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Lee LC, Su MT, Bao L, Lee PL, Tutwiler S, Yeh TK, Chang CY. MicroRNAs modulate CaMKIIα/SIRT1 signaling pathway as a biomarker of cognitive ability in adolescents. Brain Behav Immun Health 2025; 44:100970. [PMID: 40103671 PMCID: PMC11919301 DOI: 10.1016/j.bbih.2025.100970] [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: 10/04/2024] [Revised: 01/17/2025] [Accepted: 02/23/2025] [Indexed: 03/20/2025] Open
Abstract
The dynamic regulation of synaptic plasticity underlies memory formation, involving intricate signaling pathways with both facilitatory and inhibitory roles. MicroRNAs are emerging modulators of memory processes through their fine-tuning of gene expression. To explore the influence of miRNAs on adolescent cognitive function, we investigated the association between academic performance, cognitive ability as measured by the Inquiry for Scientific Thinking, Analytics, and Reasoning test, and plasma miRNA profiling in 486 senior high school students. Our analysis identified 38 differentially expressed miRNAs between students with high and low academic performance. Notably, miR-219 b/548e/628/885 and miR-30a/30c-1/195/204 potentially targeted genes associated with the CaMKII/SIRT1 signaling pathway, a crucial facilitator of memory consolidation. Collectively, our findings suggest that specific plasma miRNAs, particularly the CaMKII/SIRT1-related miR-30a/30c-1/195/204 cluster, potentially serve as promising biomarkers for cognitive function in adolescents. Our findings further support the proposed interaction between NF-kB activity and CaMKIIα in regulating synaptic plasticity. Under hypomethylation conditions, increased NF-kB activity, a key component of inflammation and neural plasticity, influences learning and memory. This biological pathway, representing the initiation of epigenetic memory, demonstrates significant predictive power for both cognitive ability and academic performance.
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Affiliation(s)
- Li-Ching Lee
- Institute for Research Excellence in Learning Sciences and Graduate Institute of Science Education, National Taiwan Normal University, Taipei, Taiwan
| | - Ming-Tsan Su
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Lei Bao
- Department of Physics, The Ohio State University, Columbus, OH, USA
| | - Po-Lei Lee
- Department of Electrical Engineering, National Central University, Taoyuan City, Taiwan
| | - Shane Tutwiler
- Learning Foundations, University of Rhode Island, Kingston, RI, USA
| | - Ting-Kuang Yeh
- Institute for Research Excellence in Learning Sciences and Graduate Institute of Science Education, National Taiwan Normal University, Taipei, Taiwan
- Institute of Marine Environment Science and Technology, National Taiwan Normal University, Taipei, Taiwan
- Department of Earth Sciences, National Taiwan Normal University, Taipei, Taiwan
| | - Chun-Yen Chang
- Institute for Research Excellence in Learning Sciences and Graduate Institute of Science Education, National Taiwan Normal University, Taipei, Taiwan
- Department of Earth Sciences, National Taiwan Normal University, Taipei, Taiwan
- Department of Biology, Universitas Negeri Malang, Indonesia
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Choudhary A, Kumar A, Jindal M, Rhuthuparna M, Munshi A. MicroRNA signatures in neuroplasticity, neuroinflammation and neurotransmission in association with depression. J Physiol Biochem 2025; 81:85-97. [PMID: 39695016 DOI: 10.1007/s13105-024-01065-4] [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: 06/18/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Depression is a multifactorial disorder that occurs mainly on account of the dysregulation of neuroplasticity, neurotransmission and neuroinflammation in the brain. In addition to environmental /lifestyle factors, the pathogenesis of disease has been associated with genetic and epigenetic factors that affect the reprogramming of normal brain function. MicroRNA (miRNAs), a type of non-coding RNAs, are emerging as significant players that play a vital role in the regulation of gene expression and have been extensively explored in neurodegenerative disorders. Recent studies have also shown the role of gut microbiota that forms a complex bidirectional network with gut brain axis, impacting neuroinflammation in case of Parkinson's disease and depression. Translating targeted miRNA-based therapies for the treatment of neurological disorders including depression, into clinical practice remains challenging due to the ineffective delivery of the therapeutic molecules and off-target effects of the specific miRNAs. This review provides significant insights into how miRNAs are emerging as vital players in the development of depression, especially the ones involved in three important processes including neuroplasticity, neurotransmission and neuroinflammation. In this review, the current status of miRNAs as biomarkers for therapeutic interventions in the case of depression has been discussed along with an overview of future perspectives, like use of nanotechnology and gene editing, keeping in view other multifactorial disorders where such interventions by mimics and inhibitors have already reached clinical trials. The challenges for targeting the specific miRNAs for therapeutic outcomes have also been highlighted.
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Affiliation(s)
- Anita Choudhary
- Department of Human Genetics and Molecular Medicines, Central University of Punjab, Bathinda, India
| | - Anil Kumar
- Department of Human Genetics and Molecular Medicines, Central University of Punjab, Bathinda, India
| | - Manav Jindal
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Bathinda, India
| | - M Rhuthuparna
- Department of Human Genetics and Molecular Medicines, Central University of Punjab, Bathinda, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicines, Central University of Punjab, Bathinda, India.
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3
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Khosroshahi PA, Ghanbari M. MicroRNA dysregulation in glutamate and dopamine pathways of schizophrenia: From molecular pathways to diagnostic and therapeutic approaches. Prog Neuropsychopharmacol Biol Psychiatry 2024; 135:111081. [PMID: 39002925 DOI: 10.1016/j.pnpbp.2024.111081] [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: 12/01/2023] [Revised: 06/28/2024] [Accepted: 07/07/2024] [Indexed: 07/15/2024]
Abstract
Schizophrenia is a complex psychiatric disorder, and genetic and environmental factors have been implicated in its development. Dysregulated glutamatergic and dopaminergic transmission pathways are involved in schizophrenia development. Besides genetic mutations, epigenetic dysregulation has a considerable role in dysregulating molecular pathways involved in schizophrenia. MicroRNAs (miRNAs) are small, non-coding RNAs that target specific mRNAs and inhibit their translation into proteins. As epigenetic factors, miRNAs regulate many genes involved in glutamate and dopamine signaling pathways; thereby, their dysregulation can contribute to the development of schizophrenia. Secretion of specific miRNAs from damaged cells into body fluids can make them one of the ideal non-invasive biomarkers in the early diagnosis of schizophrenia. Also, understanding the molecular mechanisms of miRNAs in schizophrenia pathogenesis can pave the way for developing novel treatments for patients with schizophrenia. In this study, we reviewed the glutamatergic and dopaminergic pathophysiology and highlighted the role of miRNA dysregulation in schizophrenia development. Besides, we shed light on the significance of circulating miRNAs for schizophrenia diagnosis and the recent findings on the miRNA-based treatment for schizophrenia.
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Affiliation(s)
| | - Mohammad Ghanbari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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Pang Y, Ruan X, Liu W, Hou L, Yin B, Shu P, Peng X. MicroRNA-495 Modulates Neuronal Layer Fate Determination by Targeting Tcf4. Int J Biol Sci 2024; 20:6207-6221. [PMID: 39664574 PMCID: PMC11628341 DOI: 10.7150/ijbs.94739] [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: 01/26/2024] [Accepted: 10/25/2024] [Indexed: 12/13/2024] Open
Abstract
During cortical development, the differentiation potential of neural progenitor cells (NPCs) is one of the most critical steps in normal cortical formation and function. Defects in this process can lead to many brain disorders. MicroRNA dysregulation in the dorsolateral prefrontal cortex is associated with risk for a variety of developmental and psychiatric conditions. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we found that microRNA-495-3p (miR-495) is expressed in NPCs of the developing mouse cerebral cortex. Furthermore, aberrant expression of miR-495 promotes the formation of superficial neurons. Our results suggest that miR-495 can target transcription factor 4 (TCF4), a gene linked to the neurodevelopmental disorder Pitt-Hopkins syndrome (PTHS), to ensure normal differentiation of NPCs in the developing cerebral cortex. Furthermore, TCF4 loss-of-function and gain-of-function experiments show opposite effects on miR-495 regulation of neural progenitor differentiation potential. Together, these results demonstrated that miR-495 regulates cortical development through TCF4 for the first time.
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Affiliation(s)
- Yunli Pang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Xiangbin Ruan
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Wei Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Lin Hou
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Bin Yin
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Pengcheng Shu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Xiaozhong Peng
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
- State Key Laboratory of Respiratory Health and Multimorbidity, Beijing 100005, China
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
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5
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Saikia B, Dhanushkodi A. Engineered exosome therapeutics for neurodegenerative diseases. Life Sci 2024; 356:123019. [PMID: 39209250 DOI: 10.1016/j.lfs.2024.123019] [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: 05/03/2024] [Revised: 08/14/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
An increase in life expectancy comes with a higher risk for age-related neurological and cognitive dysfunctions. Given the psycho-socioeconomic burden due to unhealthy aging in the coming decades, the United Nations has declared 2021-2030 as a decade of healthy aging. In this line, multipotent mesenchymal stromal cell-based therapeutics received special interest from the research community. Based on decades of research on cell therapy, a consensus has emerged that the therapeutic effects of cell therapy are due to the paracrine mechanisms rather than cell replacement. Exosomes, a constituent of the secretome, are nano-sized vesicles that have been a focus of intense research in recent years as a possible therapeutic agent or as a cargo to deliver drugs of interest into the central nervous system to induce neurogenesis, reduce neuroinflammation, confer neuroregeneration/neuroprotection, and improve cognitive and motor functions. In this review, we have discussed the neuroprotective properties of exosomes derived from adult mesenchymal stem cells, with a special focus on the role of exosomal miRNAs. We also reviewed various strategies to improve exosome production and their content for better therapeutic effects. Further, we discussed the utilization of ectomesenchymal stem cells like dental pulp stem cells and their exosomes in treating neurodegenerative diseases.
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Affiliation(s)
- Biplob Saikia
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Manipal, India
| | - Anandh Dhanushkodi
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Manipal, India.
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Pan Y, Zhang L, Ma W, Ibrahim YM, Zhang W, Wang M, Wang X, Xu Y, Gao C, Chen H, Zhang H, Xia C, Wang Y. miR-191-5p suppresses PRRSV replication by targeting porcine EGFR to enhance interferon signaling. Front Microbiol 2024; 15:1473504. [PMID: 39469460 PMCID: PMC11514493 DOI: 10.3389/fmicb.2024.1473504] [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: 07/31/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024] Open
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is a major thread to the global swine industry, lack of effective control strategies. This study explores the regulatory role of a small non-coding RNA, miR-191-5p, in PRRSV infection. We observed that miR-191-5p significantly inhibits PRRSV in porcine alveolar macrophages (PAMs), contrasting with negligible effects in MARC-145 and HEK293-CD163 cells, suggesting a cell-specific antiviral effect. Further investigation unveiled that miR-191-5p directly targets the porcine epidermal growth factor receptor (EGFR), whose overexpression or EGF-induced activation suppresses type I interferon (IFN-I) signaling, promoting PRRSV replication. In contrast, siRNA-or miR-191-5p-induced EGFR downregulation or EGFR inhibitor boosts IFN-I signaling, reducing viral replication. Notably, this miRNA alleviates the suppressive effect of EGF on IFN-I signaling, underscoring its regulatory function. Further investigation revealed interconnections among miR-191-5p, EGFR and signal transducer and activator of transcription 3 (STAT3). Modulation of STAT3 activity influenced IFN-I signaling and PRRSV replication, with STAT3 knockdown countering EGFR activation-induced virus replication. Combination inhibition of STAT3 and miR-191-5p suggests that STAT3 acts downstream in EGFR's antiviral response. Furthermore, miR-191-5p's broad efficacy in restricting various PRRSV strains in PAMs was identified. Collectively, these findings elucidate a novel mechanism of miR-191-5p in activating host IFN-I signaling to inhibit PRRSV replication, highlighting its potential in therapeutic applications against PRRSV.
