R.); (J.Q.)
- Department of Legal Medicine and Psychiatry, Complutense University, 28040 Madrid, Spain;
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcalá de Henares, Spain; (M.A.O.); (C.G.-M.); (O.F.-M.); (G.L.); (J.M.); (L.M.-M.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine, University Hospital Príncipe de Asturias, (CIBEREHD), 28806 Alcalá de Henares, Spain
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Early life and adult stress promote sex dependent changes in hypothalamic miRNAs and environmental enrichment prevents stress-induced miRNA and gene expression changes in rats. BMC Genomics 2021; 22:701. [PMID: 34583641 PMCID: PMC8480023 DOI: 10.1186/s12864-021-08003-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 09/13/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The hypothalamus plays a key role in the stress response. While early life stress (ELS) increases susceptibility to psychiatric disorders including major depressive disorder (MDD), acute stress during adulthood can also precipitate MDD after ELS. AIM Here, we tested the expression of miRNAs following ELS and susceptibility to depression-like behavior and whether sex or acute stress exacerbates this response. We also tested whether environmental enrichment (Enr) promotes early life and adult behavioral stress resilience and its effect on hypothalamic miRNA and gene expression. Following rat maternal separation (MS) as an ELS model, Enr from weaning through adulthood, and restraint (RS) as acute adult stress, we tested both animal behavior and miRNA expression in the hypothalamus. Target genes and their enrichment and ontology were analyzed using bioinformatic tools. Target gene expression changes were tested using qPCR, and miRNA promoter methylation was studied using methylated-DNA immunoprecipitation qPCR. RESULTS MS, Enr, RS, and sex altered hypothalamic miRNAs, including several previously reported in MS literature: miRs-29, - 124, - 132, - 144, - 504. Sex had a significant effect on the greatest number of miRNAs. Also, Enr reversed downregulation of miR-29b-1-5p and -301b-3p in MS. qPCR showed that MAPK6 and MMP19, targets of miR-301b-3p, were upregulated in MS and reversed by Enr. Additionally, miR-219a was hypermethylated in MS coinciding with decreased miR-219a expression. CONCLUSIONS This study found that sex plays a critical role in the hypothalamic miRNA response to both ELS and acute stress, with males expressing greater changes following postnatal stress. Moreover, enrichment significantly altered behavior as well as hypothalamic miRNA expression and their gene targets. Because of its role as the initiator of the autonomic stress response and connection to hedonic and motivational behavior, the hypothalamic miRNA landscape may significantly alter both the short and long-term behavioral response to stress.
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MicroRNA Regulates Early-Life Stress–Induced Depressive Behavior via Serotonin Signaling in a Sex-Dependent Manner in the Prefrontal Cortex of Rats. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2021; 1:180-189. [PMID: 36325302 PMCID: PMC9616342 DOI: 10.1016/j.bpsgos.2021.05.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/06/2021] [Accepted: 05/23/2021] [Indexed: 01/01/2023] Open
Abstract
Background The underlying neurobiology of early-life stress (ELS)-induced major depressive disorder is not clearly understood. Methods In this study, we used maternal separation (MS) as a rodent model of ELS and tested whether microRNAs (miRNAs) target serotonin genes to regulate ELS-induced depression-like behavior and whether this effect is sex dependent. We also examined whether environmental enrichment prevents susceptibility to depression- and anxiety-like behavior following MS and whether enrichment effects are mediated through serotonin genes and their corresponding miRNAs. Results MS decreased sucrose preference, which was reversed by enrichment. Males also exhibited greater changes in forced swim climbing and escape latency tests only following enrichment. Slc6a4 and Htr1a were upregulated in the frontal cortex following MS. In male MS rats, enrichment slightly reversed Htr1a expression to levels similar to control rats. miR-200a-3p and miR-322-5p, which target SLC6A4, were decreased by MS, but not significantly. An HTR1A-targeting miRNA, miR-320-5p, was also downregulated by MS and showed slight reversal by enrichment in male animals. miR-320-5p targeting of Htr1a was validated in vitro using SHSY neuroblastoma cell lines. Conclusions Altogether, this study implicates miRNA interaction with the serotonin pathway in ELS-induced susceptibility to depression-related reward deficits. Furthermore, because of its recovery by enrichment in males, miR-320 may represent a viable sex-specific target for reward-related deficits in major depressive disorder.