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Affiliation(s)
- Yu Pan
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Lin Zhang
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Wenjie Ma
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yassein M. Ibrahim
- National Center of Technology Innovation for Pigs, Chongqing Academy of Animal Science, Chongqing, China
| | - Wenli Zhang
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Mengjie Wang
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xinrong Wang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Yunfei Xu
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Caixia Gao
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Hongyan Chen
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - He Zhang
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Changyou Xia
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yue Wang
- State Key Laboratory for Animal Disease Control and Prevention Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
- National Center of Technology Innovation for Pigs, Chongqing Academy of Animal Science, Chongqing, China
- College of Veterinary Medicine, Southwest University, Chongqing, China
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7
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Agostini S, Mancuso R, Citterio LA, Caputo D, Oreni L, Nuzzi R, Pasanisi MB, Rovaris M, Clerici M. Serum miR-34a-5p, miR-103a-3p, and miR-376a-3p as possible biomarkers of conversion from relapsing-remitting to secondary progressive multiple sclerosis. Neurobiol Dis 2024; 200:106648. [PMID: 39181188 DOI: 10.1016/j.nbd.2024.106648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024] Open
Abstract
Relapsing-remitting (RR) Multiple Sclerosis (MS) is the most common form of the disease; RRMS patients can maintain their clinical phenotype throughout life or can develop a secondary progressive (SP) course over time. We investigated whether circulating miRNAs can predict RR-to-SPMS conversion. A serum miRNAs profile was initially analyzed in a cross-sectional study by qPCR in 16 patients (8 RRMS and 8 SPMS) (Discovery cohort). Three miRNAs, i.e. miR-34a-5p, miR-103a-3p and miR-376a-3p, were significantly up-regulated in SPMS compared to RRMS patients (p < 0.0 5). Serum concentration of the same miRNAs was subsequently analyzed in a retrospective study by ddPCR at baseline in 69 RRMS patients who did (N = 36 cSPMS) or did not (N = 33) convert into SPMS over a 10-year observation period (Study cohort). The results showed that these miRNAs were significantly increased at baseline only in those RRMS patients who converted to SPMS over time. miR-34a-5p and miR-376a-3p alone were significantly increased in cSPMS sera at the end of the 10-years period too. Serum concentration of miR-34a-5p, miR-103a-3p and miR-376a-3p is increased in RRMS patients several years before their conversion to SPMS. These miRNAs might be useful biomarkers to predict the conversion from RRMS to SPMS.
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Affiliation(s)
| | | | | | | | - Letizia Oreni
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
| | | | | | - Marco Rovaris
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
| | - Mario Clerici
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Zakowicz P, Narozna B, Kozlowski T, Bargiel W, Grabarczyk M, Terczynska M, Pilecka J, Wasicka-Przewozna K, Pawlak J, Skibinska M. Peripheral Brain-Derived Neurotrophic Factor (BDNF) and Its Regulatory miRNAs as Biological Correlates of Impulsivity in Young Adults. Metabolites 2024; 14:529. [PMID: 39452910 PMCID: PMC11509573 DOI: 10.3390/metabo14100529] [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: 08/30/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Background: Impulsivity assessment may serve as a valuable clinical tool in the stratification of suicide risk. Acting without forethought is a crucial feature in the psychopathology of many psychiatric disturbances and corresponds with suicidal ideations, behaviors, and attempts. Methods: We present data on biological and psychological correlates of impulsivity among young adults (n = 47). Psychological analysis included both the self-description questionnaire-Barratt Impulsiveness Scale (BIS-11)-and neuropsychological behavioral tests, including the Iowa Gambling Task (IGT), the Simple Response Time task (SRT), and the Continuous Performance Test (CPT). mRNA and micro-RNA were isolated from peripheral blood mononuclear cells (PBMC). Expression levels of Brain-Derived Neurotrophic Factor (BDNF) mRNA and its regulatory micro RNAs, mir-1-3p, mir-15a-5p, mir-26a-5p, mir-26b-5p, and mir-195-5p, were analyzed using the quantitative reverse transcription polymerase chain reaction (RT-qPCR) method. proBDNF and BDNF plasma protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). Results: Significant correlations between BDNF mRNA and mir-15a-5p as well as proBDNF levels and mir-1-3p were detected. proBDNF protein levels correlated with motor and perseverance, while mir-26b correlated with cognitive complexity subdimensions of the BIS-11 scale. Correlations between BDNF, miRNAs, and the results of neuropsychological tests were also detected. Conclusions: The BDNF pathway shows a clinical potential in searching for biomarkers of impulse-control impairment. BDNF-regulatory micro-RNAs are detectable and related to clinical parameters in the studied population, which needs further research.
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Affiliation(s)
- Przemyslaw Zakowicz
- Collegium Medicum, University of Zielona Gora, 65-417 Zielona Gora, Poland
- Center for Children and Adolescent Treatment in Zabor, 66-003 Zabor, Poland
| | - Beata Narozna
- Molecular and Cell Biology Unit, Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Tomasz Kozlowski
- Student’s Research Group “Biology of the Neuron”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Weronika Bargiel
- Student’s Research Group “Biology of the Neuron”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Maksymilian Grabarczyk
- Student’s Research Group “Biology of the Neuron”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Maria Terczynska
- Student’s Research Group “Biology of the Neuron”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Julia Pilecka
- Student’s Research Group “Biology of the Neuron”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Karolina Wasicka-Przewozna
- Student’s Research Group “Biology of the Neuron”, Department of Psychiatric Genetics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Joanna Pawlak
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Maria Skibinska
- Department of Psychiatric Genetics, Poznan University of Medical Sciences, 61-701 Poznan, Poland
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Sun X, Wu S, Mao C, Qu Y, Xu Z, Xie Y, Jiang D, Song Y. Therapeutic Potential of Hydrogen Sulfide in Ischemia and Reperfusion Injury. Biomolecules 2024; 14:740. [PMID: 39062455 PMCID: PMC11274451 DOI: 10.3390/biom14070740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/14/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Ischemia-reperfusion (I/R) injury, a prevalent pathological condition in medical practice, presents significant treatment challenges. Hydrogen sulfide (H2S), acknowledged as the third gas signaling molecule, profoundly impacts various physiological and pathophysiological processes. Extensive research has demonstrated that H2S can mitigate I/R damage across multiple organs and tissues. This review investigates the protective effects of H2S in preventing I/R damage in the heart, brain, liver, kidney, intestines, lungs, stomach, spinal cord, testes, eyes, and other tissues. H2S provides protection against I/R damage by alleviating inflammation and endoplasmic reticulum stress; inhibiting apoptosis, oxidative stress, and mitochondrial autophagy and dysfunction; and regulating microRNAs. Significant advancements in understanding the mechanisms by which H2S reduces I/R damage have led to the development and synthesis of H2S-releasing agents such as diallyl trisulfide-loaded mesoporous silica nanoparticles (DATS-MSN), AP39, zofenopril, and ATB-344, offering a new therapeutic avenue for I/R injury.
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Affiliation(s)
- Xutao Sun
- Department of Typhoid, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
| | - Siyu Wu
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (S.W.); (C.M.); (Y.Q.); (Z.X.)
| | - Caiyun Mao
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (S.W.); (C.M.); (Y.Q.); (Z.X.)
| | - Ying Qu
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (S.W.); (C.M.); (Y.Q.); (Z.X.)
| | - Zihang Xu
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (S.W.); (C.M.); (Y.Q.); (Z.X.)
| | - Ying Xie
- Department of Synopsis of the Golden Chamber, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
| | - Deyou Jiang
- Department of Synopsis of the Golden Chamber, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
| | - Yunjia Song
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (S.W.); (C.M.); (Y.Q.); (Z.X.)
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10
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Pereira JD, Teixeira LCR, Mamede I, Alves MT, Caramelli P, Luizon MR, Veloso AA, Gomes KB. miRNAs in cerebrospinal fluid associated with Alzheimer's disease: A systematic review and pathway analysis using a data mining and machine learning approach. J Neurochem 2024; 168:977-994. [PMID: 38390627 DOI: 10.1111/jnc.16060] [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: 07/26/2023] [Revised: 12/20/2023] [Accepted: 01/13/2024] [Indexed: 02/24/2024]
Abstract
Alzheimer's disease (AD) is the most common type and accounts for 60%-70% of the reported cases of dementia. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in gene expression regulation. Although the diagnosis of AD is primarily clinical, several miRNAs have been associated with AD and considered as potential markers for diagnosis and progression of AD. We sought to match AD-related miRNAs in cerebrospinal fluid (CSF) found in the GeoDataSets, evaluated by machine learning, with miRNAs listed in a systematic review, and a pathway analysis. Using machine learning approaches, we identified most differentially expressed miRNAs in Gene Expression Omnibus (GEO), which were validated by the systematic review, using the acronym PECO-Population (P): Patients with AD, Exposure (E): expression of miRNAs, Comparison (C): Healthy individuals, and Objective (O): miRNAs differentially expressed in CSF. Additionally, pathway enrichment analysis was performed to identify the main pathways involving at least four miRNAs selected. Four miRNAs were identified for differentiating between patients with and without AD in machine learning combined to systematic review, and followed the pathways analysis: miRNA-30a-3p, miRNA-193a-5p, miRNA-143-3p, miRNA-145-5p. The pathways epidermal growth factor, MAPK, TGF-beta and ATM-dependent DNA damage response, were regulated by these miRNAs, but only the MAPK pathway presented higher relevance after a randomic pathway analysis. These findings have the potential to assist in the development of diagnostic tests for AD using miRNAs as biomarkers, as well as provide understanding of the relationship between different pathophysiological mechanisms of AD.
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Affiliation(s)
- Jessica Diniz Pereira
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Izabela Mamede
- Intituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Paulo Caramelli
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marcelo Rizzatti Luizon
- Intituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Adriano Alonso Veloso
- Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Karina Braga Gomes
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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11
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De Assis GG, Murawska-Ciałowicz E. BDNF Modulation by microRNAs: An Update on the Experimental Evidence. Cells 2024; 13:880. [PMID: 38786102 PMCID: PMC11119608 DOI: 10.3390/cells13100880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/06/2024] [Accepted: 05/18/2024] [Indexed: 05/25/2024] Open
Abstract
MicroRNAs can interfere with protein function by suppressing their messenger RNA translation or the synthesis of its related factors. The function of brain-derived neurotrophic factor (BDNF) is essential to the proper formation and function of the nervous system and is seen to be regulated by many microRNAs. However, understanding how microRNAs influence BDNF actions within cells requires a wider comprehension of their integrative regulatory mechanisms. Aim: In this literature review, we have synthesized the evidence of microRNA regulation on BDNF in cells and tissues, and provided an analytical discussion about direct and indirect mechanisms that appeared to be involved in BDNF regulation by microRNAs. Methods: Searches were conducted on PubMed.gov using the terms "BDNF" AND "MicroRNA" and "brain-derived neurotrophic factor" AND "MicroRNA", updated on 1 September 2023. Papers without open access were requested from the authors. One hundred and seventy-one papers were included for review and discussion. Results and Discussion: The local regulation of BDNF by microRNAs involves a complex interaction between a series of microRNAs with target proteins that can either inhibit or enhance BDNF expression, at the core of cell metabolism. Therefore, understanding this homeostatic balance provides resources for the future development of vector-delivery-based therapies for the neuroprotective effects of BDNF.