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17
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Li Y, Fan C, Wang L, Lan T, Gao R, Wang W, Yu SY. MicroRNA-26a-3p rescues depression-like behaviors in male rats via preventing hippocampal neuronal anomalies. J Clin Invest 2021; 131:e148853. [PMID: 34228643 DOI: 10.1172/jci148853] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 07/01/2021] [Indexed: 12/11/2022] Open
Abstract
Depression is a neuropsychiatric disease associated with neuronal anomalies within specific brain regions. In the present study, we screened microRNA (miRNA) expression profiles in the dentate gyrus (DG) of the hippocampus and found that miR-26a-3p was markedly downregulated in a rat model of depression, whereas upregulation of miR-26a-3p within DG regions rescued the neuronal deterioration and depression-like phenotypes resulting from stress exposure, effects that appear to be mediated by the PTEN pathway. The knockdown of miR-26a-3p in DG regions of normal control rats induced depression-like behaviors, effects that were accompanied by activation of the PTEN/PI3K/Akt signaling pathway and neuronal deterioration via suppression of autophagy, impairments in synaptic plasticity, and promotion of neuronal apoptosis. In conclusion, these results suggest that miR-26a-3p deficits within the hippocampal DG mediated the neuronal anomalies contributing to the display of depression-like behaviors. This miRNA may serve as a potential therapeutic target for the treatment of depression.
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Affiliation(s)
- Ye Li
- Department of Physiology and
| | | | - Liyan Wang
- Morphological Experimental Center, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | | | - Rui Gao
- Department of Microorganism, Jinan Nursing Vocational College, Lvyoulu Road, Jinan, Shandong Province, China
| | | | - Shu Yan Yu
- Department of Physiology and.,Shandong Key Laboratory of Mental Disorders, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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18
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Sauer M, Was N, Ziegenhals T, Wang X, Hafner M, Becker M, Fischer U. The miR-26 family regulates neural differentiation-associated microRNAs and mRNAs by directly targeting REST. J Cell Sci 2021; 134:jcs257535. [PMID: 34151974 PMCID: PMC11443607 DOI: 10.1242/jcs.257535] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 05/11/2021] [Indexed: 01/13/2023] Open
Abstract
Repressor element 1-silencing transcription factor (REST) plays a crucial role in the differentiation of neural progenitor cells (NPCs). C-terminal domain small phosphatases (CTDSPs) are REST effector proteins that reduce RNA polymerase II activity on genes required for neurogenesis. miR-26b regulates neurogenesis in zebrafish by targeting ctdsp2 mRNA, but the molecular events triggered by this microRNA (miR) remain unknown. Here, we show in a murine embryonic stem cell differentiation paradigm that inactivation of miR-26 family members disrupts the formation of neurons and astroglia and arrests neurogenesis at the neural progenitor level. Furthermore, we show that miR-26 directly targets Rest, thereby inducing the expression of a large set of REST complex-repressed neuronal genes, including miRs required for induction of the neuronal gene expression program. Our data identify the miR-26 family as the trigger of a self-amplifying system required for neural differentiation that acts upstream of REST-controlled miRs.
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Affiliation(s)
- Mark Sauer
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, D-97078 Würzburg, Germany
| | - Nina Was
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, D-97078 Würzburg, Germany
| | - Thomas Ziegenhals
- Department of Biochemistry, Theodor Boveri-Institute, University of Würzburg, D-97074 Würzburg, Germany
| | - Xiantao Wang
- RNA Molecular Biology Group, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD 20892, USA
| | - Markus Hafner
- RNA Molecular Biology Group, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD 20892, USA
| | - Matthias Becker
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, D-97078 Würzburg, Germany
| | - Utz Fischer
- Department of Biochemistry, Theodor Boveri-Institute, University of Würzburg, D-97074 Würzburg, Germany
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Bortolozzi A, Manashirov S, Chen A, Artigas F. Oligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson's disease. Pharmacol Ther 2021; 227:107873. [PMID: 33915178 DOI: 10.1016/j.pharmthera.2021.107873] [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: 11/18/2020] [Accepted: 04/05/2021] [Indexed: 12/25/2022]
Abstract
Remarkable advances in understanding the role of RNA in health and disease have expanded considerably in the last decade. RNA is becoming an increasingly important target for therapeutic intervention; therefore, it is critical to develop strategies for therapeutic modulation of RNA function. Oligonucleotides, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA mimic (miRNA), and anti-microRNA (antagomir) are perhaps the most direct therapeutic strategies for addressing RNA. Among other mechanisms, most oligonucleotide designs involve the formation of a hybrid with RNA that promotes its degradation by activation of endogenous enzymes such as RNase-H (e.g., ASO) or the RISC complex (e.g. RNA interference - RNAi for siRNA and miRNA). However, the use of oligonucleotides for the treatment of brain disorders is seriously compromised by two main limitations: i) how to deliver oligonucleotides to the brain compartment, avoiding the action of peripheral RNAses? and once there, ii) how to target specific neuronal populations? We review the main molecular pathways in major depressive disorder (MDD) and Parkinson's disease (PD), and discuss the challenges associated with the development of novel oligonucleotide therapeutics. We pay special attention to the use of conjugated ligand-oligonucleotide approach in which the oligonucleotide sequence is covalently bound to monoamine transporter inhibitors (e.g. sertraline, reboxetine, indatraline). This strategy allows their selective accumulation in the monoamine neurons of mice and monkeys after their intranasal or intracerebroventricular administration, evoking preclinical changes predictive of a clinical therapeutic action after knocking-down disease-related genes. In addition, recent advances in oligonucleotide therapeutic clinical trials are also reviewed.