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Affiliation(s)
- Gilmara Gomes De Assis
- Department of Restorative Dentistry, Araraquara School of Dentistry, São Paulo State University (UNESP), Araraquara 14801-385, SP, Brazil
| | - Eugenia Murawska-Ciałowicz
- Department of Physiology and Biochemistry, Wroclaw University of Health and Sport Sciences, 51-612 Wrocław, Poland;
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12
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Liu X, Dong L, Jiang Z, Song M, Yan P. Identifying the differentially expressed peripheral blood microRNAs in psychiatric disorders: a systematic review and meta-analysis. Front Psychiatry 2024; 15:1390366. [PMID: 38827444 PMCID: PMC11140110 DOI: 10.3389/fpsyt.2024.1390366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/25/2024] [Indexed: 06/04/2024] Open
Abstract
Background Evidence has suggested that microRNAs (miRNAs) may play an important role in the pathogenesis of psychiatric disorders (PDs), but the results remain inconclusive. We aimed to identify specific differentially expressed miRNAs and their overlapping miRNA expression profiles in schizophrenia (SZ), major depression disorder (MDD), and bipolar disorder (BD), the three major PDs. Methods The literatures up to September 30, 2023 related to peripheral blood miRNAs and PDs were searched and screened from multiple databases. The differences in miRNA levels between groups were illustrated by the standardized mean difference (SMD) and 95% confidence interval (95% CI). Results In total, 30 peripheral blood miRNAs were included in the meta-analysis, including 16 for SZ, 12 for MDD, and 2 for BD, each was reported in more than 3 independent studies. Compared with the control group, miR-181b-5p, miR-34a-5p, miR-195-5p, miR-30e-5p, miR-7-5p, miR-132-3p, miR-212-3p, miR-206, miR-92a-3p and miR-137-3p were upregulated in SZ, while miR-134-5p, miR-107 and miR-99b-5p were downregulated. In MDD, miR-124-3p, miR-132-3p, miR-139-5p, miR-182-5p, miR-221-3p, miR-34a-5p and miR-93-5p were upregulated, while miR-144-5p and miR-135a-5p were downregulated. However, we failed to identify statistically differentially expressed miRNAs in BD. Interestingly, miR-132-3p and miR-34a-5p were upregulated in both SZ and MDD. Conclusions Our study identified 13 differentially expressed miRNAs in SZ and 9 in MDD, among which miR-132-3p and miR-34a-5p were upregulated in both SZ and MDD by systematically analyzing qualified studies. These miRNAs may be used as potential biomarkers for the diagnosis of SZ and MDD in the future. Systematic Review Registration http://www.crd.york.ac.uk/PROSPERO, identifier CRD42023486982.
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Affiliation(s)
- Xiaoyan Liu
- Department of Psychiatry, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liying Dong
- Internal Medicine of Traditional Chinese Medicine, The 4th Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhaowei Jiang
- Internal Medicine of Traditional Chinese Medicine, The 4th Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mingfen Song
- Molecular Biology Laboratory, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Pan Yan
- Molecular Biology Laboratory, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
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13
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Khavari B, Barnett MM, Mahmoudi E, Geaghan MP, Graham A, Cairns MJ. microRNA and the Post-Transcriptional Response to Oxidative Stress during Neuronal Differentiation: Implications for Neurodevelopmental and Psychiatric Disorders. Life (Basel) 2024; 14:562. [PMID: 38792584 PMCID: PMC11121913 DOI: 10.3390/life14050562] [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: 03/12/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Oxidative stress is one of the most important environmental exposures associated with psychiatric disorders, but the underlying molecular mechanisms remain to be elucidated. In a previous study, we observed a substantial alteration of the gene expression landscape in neuron-like cells that were differentiated from SH-SY5Y cells after or during exposure to oxidative stress, with a subset of dysregulated genes being enriched for neurodevelopmental processes. To further explore the regulatory mechanisms that might account for such profound perturbations, we have now applied small RNA-sequencing to investigate changes in the expression of miRNAs. These molecules are known to play crucial roles in brain development and response to stress through their capacity to suppress gene expression and influence complex biological networks. Through these analyses, we observed more than a hundred differentially expressed miRNAs, including 80 previously reported to be dysregulated in psychiatric disorders. The seven most influential miRNAs associated with pre-treatment exposure, including miR-138-5p, miR-96-5p, miR-34c-5p, miR-1287-5p, miR-497-5p, miR-195-5p, and miR-16-5p, supported by at least 10 negatively correlated mRNA connections, formed hubs in the interaction network with 134 genes enriched with neurobiological function, whereas in the co-treatment condition, miRNA-mRNA interaction pairs were enriched in cardiovascular and immunity-related disease ontologies. Interestingly, 12 differentially expressed miRNAs originated from the DLK1-DIO3 location, which encodes a schizophrenia-associated miRNA signature. Collectively, our findings suggest that early exposure to oxidative stress, before and during prenatal neuronal differentiation, might increase the risk of mental illnesses in adulthood by disturbing the expression of miRNAs that regulate neurodevelopmentally significant genes and networks.
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Affiliation(s)
- Behnaz Khavari
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia; (B.K.); (M.M.B.)
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Michelle M. Barnett
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia; (B.K.); (M.M.B.)
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Ebrahim Mahmoudi
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia; (B.K.); (M.M.B.)
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Michael P. Geaghan
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia; (B.K.); (M.M.B.)
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Adam Graham
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia; (B.K.); (M.M.B.)
| | - Murray J. Cairns
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia; (B.K.); (M.M.B.)
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
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14
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Mellios N, Papageorgiou G, Gorgievski V, Maxson G, Hernandez M, Otero M, Varangis M, Dell'Orco M, Perrone-Bizzozero N, Tzavara E. Regulation of neuronal circHomer1 biogenesis by PKA/CREB/ERK-mediated pathways and effects of glutamate and dopamine receptor blockade. RESEARCH SQUARE 2024:rs.3.rs-3547375. [PMID: 38260249 PMCID: PMC10802743 DOI: 10.21203/rs.3.rs-3547375/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
There are currently only very few efficacious drug treatments for SCZ and BD, none of which can significantly ameliorate cognitive symptoms. Thus, further research is needed in elucidating molecular pathways linked to cognitive function and antipsychotic treatment. Circular RNAs (circRNAs) are stable brain-enriched non-coding RNAs, derived from the covalent back-splicing of precursor mRNA molecules. CircHomer1 is a neuronal-enriched, activity-dependent circRNA, derived from the precursor of the long HOMER1B mRNA isoform, which is significantly downregulated in the prefrontal cortex of subjects with psychosis and is able to regulate cognitive function. Even though its relevance to psychiatric disorders and its role in brain function and synaptic plasticity have been well established, little is known about the molecular mechanisms that underlie circHomer1 biogenesis in response to neuronal activity and psychiatric drug treatment. Here we suggest that the RNA-binding protein (RBP) FUS positively regulates neuronal circHomer1 expression. Furthermore, we show that the MEK/ERK and PKA/CREB pathways positively regulate neuronal circHomer1 expression, as well as promote the transcription of Fus and Eif4a3, another RBP previously shown to activate circHomer1 biogenesis. We then demonstrate via both in vitro and in vivo studies that NMDA and mGluR5 receptors are upstream modulators of circHomer1 expression. Lastly, we report that in vivo D2R antagonism increases circHomer1 expression, whereas 5HT2AR blockade reduces circHomer1 levels in multiple brain regions. Taken together, this study allows us to gain novel insights into the molecular circuits that underlie the biogenesis of a psychiatric disease-associated circRNA.
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15
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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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16
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Grosu ȘA, Dobre M, Milanesi E, Hinescu ME. Blood-Based MicroRNAs in Psychotic Disorders-A Systematic Review. Biomedicines 2023; 11:2536. [PMID: 37760977 PMCID: PMC10525934 DOI: 10.3390/biomedicines11092536] [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: 07/03/2023] [Revised: 09/01/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Psychotic disorders are a heterogenous class of mental illness, with an intricate pathophysiology, involving genetics and environmental factors, and their interaction. The identification of accessible biomarkers in bodily systems such as blood may lead to more accurate diagnosis, and more effective treatments targeting dysfunctional pathways, and could assist in monitoring the disease evolution. This systematic review aims to highlight the dysregulated microRNAs (miRNAs) in the peripheral blood of patients with psychotic disorders. Using the PRISMA protocol, PubMed and Science Direct databases were investigated and 22 articles were included. Fifty-five different miRNAs were found differentially expressed in the blood of psychotic patients compared to controls. Seventeen miRNAs (miR-34a, miR-181b, miR-432, miR-30e, miR-21, miR-137, miR-134, miR-7, miR-92a, miR-1273d, miR-1303, miR-3064-5p, miR-3131, miR-3687, miR-4428, miR-4725-3p, and miR-5096) were dysregulated with the same trend (up- or down-regulation) in at least two studies. Of note, miR-34a and miR-181b were up-regulated in the blood of psychotic patients in seven and six studies, respectively. Moreover, the level of miR-181b in plasma was found to be positively correlated with the amelioration of negative symptoms. The panel of miRNAs identified in this review could be validated in future studies in large and well-characterized cohorts of psychotic patients.
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Affiliation(s)
- Ștefania-Alexandra Grosu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (Ș.-A.G.); (M.E.H.)
| | - Maria Dobre
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania;
| | - Elena Milanesi
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (Ș.-A.G.); (M.E.H.)
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania;
| | - Mihail Eugen Hinescu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (Ș.-A.G.); (M.E.H.)
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania;
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17
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Freiría-Martínez L, Iglesias-Martínez-Almeida M, Rodríguez-Jamardo C, Rivera-Baltanás T, Comís-Tuche M, Rodrígues-Amorím D, Fernández-Palleiro P, Blanco-Formoso M, Diz-Chaves Y, González-Freiria N, Suárez-Albo M, Martín-Forero-Maestre M, Durán Fernández-Feijoo C, Fernández-Lorenzo JR, Concheiro Guisán A, Olivares JM, Spuch C. Human Breast Milk microRNAs, Potential Players in the Regulation of Nervous System. Nutrients 2023; 15:3284. [PMID: 37513702 PMCID: PMC10384760 DOI: 10.3390/nu15143284] [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: 06/15/2023] [Revised: 07/12/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
Human milk is the biological fluid with the highest exosome amount and is rich in microRNAs (miRNAs). These are key regulators of gene expression networks in both normal physiologic and disease contexts, miRNAs can influence many biological processes and have also shown promise as biomarkers for disease. One of the key aspects in the regeneration of the nervous system is that there are practically no molecules that can be used as potential drugs. In the first weeks of lactation, we know that human breast milk must contain the mechanisms to transmit molecular and biological information for brain development. For this reason, our objective is to identify new modulators of the nervous system that can be used to investigate neurodevelopmental functions based on miRNAs. To do this, we collected human breast milk samples according to the time of delivery and milk states: mature milk and colostrum at term; moderate and very preterm mature milk and colostrum; and late preterm mature milk. We extracted exosomes and miRNAs and realized the miRNA functional assays and target prediction. Our results demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function. We found 132 different miRNAs were identified across all samples. Sixty-nine miRNAs had significant differential expression after paired group comparison. These miRNAs are implicated in gene regulation of dopaminergic/glutamatergic synapses and neurotransmitter secretion and are related to the biological process that regulates neuron projection morphogenesis and synaptic vesicle transport. We observed differences according to the delivery time and with less clarity according to the milk type. Our data demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function.
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Affiliation(s)
- Luis Freiría-Martínez
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Marta Iglesias-Martínez-Almeida
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Cynthia Rodríguez-Jamardo
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Tania Rivera-Baltanás
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
| | - María Comís-Tuche
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Daniela Rodrígues-Amorím
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Patricia Fernández-Palleiro
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
| | - María Blanco-Formoso
- Department of Physical Chemistry, Singular Center for Biomedical Research (CINBIO), Universidade de Vigo, 36310 Vigo, Spain
| | - Yolanda Diz-Chaves
- Laboratory of Endocrinology, Singular Center for Biomedical Research (CINBIO), Universidade de Vigo, 36310 Vigo, Spain
| | | | - María Suárez-Albo
- Neonatal Intensive Care Unit, Alvaro Cunqueiro Hospital, 36312 Vigo, Spain
| | | | | | | | | | - Jose Manuel Olivares
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- CIBERSAM (Network Biomedical Research Center on Mental Health), 28029 Madrid, Spain
| | - Carlos Spuch
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- CIBERSAM (Network Biomedical Research Center on Mental Health), 28029 Madrid, Spain
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Kodali M, Madhu LN, Reger RL, Milutinovic B, Upadhya R, Attaluri S, Shuai B, Shankar G, Shetty AK. A single intranasal dose of human mesenchymal stem cell-derived extracellular vesicles after traumatic brain injury eases neurogenesis decline, synapse loss, and BDNF-ERK-CREB signaling. Front Mol Neurosci 2023; 16:1185883. [PMID: 37284464 PMCID: PMC10239975 DOI: 10.3389/fnmol.2023.1185883] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/28/2023] [Indexed: 06/08/2023] Open
Abstract
An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prevent hippocampal neurogenesis decline and synapse loss in the chronic phase of TBI. C57BL6 mice undergoing unilateral controlled cortical impact injury (CCI) received a single IN administration of different doses of EVs or the vehicle at 90 min post-TBI. Quantifying neurogenesis in the subgranular zone-granule cell layer (SGZ-GCL) through 5'-bromodeoxyuridine and neuron-specific nuclear antigen double labeling at ~2 months post-TBI revealed decreased neurogenesis in TBI mice receiving vehicle. However, in TBI mice receiving EVs (12.8 and 25.6 × 109 EVs), the extent of neurogenesis was matched to naive control levels. A similar trend of decreased neurogenesis was seen when doublecortin-positive newly generated neurons were quantified in the SGZ-GCL at ~3 months post-TBI. The above doses of EVs treatment after TBI also reduced the loss of pre-and post-synaptic marker proteins in the hippocampus and the somatosensory cortex. Moreover, at 48 h post-treatment, brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated cyclic AMP response-element binding protein (p-CREB) levels were downregulated in TBI mice receiving the vehicle but were closer to naïve control levels in TBI mice receiving above doses of hMSC-EVs. Notably, improved BDNF concentration observed in TBI mice receiving hMSC-EVs in the acute phase was sustained in the chronic phase of TBI. Thus, a single IN dose of hMSC-EVs at 90 min post-TBI can ease TBI-induced declines in the BDNF-ERK-CREB signaling, hippocampal neurogenesis, and synapses.
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19
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Hu W, Wong JYY, Dai Y, Ren D, Blechter B, Duan H, Niu Y, Xu J, Fu W, Meliefste K, Zhou B, Yang J, Ye M, Jia X, Meng T, Bin P, Rahman ML, Dean Hosgood H, Vermeulen RC, Silverman DT, Zheng Y, Lan Q, Rothman N. Occupational exposure to diesel engine exhaust and serum levels of microRNAs in a cross-sectional molecular epidemiology study in China. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2023; 64:159-166. [PMID: 36762959 DOI: 10.1002/em.22533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/29/2023] [Accepted: 02/08/2023] [Indexed: 05/03/2023]
Abstract
Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel-induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross-sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two-stage study, first measuring 405 miRNAs in a pilot study of six DEE-exposed workers exposed and six controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range: 47.7, 6.1-79.7 μg/m3 ) and 46 controls. The relationship between exposure to DEE and EC with miRNA levels was analyzed using linear regression adjusted for potential confounders. Serum levels of four miRNAs were significantly lower (miR-191-5p, miR-93-5p, miR-423-3p, miR-122-5p) and one miRNA was significantly higher (miR-92a-3p) in DEE exposed workers compared to controls. Of these miRNAs, miR-191-5p (ptrend = .001, FDR = 0.04) and miR-93-5p (ptrend = .009, FDR = 0.18) showed evidence of an inverse exposure-response with increasing EC levels. Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function.
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Affiliation(s)
- Wei Hu
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Jason Y Y Wong
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Yufei Dai
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Dianzhi Ren
- Chaoyang Center for Disease Control and Prevention, Chaoyang, China
| | - Batel Blechter
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Huawei Duan
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yong Niu
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jun Xu
- School of Public Health, The University of Hong Kong, Hong Kong, China
| | - Wei Fu
- Chaoyang Center for Disease Control and Prevention, Chaoyang, China
| | - Kees Meliefste
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | | | - Jufang Yang
- Chaoyang Center for Disease Control and Prevention, Chaoyang, China
| | - Meng Ye
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaowei Jia
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Tao Meng
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ping Bin
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Mohammad L Rahman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - H Dean Hosgood
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Division of Epidemiology, Albert Einstein College of Medicine, The Bronx, New York, USA
| | - Roel C Vermeulen
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Debra T Silverman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Yuxin Zheng
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Qing Lan
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Nathaniel Rothman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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20
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Elangovan A, Venkatesan D, Selvaraj P, Pasha MY, Babu HWS, Iyer M, Narayanasamy A, Subramaniam MD, Valsala Gopalakrishnan A, Kumar NS, Vellingiri B. miRNA in Parkinson's disease: From pathogenesis to theranostic approaches. J Cell Physiol 2023; 238:329-354. [PMID: 36502506 DOI: 10.1002/jcp.30932] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/22/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022]
Abstract
Parkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non-motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor-alpha and interleukin-6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.
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Affiliation(s)
- Ajay Elangovan
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India
| | - Dhivya Venkatesan
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India
| | - Priyanka Selvaraj
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India
| | - Md Younus Pasha
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India
| | - Harysh Winster Suresh Babu
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India.,Department of Zoology, Disease Proteomics Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India
| | - Mahalaxmi Iyer
- Livestock Farming, & Bioresources Technology, Tamil Nadu, India
| | - Arul Narayanasamy
- Department of Zoology, Disease Proteomics Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India
| | - Mohana Devi Subramaniam
- Department of Genetics and Molecular Biology, Vision Research Foundation, Tamil Nadu, Chennai, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bioscience and Technology, Vellore Institute of Technology (VIT), Tamil Nadu, Vellore, India
| | | | - Balachandar Vellingiri
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Tamil Nadu, Coimbatore, India.,Stem cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab, Punjab, Bathinda, India
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21
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Lekk I, Cabrera-Cabrera F, Turconi G, Tuvikene J, Esvald EE, Rähni A, Casserly L, Garton DR, Andressoo JO, Timmusk T, Koppel I. Untranslated regions of brain-derived neurotrophic factor mRNA control its translatability and subcellular localization. J Biol Chem 2023; 299:102897. [PMID: 36639028 PMCID: PMC9943900 DOI: 10.1016/j.jbc.2023.102897] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) promotes neuronal survival and growth during development. In the adult nervous system, BDNF is important for synaptic function in several biological processes such as memory formation and food intake. In addition, BDNF has been implicated in development and maintenance of the cardiovascular system. The Bdnf gene comprises several alternative untranslated 5' exons and two variants of 3' UTRs. The effects of these entire alternative UTRs on translatability have not been established. Using reporter and translating ribosome affinity purification analyses, we show that prevalent Bdnf 5' UTRs, but not 3' UTRs, exert a repressive effect on translation. However, contrary to previous reports, we do not detect a significant effect of neuronal activity on BDNF translation. In vivo analysis via knock-in conditional replacement of Bdnf 3' UTR by bovine growth hormone 3' UTR reveals that Bdnf 3' UTR is required for efficient Bdnf mRNA and BDNF protein production in the brain, but acts in an inhibitory manner in lung and heart. Finally, we show that Bdnf mRNA is enriched in rat brain synaptoneurosomes, with higher enrichment detected for exon I-containing transcripts. In conclusion, these results uncover two novel aspects in understanding the function of Bdnf UTRs. First, the long Bdnf 3' UTR does not repress BDNF expression in the brain. Second, exon I-derived 5' UTR has a distinct role in subcellular targeting of Bdnf mRNA.
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Affiliation(s)
- Ingrid Lekk
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | | | - Giorgio Turconi
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland,Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jürgen Tuvikene
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia,Protobios Llc, Tallinn, Estonia
| | - Eli-Eelika Esvald
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia,Protobios Llc, Tallinn, Estonia
| | - Annika Rähni
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia,Protobios Llc, Tallinn, Estonia
| | - Laoise Casserly
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland,Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Daniel R. Garton
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland,Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jaan-Olle Andressoo
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.
| | - Tõnis Timmusk
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia; Protobios Llc, Tallinn, Estonia.
| | - Indrek Koppel
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
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22
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Wang L, Shui X, Zhang M, Mei Y, Xia Y, Lan G, Hu L, Gan CL, Tian Y, Li R, Gu X, Zhang T, Chen D, Lee TH. MiR-191-5p Attenuates Tau Phosphorylation, Aβ Generation, and Neuronal Cell Death by Regulating Death-Associated Protein Kinase 1. ACS Chem Neurosci 2022; 13:3554-3566. [PMID: 36454178 DOI: 10.1021/acschemneuro.2c00423] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Dysregulation of microRNAs has been implicated in diverse diseases, including Alzheimer's disease (AD). MiR-191-5p in plasma/serum has been identified as a novel and promising noninvasive diagnostic biomarker for AD. However, whether miR-191-5p is involved in AD pathogenesis is largely unknown, and its levels in human AD brains are undetermined. Herein, we demonstrated that miR-191-5p downregulated tau phosphorylation at multiple AD-related sites and promoted neurite outgrowth using immunoblotting, immunofluorescence, and neurite outgrowth assays. Moreover, immunoblotting and enzyme-linked immunosorbent assays indicated that miR-191-5p decreased amyloid precursor protein phosphorylation levels and beta-amyloid (Aβ) generation. Furthermore, miR-191-5p reduced ceramide-induced neuronal cell death analyzed by trypan blue staining, the in situ cell death detection kit, and Annexin V-FITC/PI flow cytometry. Next, we verified that death-associated protein kinase 1 (DAPK1) was a direct target of miR-191-5p through the dual luciferase reporter assay and confirmed that the effects of miR-191-5p were antagonized by restoration of DAPK1 expression. Finally, the hippocampal miR-191-5p level was found to be decreased in humans with AD compared with controls and was inversely correlated with the DAPK1 expression level. Collectively, these findings suggest that miR-191-5p might exert inhibitory effects on tau phosphorylation, Aβ secretion, and neuronal cell death by directly targeting DAPK1, providing an attractive therapeutic option for AD.
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Affiliation(s)
- Long Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Xindong Shui
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Mi Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Yingxue Mei
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Yongfang Xia
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Guihua Lan
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Li Hu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Chen-Ling Gan
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Yuan Tian
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Ruomeng Li
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Xi Gu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Tao Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Dongmei Chen
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
| | - Tae Ho Lee
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian350122, China
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23
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Emerging Role of MicroRNA-30c in Neurological Disorders. Int J Mol Sci 2022; 24:ijms24010037. [PMID: 36613480 PMCID: PMC9819962 DOI: 10.3390/ijms24010037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) are a class of small non-coding RNAs that negatively regulate the expression of target genes by interacting with 3' untranslated regions of target mRNAs to induce mRNA degradation and translational repression. The miR-30 family members are involved in the development of many tissues and organs and participate in the pathogenesis of human diseases. As a key member of the miR-30 family, miR-30c has been implicated in neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. Mechanistically, miR-30c may act as a multi-functional regulator of different pathogenic processes such as autophagy, apoptosis, endoplasmic reticulum stress, inflammation, oxidative stress, thrombosis, and neurovascular function, thereby contributing to different disease states. Here, we review and discuss the biogenesis, gene regulation, and the role and mechanisms of action of miR-30c in several neurological disorders and therapeutic potential in clinics.