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Affiliation(s)
- Analia Bortolozzi
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
| | - Sharon Manashirov
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; miCure Therapeutics LTD., Tel-Aviv, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Alon Chen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Francesc Artigas
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain
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Sałaciak K, Pytka K. Biased agonism in drug discovery: Is there a future for biased 5-HT 1A receptor agonists in the treatment of neuropsychiatric diseases? Pharmacol Ther 2021; 227:107872. [PMID: 33905796 DOI: 10.1016/j.pharmthera.2021.107872] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022]
Abstract
Serotonin (5-HT) is one of the fundamental neurotransmitters that contribute to the information essential for an organism's normal, physiological function. Serotonin acts centrally and systemically. The 5-HT1A receptor is the most widespread serotonin receptor, and participates in many brain-related disorders, including anxiety, depression, and cognitive impairments. The 5-HT1A receptor can activate several different biochemical pathways and signals through both G protein-dependent and G protein-independent pathways. Preclinical experiments indicate that distinct signaling pathways in specific brain regions may be crucial for antidepressant-like, anxiolytic-like, and procognitive responses. Therefore, the development of new ligands that selectively target a particular signaling pathway(s) could open new possibilities for more effective and safer pharmacotherapy. This review discusses the current state of preclinical studies focusing on the concept of functional selectivity (biased agonism) regarding the 5-HT1A receptor and its role in antidepressant-like, anxiolytic-like, and procognitive regulation. Such work highlights not only the differential effects of targeted autoreceptors, vs. heteroreceptors, but also the importance of targeting specific downstream intracellular signaling processes, thereby enhancing favorable over unfavorable signaling activation.
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Affiliation(s)
- Kinga Sałaciak
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
| | - Karolina Pytka
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
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21
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Miao C, Chang J. The important roles of microRNAs in depression: new research progress and future prospects. J Mol Med (Berl) 2021; 99:619-636. [PMID: 33641067 DOI: 10.1007/s00109-021-02052-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 01/04/2021] [Accepted: 02/16/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-encoding, single-stranded RNA molecules of about 22 nucleotides in length encoded by endogenous genes involved in posttranscriptional gene expression regulation. Studies have shown that miRNAs participate in a series of important pathophysiological processes, including the pathogenesis of depression. This article systematically summarized the research results published in the field of miRNAs and depression, which mainly involved three topics: circulating miRNAs as markers for diagnosis and prognosis of depression, the regulatory roles of miRNAs in the pathogenesis of depression, and the roles of miRNAs in the mechanisms of depression treatment. By summarizing and analyzing the research literature in recent years, we found that some circulating miRNAs can be potential biomarkers for the diagnosis and prognostic evaluation of depression. miRNAs that disorderly expressed during the disease play important roles in the depression pathogenesis, and miRNAs also play roles in the mechanisms of psychotherapy and drug therapy for depression. Elucidating the important roles of miRNAs in depression will bring people's understanding of the pathogenesis of depression to a new level. In addition, these miRNAs may be developed as new biomarkers for diagnosing depression, or as drug targets, or these molecules may be used as new drugs, which may provide new means for the treatment of depression. KEY MESSAGES: • The research results of miRNAs and depression are reviewed. • Circulating miRNAs can be potential biomarkers for depression. • MiRNAs play important roles in the depression pathogenesis. • MiRNAs play important roles in drug therapy for depression.