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24
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Abdolahi S, Zare-Chahoki A, Noorbakhsh F, Gorji A. A Review of Molecular Interplay between Neurotrophins and miRNAs in Neuropsychological Disorders. Mol Neurobiol 2022; 59:6260-6280. [PMID: 35916975 PMCID: PMC9463196 DOI: 10.1007/s12035-022-02966-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/17/2022] [Indexed: 01/10/2023]
Abstract
Various neurotrophins (NTs), including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4, promote cellular differentiation, survival, and maintenance, as well as synaptic plasticity, in the peripheral and central nervous system. The function of microRNAs (miRNAs) and other small non-coding RNAs, as regulators of gene expression, is pivotal for the appropriate control of cell growth and differentiation. There are positive and negative loops between NTs and miRNAs, which exert modulatory effects on different signaling pathways. The interplay between NTs and miRNAs plays a crucial role in the regulation of several physiological and pathological brain procedures. Emerging evidence suggests the diagnostic and therapeutic roles of the interactions between NTs and miRNAs in several neuropsychological disorders, including epilepsy, multiple sclerosis, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, anxiety disorders, depression, post-traumatic stress disorder, bipolar disorder, and drug abuse. Here, we review current data regarding the regulatory interactions between NTs and miRNAs in neuropsychological disorders, for which novel diagnostic and/or therapeutic strategies are emerging. Targeting NTs-miRNAs interactions for diagnostic or therapeutic approaches needs to be validated by future clinical studies.
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Affiliation(s)
- Sara Abdolahi
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
| | - Ameneh Zare-Chahoki
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Gorji
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Neurosurgery, Westfälische Wilhelms-Universität, Münster, Germany.
- Department of Neurology and Institute for Translational Neurology, Westfälische Wilhelms-Universität, Münster, Germany.
- Epilepsy Research Center, Westfälische Wilhelms-Universität, 48149, Münster, Germany.
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25
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Relationship between the expression level of miRNA-4485 and the severity of depressive symptoms in major depressive disorder patients. THE EUROPEAN JOURNAL OF PSYCHIATRY 2022. [DOI: 10.1016/j.ejpsy.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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26
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Gao YN, Zhang YQ, Wang H, Deng YL, Li NM. A New Player in Depression: MiRNAs as Modulators of Altered Synaptic Plasticity. Int J Mol Sci 2022; 23:ijms23094555. [PMID: 35562946 PMCID: PMC9101307 DOI: 10.3390/ijms23094555] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/15/2022] [Accepted: 04/18/2022] [Indexed: 01/04/2023] Open
Abstract
Depression is a psychiatric disorder that presents with a persistent depressed mood as the main clinical feature and is accompanied by cognitive impairment. Changes in neuroplasticity and neurogenesis greatly affect depression. Without genetic changes, epigenetic mechanisms have been shown to function by regulating gene expression during the body’s adaptation to stress. Studies in recent years have shown that as important regulatory factors in epigenetic mechanisms, microRNAs (miRNAs) play important roles in the development and progression of depression through the regulation of protein expression. Herein, we review the mechanisms of miRNA-mediated neuroplasticity in depression and discus synaptic structural plasticity, synaptic functional plasticity, and neurogenesis. Furthermore, we found that miRNAs regulate neuroplasticity through several signalling pathways to affect cognitive functions. However, these pathways do not work independently. Therefore, we try to identify synergistic correlations between miRNAs and multiple signalling pathways to broaden the potential pathogenesis of depression. In addition, in the future, dual-function miRNAs (protection/injury) are promising candidate biomarkers for the diagnosis of depression, and their regulated genes can potentially be used as target genes for the treatment of depression.
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Affiliation(s)
- Ya-Nan Gao
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (Y.-N.G.); (H.W.)
| | - Yong-Qian Zhang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (Y.-Q.Z.); (Y.-L.D.)
| | - Hao Wang
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (Y.-N.G.); (H.W.)
| | - Yu-Lin Deng
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (Y.-Q.Z.); (Y.-L.D.)
| | - Nuo-Min Li
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (Y.-N.G.); (H.W.)
- Correspondence:
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27
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Deng B, Zhang Z, Zhou H, Zhang X, Niu S, Yan X, Yan J. MicroRNAs in Methamphetamine-Induced Neurotoxicity and Addiction. Front Pharmacol 2022; 13:875666. [PMID: 35496314 PMCID: PMC9046672 DOI: 10.3389/fphar.2022.875666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/31/2022] [Indexed: 12/21/2022] Open
Abstract
Methamphetamine (METH) abuse remains a significant public health concern globally owing to its strong addictive properties. Prolonged abuse of the drug causes irreversible damage to the central nervous system. To date, no efficient pharmacological interventions are available, primarily due to the unclear mechanisms underlying METH action in the brain. Recently, microRNAs (miRNAs) have been identified to play critical roles in various cellular processes. The expression levels of some miRNAs are altered after METH administration, which may influence the transcription of target genes to regulate METH toxicity or addiction. This review summarizes the miRNAs in the context of METH use, discussing their role in the reward effect and neurotoxic sequelae. Better understanding of the molecular mechanisms involved in METH would be helpful for the development of new therapeutic strategies in reducing the harm of the drug.
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Affiliation(s)
- Bi Deng
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhirui Zhang
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Huixuan Zhou
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xinran Zhang
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Shuliang Niu
- School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
| | - Xisheng Yan
- Department of Cardiovascular Medicine, Wuhan Third Hospital and Tongren Hospital of Wuhan University, Wuhan, China
| | - Jie Yan
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
- *Correspondence: Jie Yan,
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28
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Sun T, Zhao K, Liu M, Cai Z, Zeng L, Zhang J, Li Z, Liu R. miR-30a-5p induces Aβ production via inhibiting the nonamyloidogenic pathway in Alzheimer’s disease. Pharmacol Res 2022; 178:106153. [DOI: 10.1016/j.phrs.2022.106153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/16/2022] [Accepted: 03/01/2022] [Indexed: 12/30/2022]
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29
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Roy B, Lee E, Li T, Rampersaud M. Role of miRNAs in Neurodegeneration: From Disease Cause to Tools of Biomarker Discovery and Therapeutics. Genes (Basel) 2022; 13:genes13030425. [PMID: 35327979 PMCID: PMC8951370 DOI: 10.3390/genes13030425] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/14/2022] [Accepted: 02/18/2022] [Indexed: 11/16/2022] Open
Abstract
Neurodegenerative diseases originate from neuronal loss in the central nervous system (CNS). These debilitating diseases progress with age and have become common due to an increase in longevity. The National Institute of Environmental Health Science’s 2021 annual report suggests around 6.2 million Americans are living with Alzheimer’s disease, and there is a possibility that there will be 1.2 million Parkinson’s disease patients in the USA by 2030. There is no clear-cut universal mechanism for identifying neurodegenerative diseases, and therefore, they pose a challenge for neurobiology scientists. Genetic and environmental factors modulate these diseases leading to familial or sporadic forms. Prior studies have shown that miRNA levels are altered during the course of the disease, thereby suggesting that these noncoding RNAs may be the contributing factor in neurodegeneration. In this review, we highlight the role of miRNAs in the pathogenesis of neurodegenerative diseases. Through this review, we aim to achieve four main objectives: First, we highlight how dysregulation of miRNA biogenesis led to these diseases. Second, we highlight the computational or bioinformatics tools required to identify the putative molecular targets of miRNAs, leading to biological molecular pathways or mechanisms involved in these diseases. Third, we focus on the dysregulation of miRNAs and their target genes leading to several neurodegenerative diseases. In the final section, we highlight the use of miRNAs as potential diagnostic biomarkers in the early asymptomatic preclinical diagnosis of these age-dependent debilitating diseases. Additionally, we discuss the challenges and advances in the development of miRNA therapeutics for brain targeting. We list some of the innovative strategies employed to deliver miRNA into target cells and the relevance of these viral and non-viral carrier systems in RNA therapy for neurodegenerative diseases. In summary, this review highlights the relevance of studying brain-enriched miRNAs, the mechanisms underlying their regulation of target gene expression, their dysregulation leading to progressive neurodegeneration, and their potential for biomarker marker and therapeutic intervention. This review thereby highlights ways for the effective diagnosis and prevention of these neurodegenerative disorders in the near future.
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Affiliation(s)
- Bidisha Roy
- Life Science Centre, Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07012, USA
- Correspondence:
| | - Erica Lee
- Department of Pathology, Icahn School of Medicine, New York, NY 10029, USA; (E.L.); (T.L.); (M.R.)
| | - Teresa Li
- Department of Pathology, Icahn School of Medicine, New York, NY 10029, USA; (E.L.); (T.L.); (M.R.)
| | - Maria Rampersaud
- Department of Pathology, Icahn School of Medicine, New York, NY 10029, USA; (E.L.); (T.L.); (M.R.)
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30
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Tsamou M, Carpi D, Pistollato F, Roggen EL. Sporadic Alzheimer's Disease- and Neurotoxicity-Related microRNAs Affecting Key Events of Tau-Driven Adverse Outcome Pathway Toward Memory Loss. J Alzheimers Dis 2022; 86:1427-1457. [PMID: 35213375 DOI: 10.3233/jad-215434] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer's disease (sAD). OBJECTIVE Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. METHODS Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to create miR-target interaction networks. RESULTS The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. CONCLUSION Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms.
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Affiliation(s)
- Maria Tsamou
- ToxGenSolutions (TGS), Maastricht, The Netherlands
| | - Donatella Carpi
- European Commission, Joint Research Centre (JRC), Ispra VA, Italy
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31
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Male sex bias in early and late onset neurodevelopmental disorders: shared aspects and differences in autism spectrum disorder, attention deficit/hyperactivity disorder, and schizophrenia. Neurosci Biobehav Rev 2022; 135:104577. [DOI: 10.1016/j.neubiorev.2022.104577] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/23/2022] [Accepted: 02/11/2022] [Indexed: 12/22/2022]
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32
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Deng M, Wang Y, Yu S, Fan Q, Qiu J, Wang Z, Xiao Z. Exploring Association Between Serotonin and Neurogenesis Related Genes in Obsessive-Compulsive Disorder in Chinese Han People: Promising Association Between DMRT2, miR-30a-5p, and Early-Onset Patients. Front Psychiatry 2022; 13:857574. [PMID: 35633798 PMCID: PMC9137639 DOI: 10.3389/fpsyt.2022.857574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/04/2022] [Indexed: 12/02/2022] Open
Abstract
Obsessive-compulsive disorder (OCD) is a deliberating disorder with complex genetic and environmental etiologies. Hypotheses about OCD mainly include dysregulated neurotransmitters, especially serotonin, and disturbed neurodevelopment. Single nucleotide polymorphism (SNP) association studies regarding OCD are often met with inconsistent results. However, stratification by age of onset may sometimes help to limit the heterogenicity of OCD patients. Therefore, we conducted a stratified SNP association study enrolling 636 patients and 612 healthy controls. Patients were stratified by age of onset as early-onset (EO-OCD) and late-onset (LO-OCD). Blood extracted from the patients was used to genotype 18 loci, including serotonin system genes, Slitrk1, Slitrk5, and DMRT2 and related miRNA genes. Logistic regression was used to compare allele and genotype frequencies of variants. A general linear model was used to evaluate the association between variants and trait anxiety. In our study, rs3824419 in DMRT2 was associated with EO-OCD, G allele was the risk allele. Rs2222722 in miR-30a-5p was associated with EO-OCD, with the C allele being the risk allele. Rs1000952 in HTR3D was found associated with trait anxiety in OCD patients. The significance disappeared after FDR correction. Our results supported neurodevelopment-related genes, DMRT2 and miR-30a-5p, to be related to EO-OCD. However, we cannot prove serotonin genes to be directly associated with EO-OCD. While an association between HTR3D and trait anxiety was discovered, comparisons based on biological or clinical traits may be helpful in future studies. As our detective powers were limited, more large-scale studies will be needed to confirm our conclusion.
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Affiliation(s)
- Miaohan Deng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shunying Yu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Fan
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianyin Qiu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zeping Xiao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ma W, Qiu Z, Bai Z, Dai Y, Li C, Chen X, Song X, Shi D, Zhou Y, Pan Y, Liao Y, Liao M, Zhou Z. Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:678-693. [PMID: 34703652 PMCID: PMC8517099 DOI: 10.1016/j.omtn.2021.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 09/09/2021] [Indexed: 12/04/2022]
Abstract
The excessive and ectopic pulmonary artery smooth muscle cells (PASMCs) are crucial to the pathogenesis of pulmonary arteriole (PA) remodeling in pulmonary arterial hypertension (PAH). We previously found that microRNA (miR)-30a was significantly increased in acute myocardial infarction (AMI) patients and animals, as well as in cultured cardiomyocytes after hypoxia, suggesting that it might be strongly associated with hypoxia-related diseases. Here, we investigated the role of miR-30a in the PASMC remodeling of PAH. The expression of miR-30a was higher in the serum of PAH patients compared with healthy controls. miR-30a was mainly expressed in PAs and was increased in PASMCs after hypoxia, mediating the downregulation of p53 tumor suppressor protein (P53). Genetic knockout of miR-30a effectively decreased right ventricular (RV) systolic pressure (RVSP), PA, and RV remodeling in the Su5416/hypoxia-induced and monocrotaline (MCT)-induced PAH animals. Additionally, pharmacological inhibition of miR-30a via intratracheal liquid instillation (IT-L) delivery strategy showed high efficiency, which downregulated miR-30a to mitigate disease phenotype in the Su5416/hypoxia-induced PAH animals, and these beneficial effects could be partially reduced by simultaneous P53 inhibition. We demonstrate that inhibition of miR-30a could ameliorate experimental PAH through the miR-30a/P53 signaling pathway, and the IT-L delivery strategy shows good therapeutic outcomes, providing a novel and promising approach for the treatment of PAH.
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Affiliation(s)
- Wenrui Ma
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhihua Qiu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zeyang Bai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yong Dai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chang Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiao Chen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoxiao Song
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dingyang Shi
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yanzhao Zhou
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yajie Pan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhua Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengyang Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Corresponding author: Mengyang Liao, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
| | - Zihua Zhou
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Corresponding author: Zihua Zhou, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
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Wan W, Liu G, Li X, Liu Y, Wang Y, Pan H, Hu J. MiR-191-5p alleviates microglial cell injury by targeting Map3k12 (mitogen-activated protein kinase kinase kinase 12) to inhibit the MAPK (mitogen-activated protein kinase) signaling pathway in Alzheimer's disease. Bioengineered 2021; 12:12678-12690. [PMID: 34818971 PMCID: PMC8810200 DOI: 10.1080/21655979.2021.2008638] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Multiple reports have elucidated that microRNAs are promising biomarkers for AD diagnosis and treatment. Herein, the effect of miR-191-5p on microglial cell injury and the underlying mechanism were explored. APP/PS1 transgenic mice were utilized to establish mouse model of AD. Amyloid-β protein 1-42 (Aβ1-42)-treated microglia were applied to establish in vitro cell model of AD. MiR-191-5p expression in hippocampus and microglia was measured by reverse transcription quantitative polymerase chain reaction. The viability and apoptosis of microglia were evaluated by Cell Counting Kit-8 assays and flow cytometry analyses, respectively. The binding relationship between miR-191-5p and its downstream target mitogen-activated protein kinase kinase kinase 12 (Map3k12) was determined by luciferase reporter assays. Pathological degeneration of hippocampus was tested using hematoxylin-eosin staining and Nissl staining. Aβ expression in hippocampus was examined via immunohistochemistry. In this study, miR-191-5p was downregulated in Aβ1-42-stimulated microglia and hippocampal tissues of APP/PS1 mice. MiR-191-5p overexpression facilitated cell viability and inhibited apoptosis rate of Aβ1-42-treated microglia. Mechanically, miR-191-5p targeted Map3k12 3'-untranslated region to downregulate Map3k12 expression. MiR-191-5p inhibited Aβ1-42-induced microglial cell injury and inactivated the MAPK signaling by downregulating Map3k12. Overall, miR-191-5p alleviated Aβ1-42-induced microglia cell injury by targeting Map3k12 to inhibit the MAPK signaling pathway in microglia.
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Affiliation(s)
- Wenjun Wan
- Department of Rehabilitation Medicine, Wuhan Central Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ganzhe Liu
- Department of Neurology, Wuhan Central Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xia Li
- Department of Ultrasound Imaging, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Yu Liu
- Department of Radiology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Ying Wang
- Department of Rehabilitation Medicine, Wuhan Central Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haisong Pan
- Department of Radiology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Jun Hu
- Department of Radiology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China
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The emerging role of miRNA-132/212 cluster in neurologic and cardiovascular diseases: Neuroprotective role in cells with prolonged longevity. Mech Ageing Dev 2021; 199:111566. [PMID: 34517022 DOI: 10.1016/j.mad.2021.111566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/18/2021] [Accepted: 09/03/2021] [Indexed: 01/07/2023]
Abstract
miRNA-132/212 are small regulators of gene expression with a function that fulfills a vital function in diverse biological processes including neuroprotection of cells with prolonged longevity in neurons and the cardiovascular system. In neurons, miRNA-132 appears to be essential for controlling differentiation, development, and neural functioning. Indeed, it also universally promotes axon evolution, nervous migration, plasticity as well, it is suggested to be neuroprotective against neurodegenerative diseases. Moreover, miRNA-132/212 disorder leads to neural developmental perturbation, and the development of degenerative disorders covering Alzheimer's, Parkinson's, and epilepsy's along with psychiatric perturbations including schizophrenia. Furthermore, the cellular mechanisms of the miRNA-132/212 have additionally been explored in cardiovascular diseases models. Also, the miRNA-132/212 family modulates cardiac hypertrophy and autophagy in cardiomyocytes. The protective and effective clinical promise of miRNA-132/212 in these systems is discussed in this review. To sum up, the current progress in innovative miRNA-based therapies for human pathologies seems of extreme concern and reveals promising novel therapeutic strategies.
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Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, Lazar SV, Wang A. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J Stem Cells 2021; 13:776-794. [PMID: 34367477 PMCID: PMC8316862 DOI: 10.4252/wjsc.v13.i7.776] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/29/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are extensively studied as cell-therapy agents for neurological diseases. Recent studies consider exosomes secreted by MSCs as important mediators for MSCs’ neuroprotective functions. Exosomes transfer functional molecules including proteins, lipids, metabolites, DNAs, and coding and non-coding RNAs from MSCs to their target cells. Emerging evidence shows that exosomal microRNAs (miRNAs) play a key role in the neuroprotective properties of these exosomes by targeting several genes and regulating various biological processes. Multiple exosomal miRNAs have been identified to have neuroprotective effects by promoting neurogenesis, neurite remodeling and survival, and neuroplasticity. Thus, exosomal miRNAs have significant therapeutic potential for neurological disorders such as stroke, traumatic brain injury, and neuroinflammatory or neurodegenerative diseases and disorders. This review discusses the neuroprotective effects of selected miRNAs (miR-21, miR-17-92, miR-133, miR-138, miR-124, miR-30, miR146a, and miR-29b) and explores their mechanisms of action and applications for the treatment of various neurological disease and disorders. It also provides an overview of state-of-the-art bioengineering approaches for isolating exosomes, optimizing their yield and manipulating the miRNA content of their cargo to improve their therapeutic potential.
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Affiliation(s)
- Aida Nasirishargh
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Priyadarsini Kumar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Lalithasri Ramasubramanian
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
| | - Kaitlin Clark
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Dake Hao
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Sabrina V Lazar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Aijun Wang
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
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Hubens WHG, Krauskopf J, Beckers HJM, Kleinjans JCS, Webers CAB, Gorgels TGMF. Small RNA Sequencing of Aqueous Humor and Plasma in Patients With Primary Open-Angle Glaucoma. Invest Ophthalmol Vis Sci 2021; 62:24. [PMID: 34156425 PMCID: PMC8237107 DOI: 10.1167/iovs.62.7.24] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Purpose Identify differentially expressed microRNAs (miRNAs) in aqueous humor (AH) and blood of primary open-angle glaucoma (POAG) patients by using small RNA sequencing. These may provide insight into POAG pathophysiology or serve as diagnostic biomarker. Methods AH and plasma of nine POAG patients and 10 cataract control patients were small RNA sequenced on Illumina NovaSeq 6000. Identification of gene transcripts targeted by differentially expressed miRNAs was done with miRWalk and MirPath. These targets were used for pathway analysis and Gene Ontology enrichment. Diagnostic potential was evaluated by receiver operating characteristics analysis. Results We identified 715 miRNAs in plasma and 62 miRNAs in AH. Plasma miRNA profile did not differ between POAG and control. In contrast, in AH, seven miRNAs were differentially expressed. Hsa-miR-30a-3p, hsa-miR-143-3p, hsa-miR-211-5p, and hsa-miR-221-3p were upregulated, whereas hsa-miR-92a-3p, hsa-miR-451a, and hsa-miR-486-5p were downregulated in POAG. Compared to previous studies, hsa-mir-143-3p, hsa-miR-211-5p, and hsa-miR-221-3p were reported previously, strengthening their involvement in POAG whereas hsa-miR-30a-3p, hsa-miR-92a-3p, and hsa-miR-486-5p are implicated in POAG for the first time. Identified gene transcripts were involved in several pathways, some implicated in glaucoma before (e.g., TGF-β and neurotrophin signaling), whereas others are new (e.g., prolactin and apelin signaling). In respect to diagnostics, AH concentration of hsa-mir-143-3p had an area under the curve (AUC) of 0.889. Combined with hsa-miR-221-3p, AUC improved to 0.96. Conclusions Small RNA sequencing identified seven differentially expressed miRNAs in AH of POAG patients. The differentially expressed miRNAs may be useful as POAG biomarkers or could become targets for new therapeutic strategies.
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Affiliation(s)
- Wouter H G Hubens
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.,School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Julian Krauskopf
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Henny J M Beckers
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jos C S Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Carroll A B Webers
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Theo G M F Gorgels
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
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New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs. Biomed Pharmacother 2021; 140:111753. [PMID: 34044272 PMCID: PMC8222190 DOI: 10.1016/j.biopha.2021.111753] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/22/2021] [Accepted: 05/19/2021] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have critical role in the pathophysiology as well as recovery after ischemic stroke. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are critical for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. Moreover, exosomes have been considered as nanocarriers capable of transferring various cargos, such as lncRNAs and miRNAs to recipient cells, with prominent inter-cellular roles in the mediation of neuro-restorative events following strokes and neural injuries. In this review, we summarize the pathogenic role of ncRNAs and exosomal ncRNAs in the stroke.