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Affiliation(s)
- Chenggui Miao
- Department of Pharmacology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, 1 Qianjiang Road, Xinzhan District, Hefei, 230012, Anhui Province, China. .,Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, 230012, China. .,Anhui Provincial Key Laboratory of Chinese Medicine Compound, Anhui University of Chinese Medicine, Hefei, 230012, China. .,Institute of Life and Health Sciences, Anhui University of Science and Technology, Fengyang, 233100, China.
| | - Jun Chang
- Fourth Affiliated Hospital, Anhui Medical University, Hefei, 230032, China
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Restraint Stress in Mice Alters Set of 25 miRNAs Which Regulate Stress- and Depression-Related mRNAs. Int J Mol Sci 2020; 21:ijms21249469. [PMID: 33322800 PMCID: PMC7763317 DOI: 10.3390/ijms21249469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
In the present study, we aim to identify the effect of restrain stress (RS) on the expression of miRNAs in mouse serum. We used three genotypes of animals (mice with knock-out of the gene-encoding norepinephrine transporter, NET-KO; C57BL/6J, and SWR/J) which had previously been shown to display different sensitivity to RS, and focused on miRNAs which were altered by RS in the serum of all three genotypes. An analysis of miRNAs expression allowed for the identification of a set of 25 differentially expressed miRNAs; 10 were down-regulated compared to an appropriate control group of animals, while 15 were up-regulated. The application of DIANA-miRPath v. 3.0 allowed for the identification of selected pathways (KEGG) and Gene Ontology (GO) categories that were significantly controlled by these miRNAs, while miRWalk v. 3.0-the platform that used the machine learning based algorithm, TaRPmiR-was used to find their targets. The results indicate that 25 miRNAs, identified as altered upon RS in three genotypes of mice, are responsible for regulation of mRNA-encoding proteins that are key for the main hypotheses of depression; therefore, they may help to understand the link between stress and depression at the molecular level.
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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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Tavares GA, Torres A, de Souza JA. Early Life Stress and the Onset of Obesity: Proof of MicroRNAs' Involvement Through Modulation of Serotonin and Dopamine Systems' Homeostasis. Front Physiol 2020; 11:925. [PMID: 32848865 PMCID: PMC7399177 DOI: 10.3389/fphys.2020.00925] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/09/2020] [Indexed: 01/12/2023] Open
Abstract
Healthy persons hold a very complex system for controlling energy homeostasis. The system functions on the interconnected way between the nutritional, endocrine, neural, and epigenetic regulation, which includes the microRNAs (miRNAs). Currently, it is well accepted that experiences of early life stress (ELS) carry modification of the central control of feeding behavior, one of the factors controlling energy homeostasis. Recently, studies give us a clue on the modulation of eating behavior, which is one of the main factors associated with the development of obesity. This clue connected the neural control through the serotonin (5HT) and dopamine (DA) systems with the fine regulation of miRNAs. The first pieces of evidence highlight the presence of the miR-16 in the regulation of the serotonin transporter (SERT) as well as the receptors 1a (5HT1A) and 2a (5HT2A). On the other hand, miR-504 is related to the dopamine receptor D2 (DRD2). As our knowledge advance, we expected to discover other important pathways for the regulation of the energy homeostasis. As both neurotransmission systems and miRNAs seem to be sensible to ELS, the aim of this review is to bring new insight about the involvement of miRNAs with a central role in the control of eating behavior focusing on the influences of ELS and regulation of neurotransmission systems.
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Affiliation(s)
- Gabriel Araujo Tavares
- Nantes Université, INRAE, UMR 1280, PhAN, Nantes, France.,Laboratory of Neuroplasticity and Behavior, Graduate Program of Nutrition, Federal University of Pernambuco, Recife, Brazil
| | - Amada Torres
- Nantes Université, INRAE, UMR 1280, PhAN, Nantes, France.,Developmental Genetics and Molecular Physiology, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico - Campus Morelos, Cuernavaca, Mexico
| | - Julliet Araujo de Souza
- Laboratory of Neuroplasticity and Behavior, Graduate Program of Neuropsychiatry and Behavioral Sciences, Federal University of Pernambuco, Recife, Brazil
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25
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Xia X, Ding M, Xuan JF, Xing JX, Pang H, Yao J, Wu X, Wang BJ. Effects of HTR1B 3' region polymorphisms and functional regions on gene expression regulation. BMC Genet 2020; 21:79. [PMID: 32689951 PMCID: PMC7372893 DOI: 10.1186/s12863-020-00886-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/12/2020] [Indexed: 12/21/2022] Open
Abstract
Background The HTR1B gene encodes the 5-hydroxytryptamine (5-HT1B) receptor, which is involved in a variety of brain activities and mental disorders. The regulatory effects of non-coding regions on genomic DNA are one of many reasons for the cause of genetic-related diseases. Post-transcriptional regulation that depends on the function of 3′ regulatory regions plays a particularly important role. This study investigated the effects, on reporter gene expression, of several haplotypes of the HTR1B gene (rs6297, rs3827804, rs140792648, rs9361234, rs76194807, rs58138557, and rs13212041) and truncated fragments in order to analyze the function of the 3′ region of HTR1B. Results We found that the haplotype, A-G-Del-C-T-Ins-A, enhanced the expression level compared to the main haplotype; A-G-Del-C-G-Ins-A; G-G-Del-C-G-Ins-G decreased the expression level. Two alleles, rs76194807T and rs6297G, exhibited different relative luciferase intensities compared to their counterparts at each locus. We also found that + 2440 ~ + 2769 bp and + 1953 ~ + 2311 bp regions both had negative effects on gene expression. Conclusions The 3′ region of HTR1B has a regulatory effect on gene expression, which is likely closely associated with the interpretation of HTR1B-related disorders. In addition, the HTR1B 3′ region includes several effector binding sites that induce an inhibitory effect on gene expression.
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Affiliation(s)
- Xi Xia
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Mei Ding
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Jin-Feng Xuan
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Jia-Xin Xing
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Hao Pang
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Jun Yao
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Xue Wu
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China
| | - Bao-Jie Wang
- School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, 110122, China.
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26
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Lafourcade CA, Fernández A, Ramírez JP, Corvalán K, Carrasco MÁ, Iturriaga A, Bátiz LF, Luarte A, Wyneken U. A Role for mir-26a in Stress: A Potential sEV Biomarker and Modulator of Excitatory Neurotransmission. Cells 2020; 9:cells9061364. [PMID: 32492799 PMCID: PMC7349773 DOI: 10.3390/cells9061364] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/21/2020] [Accepted: 05/27/2020] [Indexed: 01/08/2023] Open
Abstract
Stress is a widespread problem in today’s societies, having important consequences on brain function. Among the plethora of mechanisms involved in the stress response at the molecular level, the role of microRNAs (miRNAs) is beginning to be recognized. The control of gene expression by these noncoding RNAs makes them essential regulators of neuronal and synaptic physiology, and alterations in their levels have been associated with pathological conditions and mental disorders. In particular, the excitatory (i.e., glutamate-mediated) neurotransmission is importantly affected by stress. Here, we found that loss of miR-26a-5p (miR-26a henceforth) function in primary hippocampal neurons increased the frequency and amplitude of miniature excitatory currents, as well as the expression levels of the excitatory postsynaptic scaffolding protein PSD95. Incubation of primary hippocampal neurons with corticosterone downregulated miR-26a, an effect that mirrored our in vivo results, as miR-26a was downregulated in the hippocampus as well as in blood serum-derived small extracellular vesicles (sEVs) of rats exposed to two different stress paradigms by movement restriction (i.e., stress by restraint in cages or by complete immobilization in bags). Overall, these results suggest that miR-26a may be involved in the generalized stress response and that a stress-induced downregulation of miR-26a could have long-term effects on glutamate neurotransmission.
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Affiliation(s)
- Carlos Andrés Lafourcade
- Centro de Investigación e Innovación Biomédica (CIIB), Facultad de Medicina, Universidad de los Andes, Santiago PC 7620001, Chile; (A.F.); (J.P.R.); (K.C.); (L.F.B.)
- Correspondence: (C.A.L.); (U.W.)
| | - Anllely Fernández
- Centro de Investigación e Innovación Biomédica (CIIB), Facultad de Medicina, Universidad de los Andes, Santiago PC 7620001, Chile; (A.F.); (J.P.R.); (K.C.); (L.F.B.)
| | - Juan Pablo Ramírez
- Centro de Investigación e Innovación Biomédica (CIIB), Facultad de Medicina, Universidad de los Andes, Santiago PC 7620001, Chile; (A.F.); (J.P.R.); (K.C.); (L.F.B.)
| | - Katherine Corvalán
- Centro de Investigación e Innovación Biomédica (CIIB), Facultad de Medicina, Universidad de los Andes, Santiago PC 7620001, Chile; (A.F.); (J.P.R.); (K.C.); (L.F.B.)