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Epigenetic modification of BDNF mediates neuropathic pain via miR-30a-3p/EP300 axis in CCI rats. Biosci Rep 2021; 40:226778. [PMID: 33103739 PMCID: PMC7670569 DOI: 10.1042/bsr20194442] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 09/08/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022] Open
Abstract
Recent investigation of microRNAs on chronic pain has developed a breakthrough in neuropathic pain management. In the present study, decreased expression of miR-30a-3p was reported using qRT-PCR analysis and loss of miR-30a-3p promoted neuropathic pain progression in sciatic nerve chronic constrictive injury rats through determining the pain threshold. We predicted miR-30a-3p could target E-cadherin transcriptional activator (EP300) via bioinformatics analysis. Meanwhile, we found that brain-derived neurotrophic factor (BDNF) is involved in neuropathic pain. Here, we exhibited that EP300 epigenetically up-regulated BDNF via enhancing acetylated histone H3 and H4 on the promoter. For another, miR-30a-3p was able to modify the level of BDNF and acetylated histone H3 and H4. Loss of miR-30a-3p enhanced EP300 and BDNF colocalization in CCI rats. Subsequently, it was shown that increased EP300 induced neuropathic pain by an enhancement of neuronal BDNF level in vivo. To sum up, it was revealed that epigenetic modification of BDNF promoted neuropathic pain via EP300 induced by miR-30a-3p in CCI rats.
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40
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Luo PX, Manning CE, Fass JN, Williams AV, Hao R, Campi KL, Trainor BC. Sex-specific effects of social defeat stress on miRNA expression in the anterior BNST. Behav Brain Res 2021; 401:113084. [PMID: 33358922 PMCID: PMC7864284 DOI: 10.1016/j.bbr.2020.113084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/09/2020] [Accepted: 12/16/2020] [Indexed: 12/31/2022]
Abstract
Women are more likely to suffer from stress-related affective disorders than men, but the underlying mechanisms of sex differences remain unclear. Previous works show that microRNA (miRNA) profiles are altered in stressed animals and patients with depression and anxiety disorders. In this study, we investigated how miRNA expression in the anterior bed nucleus of stria terminalis (BNST) was affected by social defeat stress in female and male California mice (Peromyscus californicus). We performed sequencing to identify miRNA transcripts in the whole brain and anterior BNST followed by qPCR analysis to compare miRNA expression between control and stressed animals. The results showed that social defeat stress induced sex-specific miRNA expression changes in the anterior BNST. Let-7a, let-7f and miR-181a-5p were upregulated in stressed female but not male mice. Our study provided evidence that social stress produces distinct molecular responses in the BNST of males and females.
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Affiliation(s)
- Pei X Luo
- Department of Psychology, University of California, Davis, CA, 95616, USA
| | - Claire E Manning
- Department of Psychology, University of California, Davis, CA, 95616, USA
| | - Joe N Fass
- Bioinformatics Core and Genome Center, University of California, Davis, CA, 95616, USA
| | - Alexia V Williams
- Department of Psychology, University of California, Davis, CA, 95616, USA
| | - Rebecca Hao
- Department of Psychology, University of California, Davis, CA, 95616, USA
| | - Katharine L Campi
- Department of Psychology, University of California, Davis, CA, 95616, USA
| | - Brian C Trainor
- Department of Psychology, University of California, Davis, CA, 95616, USA.
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Ehinger Y, Phamluong K, Darevesky D, Welman M, Moffat JJ, Sakhai SA, Whiteley EL, Berger AL, Laguesse S, Farokhnia M, Leggio L, Lordkipanidzé M, Ron D. Differential correlation of serum BDNF and microRNA content in rats with rapid or late onset of heavy alcohol use. Addict Biol 2021; 26:e12890. [PMID: 32135570 DOI: 10.1111/adb.12890] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 02/13/2020] [Accepted: 02/15/2020] [Indexed: 12/22/2022]
Abstract
Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs (miRs) targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the two-bottle choice paradigm (IA20%2BC) and measured circulating levels of BDNF protein and miRs targeting BDNF in the serum of Long-Evans rats before and after 8 weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified, whereas 70% of the rats gradually escalate their alcohol intake (late onset), and 30% of alcohol users exhibit a very rapid onset of drinking (rapid onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both rapid onset and late onset rats. In contrast, increased expression of the miRs targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the rapid onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Together, these data suggest that rats exhibit both late and rapid onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the rapid onset rats.
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Affiliation(s)
- Yann Ehinger
- Department of Neurology University of California, San Francisco San Francisco California
| | - Khanhky Phamluong
- Department of Neurology University of California, San Francisco San Francisco California
| | - David Darevesky
- Department of Neurology University of California, San Francisco San Francisco California
| | - Melanie Welman
- Research Center Montreal Heart Institute Montreal Quebec Canada
| | - Jeffrey J. Moffat
- Department of Neurology University of California, San Francisco San Francisco California
| | - Samuel A. Sakhai
- Department of Neurology University of California, San Francisco San Francisco California
| | - Ellanor L. Whiteley
- Department of Neurology University of California, San Francisco San Francisco California
| | - Anthony L. Berger
- Department of Neurology University of California, San Francisco San Francisco California
| | - Sophie Laguesse
- Department of Neurology University of California, San Francisco San Francisco California
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section National Institute on Drug Abuse Intramural Research Program Baltimore Maryland
- Medication Development Program, National Institute on Drug Abuse Intramural Research Program National Institutes of Health Baltimore Maryland
- National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research National Institutes of Health Bethesda Maryland
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section National Institute on Drug Abuse Intramural Research Program Baltimore Maryland
- Medication Development Program, National Institute on Drug Abuse Intramural Research Program National Institutes of Health Baltimore Maryland
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences Brown University Providence Rhode Island
- National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research National Institutes of Health Bethesda Maryland
| | - Marie Lordkipanidzé
- Research Center Montreal Heart Institute Montreal Quebec Canada
- Faculty of Pharmacy University of Montreal Montreal Quebec Canada
| | - Dorit Ron
- Department of Neurology University of California, San Francisco San Francisco California
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Pan S, Feng W, Li Y, Huang J, Chen S, Cui Y, Tian B, Tan S, Wang Z, Yao S, Chiappelli J, Kochunov P, Chen S, Yang F, Li CSR, Tian L, Tan Y, Elliot Hong L. The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure. Transl Psychiatry 2021; 11:117. [PMID: 33558459 PMCID: PMC7870897 DOI: 10.1038/s41398-021-01240-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 01/08/2021] [Accepted: 01/20/2021] [Indexed: 01/10/2023] Open
Abstract
Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = -0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002-0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy.
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Affiliation(s)
- Shujuan Pan
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Wei Feng
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Yanli Li
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Junchao Huang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Song Chen
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Yimin Cui
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Baopeng Tian
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Shuping Tan
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Zhiren Wang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Shangwu Yao
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Joshua Chiappelli
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
| | - Peter Kochunov
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
| | - Shuo Chen
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
| | - Fude Yang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Chiang-Shan R. Li
- grid.47100.320000000419368710Department of Psychiatry, Yale University School of Medicine, New Haven, CT USA
| | - Li Tian
- grid.10939.320000 0001 0943 7661Faculty of Medicine, Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Yunlong Tan
- Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China.
| | - L. Elliot Hong
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
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Pejhan S, Rastegar M. Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease. Biomolecules 2021; 11:75. [PMID: 33429932 PMCID: PMC7827577 DOI: 10.3390/biom11010075] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/01/2021] [Accepted: 01/03/2021] [Indexed: 12/16/2022] Open
Abstract
Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.
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Affiliation(s)
| | - Mojgan Rastegar
- Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
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Ryan M, Tan VTY, Thompson N, Guévremont D, Mockett BG, Tate WP, Abraham WC, Hughes SM, Williams J. Lentivirus-Mediated Expression of Human Secreted Amyloid Precursor Protein-Alpha Promotes Long-Term Induction of Neuroprotective Genes and Pathways in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis 2021; 79:1075-1090. [PMID: 33386801 DOI: 10.3233/jad-200757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer's disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. OBJECTIVE To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. METHODS We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). RESULTS Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. CONCLUSION This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo.
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Affiliation(s)
- Margaret Ryan
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Valerie T Y Tan
- Department of Psychology, University of Otago, Dunedin, New Zealand.,Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Nasya Thompson
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Diane Guévremont
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Bruce G Mockett
- Department of Psychology, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Warren P Tate
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Wickliffe C Abraham
- Department of Psychology, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Stephanie M Hughes
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Joanna Williams
- Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, University of Otago, Dunedin, New Zealand.,Brain Research New Zealand - Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
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Huang X, Bao C, Lv Q, Zhao J, Hu G, Wu H, Li Z, Yi Z. MicroRNA-195 predicts olanzapine response in drug-free patients with schizophrenia: A prospective cohort study. J Psychopharmacol 2021; 35:23-30. [PMID: 33274684 DOI: 10.1177/0269881120959617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Disturbances of microRNA-195 have been implicated in the pathogenesis of schizophrenia. However, microRNA-195 levels in schizophrenia are controversial. AIMS To the best of our knowledge, this is the first study to examine microRNA-195 levels in untreated schizophrenia patients and their relationship to olanzapine response. METHODS We recruited 81 untreated schizophrenia patients and 96 healthy controls. The patients received 2 months olanzapine treatment. MicroRNA-195 levels in peripheral blood mononuclear cells were measured using quantitative real-time polymerase chain reaction testing. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale. RESULTS No significant differences in microRNA-195 levels were found between patients and healthy controls (p > 0.05). Olanzapine significantly reduced microRNA-195 levels after 2 months treatment (p = 0.003). Interestingly, microRNA-195 levels decreased significantly in responders (p = 0.010), but not in non-responders (p > 0.05). Both baseline microRNA-195 levels (p = 0.027, p = 0.030) and the reduction rate of microRNA-195 levels (p = 0.034, p = 0.044) were positively associated with the reduction rate of Positive and Negative Syndrome Scale total score and general psychopathological subscale score. Multiple stepwise regression analysis revealed that baseline microRNA-195 level was an independent contributor to the reduction in Positive and Negative Syndrome Scale total score and the general psychopathological subscale score (p = 0.018, p = 0.030). Finally, logistic regression analysis suggested that baseline microRNA-195 level can serve as a biomarker for response to olanzapine (p = 0.037). CONCLUSIONS Our data indicate that microRNA-195 level may predict symptomatic improvement and olanzapine response in schizophrenia patients, suggesting that microRNA-195 should be considered as a potential therapeutic target for antipsychotics.
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Affiliation(s)
- Xinxin Huang
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenxi Bao
- Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Qinyu Lv
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Zhao
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guoqin Hu
- Department of Psychiatry, Huangpu District Mental Health Center, Shanghai, China
| | - Haisu Wu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zezhi Li
- Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenghui Yi
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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46
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Chow R, Wessels JM, Foster WG. Brain-derived neurotrophic factor (BDNF) expression and function in the mammalian reproductive Tract. Hum Reprod Update 2020; 26:545-564. [PMID: 32378708 DOI: 10.1093/humupd/dmaa008] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 12/13/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Neurotrophins of the nerve growth factor family are soluble polypeptides that are best known for their role in nerve growth, survival and differentiation in the central nervous system. A growing body of literature shows that neurotrophins and their receptors are also expressed throughout the reproductive tract. OBJECTIVE AND RATIONALE Neurotrophins are key regulatory proteins in reproductive physiology during development and throughout adult life. Of the neurotrophins, the literature describing the expression and function of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, neurotrophin receptor kinase-2 (NTRK2), has been expanding rapidly. We therefore conducted a systematic inductive qualitative review of the literature to better define the role of the BDNF in the reproductive tract. We postulate that BDNF and NTRK2 are central regulatory proteins throughout the reproductive system. SEARCH METHODS An electronic search of Medline (PubMed) and Web of Science for articles relating to BDNF and the reproductive system was carried out between January 2018 and February 2019. OUTCOMES In the ovary, BDNF expression and levels have been linked with follicle organisation during ovarian development, follicle recruitment and growth and oocyte maturation. In the endometrium, BDNF is involved in cell proliferation and neurogenesis. In contrast, literature describing the role of BDNF in other reproductive tissues is sparse and BDNF-NTRK2 signalling in the male reproductive tract has been largely overlooked. Whilst estradiol appears to be the primary regulator of BDNF expression, we also identified reports describing binding sites for glucocorticoid and myocyte enhancer factor-2, a calcium-response element through activation of an N-methyl-D-aspartate (NMDA) receptor, and aryl hydrocarbon receptor nuclear transporter protein-4 (ARNT) response elements in promoter regions of the BDNF gene. Expression is also regulated by multiple microRNAs and post-translational processing of precursor proteins and intracellular shuttling. BDNF-NTRK2 signalling is modulated through tissue specific receptor expression of either the full-length or truncated NTRK2 receptor; however, the functional importance remains to be elucidated. Dysregulation of BDNF expression and circulating concentrations have been implicated in several reproductive disorders including premature ovarian failure, endometriosis, pre-eclampsia, intra-uterine growth restriction (IUGR) and several reproductive cancers. WIDER IMPLICATIONS We conclude that BDNF and its receptors are key regulatory proteins central to gonadal development, ovarian regulation and uterine physiology, as well as embryo and placenta development. Furthermore, dysregulation of BDNF-NTRK2 in reproductive diseases suggests their potential role as candidate clinical markers of disease and potential therapeutic targets.
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Affiliation(s)
- R Chow
- Department of Obstetrics & Gynaecology, McMaster University, Hamilton, Ontario, Canada
| | - J M Wessels
- Department of Obstetrics & Gynaecology, McMaster University, Hamilton, Ontario, Canada
| | - W G Foster
- Department of Obstetrics & Gynaecology, McMaster University, Hamilton, Ontario, Canada
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Cattaneo A, Suderman M, Cattane N, Mazzelli M, Begni V, Maj C, D'Aprile I, Pariante CM, Luoni A, Berry A, Wurst K, Hommers L, Domschke K, Cirulli F, Szyf M, Menke A, Riva MA. Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability. Neurobiol Stress 2020; 13:100271. [PMID: 33344724 PMCID: PMC7739180 DOI: 10.1016/j.ynstr.2020.100271] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/05/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Exposure to early life stress can interfere with neurodevelopmental trajectories to increase the vulnerability for psychiatric disorders later in life. With this respect, epigenetic mechanisms play a key role for the long-lasting changes in brain functions that may elicit and sustain psychopathologic outcomes. Here, we investigated DNA methylation changes as possible epigenetic mechanism mediating the effect of prenatal stress (PNS), an experimental paradigm associated with behavioral and molecular alterations relevant for psychiatric disorders. We identified 138 genes as being differentially methylated in the prefrontal cortex (PFC) and in the hippocampus (HIP) of male and female adult rats exposed to PNS. Among these genes, miR-30a and Neurod1 emerged as potential players for the negative outcomes associated with PNS exposure. Indeed, in addition to showing consistent methylation differences in both brain regions and in both sexes, and interacting with each other, they are both involved in Axon guidance and Neurotrophin signaling, which are important to neurodevelopmental disorders. We also found a significant reduction in the expression of a panel of genes (CAMK2A, c-JUN, LIMK1, MAP2K1, MAP2K2, PIK3CA and PLCG1) that belong to these two biological pathways and are also validated targets of miR-30a, pointing to a down-regulation of these pathways as a consequence of PNS exposure. Interestingly, we also found that miR-30a levels were significantly upregulated in depressed patients exposed to childhood trauma, as compared to control individuals. Importantly, we also found that a sub-chronic treatment with the atypical antipsychotic drug, lurasidone, during adolescence was able to prevent the up-regulation of miR-30a and normalized the expression of its target genes in response to PNS exposure. Our results demonstrate that miR-30a undergoes epigenetic changes following early life stress exposure and suggest that this miRNA could play a key role in producing broad and long-lasting alterations in neuroplasticity-related pathways, contributing to the etiology of psychiatric disorders.
MiR-30a and Neurod1 undergo epigenetic changes following PNS exposure. MiR-30 and Neurod1 are involved in Axon guidance and Neurotrophin signaling, two important pathways for neurodevelopment. We found lower expression levels of a panel of genes targeted by miR-30a. MiR-30a was significantly up-regulated in depressed patients exposed to childhood trauma. A chronic treatment with lurasidone during adolescence prevented the up-regulation of miR-30a following PNS exposure.
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Affiliation(s)
- Annamaria Cattaneo
- Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy.,Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Matthew Suderman
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, BSB 1TH, UK
| | - Nadia Cattane
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Monica Mazzelli
- Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy.,Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Veronica Begni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy
| | - Carlo Maj
- Institute for Genomic Statistics and Bioinformatics, University Hospital, Bonn, Germany
| | - Ilari D'Aprile
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Carmine M Pariante
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom
| | - Alessia Luoni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy
| | - Alessandra Berry
- Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Katharina Wurst
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Würzburg, Germany
| | - Leif Hommers
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Würzburg, Germany.,Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Francesca Cirulli
- Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Moshe Szyf
- Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade #1311, Montreal, Quebec, Canada, H3G 1Y6
| | - Andreas Menke
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Würzburg, Germany.,Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Germany.,Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marco A Riva
- Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy
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Aloizou AM, Siokas V, Sapouni EM, Sita N, Liampas I, Brotis AG, Rakitskii VN, Burykina TI, Aschner M, Bogdanos DP, Tsatsakis A, Hadjigeorgiou GM, Dardiotis E. Parkinson's disease and pesticides: Are microRNAs the missing link? THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 744:140591. [PMID: 32721662 DOI: 10.1016/j.scitotenv.2020.140591] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 06/11/2023]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder that leads to significant morbidity and decline in the quality of life. It develops due to loss of dopaminergic neurons in the substantia nigra pars compacta, and among its pathogenic factors oxidative stress plays a critical role in disease progression. Pesticides are a broad class of chemicals widely used in agriculture and households for the protection of crops from insects and fungi. Several of them have been incriminated as risk factors for PD, but the underlying mechanisms have yet to be fully understood. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in regulating mRNA translation and protein synthesis. miRNA levels have been shown to be affected in several diseases as well. Since the studies on the association between pesticides and PD have yet to reach definitive conclusions, here we review recent evidence on deregulated microRNAs upon pesticide exposure, and attempt to find an overlap between miRNAs deregulated in PD and pesticides, as a missing link between the two, and enhance future research in this direction.
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Affiliation(s)
- Athina-Maria Aloizou
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Vasileios Siokas
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
| | - Efstathia-Maria Sapouni
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Nikoleta Sita
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Ioannis Liampas
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Alexandros G Brotis
- Department of Neurosurgery, School of Medicine, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Valerii N Rakitskii
- The Federal Budgetary Establishment of Science "Federal Scientific Center of Hygiene named after F. F. Erisman" of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 2 Semashko street, Mytishchi, Moscow Oblast' 141014, Russian Federation
| | - Tatyana I Burykina
- Department of Analytical and Forensic Medical Toxicology, Sechenov University, 119048 Moscow, Russian Federation
| | - Michael Aschner
- Albert Einstein College of Medicine, Bronx, NY, USA; IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Dimitrios P Bogdanos
- Department of Rheumatology and clinical Immunology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Viopolis 40500, Larissa, Greece
| | - Aristidis Tsatsakis
- The Federal Budgetary Establishment of Science "Federal Scientific Center of Hygiene named after F. F. Erisman" of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 2 Semashko street, Mytishchi, Moscow Oblast' 141014, Russian Federation; Department of Analytical and Forensic Medical Toxicology, Sechenov University, 119048 Moscow, Russian Federation; Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Georgios M Hadjigeorgiou
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece; Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus
| | - Efthimios Dardiotis
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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Dávalos A, Pinilla L, López de Las Hazas MC, Pinto-Hernández P, Barbé F, Iglesias-Gutiérrez E, de Gonzalo-Calvo D. Dietary microRNAs and cancer: A new therapeutic approach? Semin Cancer Biol 2020; 73:19-29. [PMID: 33086083 DOI: 10.1016/j.semcancer.2020.10.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/26/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022]
Abstract
Cancer is one of the leading causes of premature death and constitutes a challenge for both low- and high-income societies. Previous evidence supports a close association between modifiable risk factors, including dietary habits, and cancer risk. Investigation of molecular mechanisms that mediate the pro-oncogenic and anti-oncogenic effects of diet is therefore fundamental. MicroRNAs (miRNAs) have received much attention in the past few decades as crucial molecular elements of human physiology and disease. Aberrant expression patterns of these small noncoding transcripts have been observed in a wide array of cancers. Interestingly, human miRNAs not only can be modulated by bioactive dietary components, but it has also been proposed that diet-derived miRNAs may contribute to the pool of human miRNAs. Results from independent groups have suggested that these exogenous miRNAs may be functional in organisms. These findings open the door to novel and innovative approaches to cancer therapy. Here, we provide an overview of the biology of miRNAs, with a special focus on plant-derived dietary miRNAs, summarize recent findings in the field of cancer, address the possible applications to clinical practice and discuss obstacles and challenges in the field.
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Affiliation(s)
- Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, Crta. de, Carr. de Canto Blanco, nº8, E, 28049 Madrid, Spain
| | - Lucía Pinilla
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Av. Alcalde Rovira Roure, 80, 25198 Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
| | - María-Carmen López de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, Crta. de, Carr. de Canto Blanco, nº8, E, 28049 Madrid, Spain
| | - Paola Pinto-Hernández
- Department of Functional Biology, Physiology, University of Oviedo, Av. Julián Clavería, 6, 33006 Oviedo, Spain
| | - Ferran Barbé
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Av. Alcalde Rovira Roure, 80, 25198 Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
| | - Eduardo Iglesias-Gutiérrez
- Department of Functional Biology, Physiology, University of Oviedo, Av. Julián Clavería, 6, 33006 Oviedo, Spain; Health Research Institute of the Principality of Asturias (ISPA), Av. Roma, s/n, 33011 Oviedo, Spain
| | - David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Av. Alcalde Rovira Roure, 80, 25198 Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain.
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50
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Giannocco G, Kizys MML, Maciel RM, de Souza JS. Thyroid hormone, gene expression, and Central Nervous System: Where we are. Semin Cell Dev Biol 2020; 114:47-56. [PMID: 32980238 DOI: 10.1016/j.semcdb.2020.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/27/2022]
Abstract
Thyroid hormones (TH; T3 and T4) play a fundamental role in the fetal stage to the adult phase, controlling gene and protein expression in virtually all tissues. The endocrine and CNS systems have relevant interaction, and the TH are pivotal for the proper functioning of the CNS. A slight failure to regulate TH availability during pregnancy and/or childhood can lead to neurological disorders, for example, autism and cognitive impairment, or depression. In this review, we highlight how TH acts in controlling gene expression, its role in the CNS, and what substances widely found in the environment can cause in this tissue. We highlight the role of Endocrine Disruptors used on an everyday basis in the processing of mRNAs responsible for neurodevelopment. We conclude that TH, more precisely T3, acts mainly throughout its nuclear receptors, that the deficiency of this hormone, either due to the lack of its main substrate iodine, or by to incorrect organification of T4 and T3 in the gland, or by a mutation in transporters, receptors and deiodinases may cause mild (dysregulated mood in adulthood) to severe neurological impairment (Allan-Herndon-Dudley syndrome, presented as early as childhood); T3 is responsible for the expression of numerous CNS genes related to oxygen transport, growth factors, myelination, cell maturation. Substances present in the environment and widely used can interfere with the functioning of the thyroid gland, the action of TH, and the functioning of the CNS.
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Affiliation(s)
- Gisele Giannocco
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil; Departamento de Ciências Biológicas, Universidade Federal de São Paulo, UNIFESP, Diadema, SP 09920-000, Brazil
| | - Marina Malta Letro Kizys
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil
| | - Rui Monteiro Maciel
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil
| | - Janaina Sena de Souza
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
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