| | - Miguel Ángel Carrasco
- Facultad de Ingeniería y Ciencias Aplicadas, Universidad de los Andes, Santiago PC 7620001, Chile;
| | - Andrés Iturriaga
- Instituto de Salud Poblacional, Facultad de Medicina, Universidad de Chile, Santiago PC 8380453, Chile;
| | - Luis Federico Bátiz
- Centro de Investigación e Innovación Biomédica (CIIB), Facultad de Medicina, Universidad de los Andes, Santiago PC 7620001, Chile; (A.F.); (J.P.R.); (K.C.); (L.F.B.)
| | - Alejandro Luarte
- Biomedical Neuroscience Institute, Universidad de Chile, Santiago PC 8380453, Chile;
| | - Ursula Wyneken
- Centro de Investigación e Innovación Biomédica (CIIB), Facultad de Medicina, Universidad de los Andes, Santiago PC 7620001, Chile; (A.F.); (J.P.R.); (K.C.); (L.F.B.)
- Correspondence: (C.A.L.); (U.W.)
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27
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Babicola L, Pietrosanto M, Ielpo D, D'Addario SL, Cabib S, Ventura R, Ferlazzo F, Helmer-Citterich M, Andolina D, Lo Iacono L. RISC RNA sequencing in the Dorsal Raphè reveals microRNAs regulatory activities associated with behavioral and functional adaptations to chronic stress. Brain Res 2020; 1736:146763. [DOI: 10.1016/j.brainres.2020.146763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/03/2020] [Accepted: 03/08/2020] [Indexed: 01/06/2023]
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28
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Allen L, Dwivedi Y. MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior. Mol Psychiatry 2020; 25:308-320. [PMID: 31740756 PMCID: PMC6974433 DOI: 10.1038/s41380-019-0597-8] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/16/2019] [Accepted: 11/05/2019] [Indexed: 12/17/2022]
Abstract
Childhood environment can have a profound impact on brain structure and function. Epigenetic mechanisms have been shown to play a critical role in adaptive and maladaptive processes by regulating gene expression without changing the genome. Over the past few years, early life stress (ELS) has been established as a major risk factor for major depression and suicidal behavior along with other psychiatric illnesses in adulthood. In recent years, the emergence of small noncoding RNAs as a mega controller of gene expression has gained attention for their role in various disease processes. Among various noncoding RNAs, microRNAs (miRNAs) are the most studied and well characterized and have emerged as a major regulator of neural plasticity and higher brain functioning. More recently, although limited in number, studies are focusing on how miRNAs can play a role in the maladaptive processes associated with ELS both at adolescent and adult age and whether these processes are critical in developing depression and suicidal behavior. In this review, we critically evaluate how postnatal ELS relates to abnormalities in miRNA expression and functions from both animal and human literature and draw connections from these findings to depression and suicidal behavior later in life.
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Affiliation(s)
- Lauren Allen
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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29
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Lo Iacono L, Ielpo D, Accoto A, Di Segni M, Babicola L, D’Addario SL, Ferlazzo F, Pascucci T, Ventura R, Andolina D. MicroRNA-34a Regulates the Depression-like Behavior in Mice by Modulating the Expression of Target Genes in the Dorsal Raphè. Mol Neurobiol 2019; 57:823-836. [DOI: 10.1007/s12035-019-01750-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 08/26/2019] [Indexed: 01/06/2023]
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30
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Jones ME, Sillivan SE, Jamieson S, Rumbaugh G, Miller CA. microRNA mir-598-3p mediates susceptibility to stress enhancement of remote fear memory. ACTA ACUST UNITED AC 2019; 26:363-372. [PMID: 31416909 PMCID: PMC6699414 DOI: 10.1101/lm.048827.118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/10/2019] [Indexed: 12/26/2022]
Abstract
microRNAs (miRNAs) have emerged as potent regulators of learning, recent memory, and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memories, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue and identified miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was down-regulated in the BLA. Further decreasing BLA mir-598-3p levels did not increase strength of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress and stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 d post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton, the core mediator of structural plasticity. Taken together, the results suggest BLA mir-598-3p may be recruited by stress to mediate a critical switch from a salient remote fear memory to one that is enhanced and extinction-resistant.
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Affiliation(s)
- Meghan E Jones
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA.,Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Stephanie E Sillivan
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA.,Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Sarah Jamieson
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA.,Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Gavin Rumbaugh
- Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Courtney A Miller
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA.,Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA
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