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Dos Santos Júnior JP, Dos Santos Júnior OH, Silva-Araujo ER, Cavalcanti Bezerra Gouveia HJ, Lacerda DC, Visco DB, Pontes Silva PB, Cadena-Burbano EV, Amaral de Souza Gonzaga Paz IA, de Souza SL, de Castro RM. Phenotypic plasticity: historical context, theories and DOHaD. Brain Res 2025; 1860:149673. [PMID: 40345363 DOI: 10.1016/j.brainres.2025.149673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/04/2025] [Accepted: 05/01/2025] [Indexed: 05/11/2025]
Abstract
The Developmental Origins of Health and Disease (DOHaD) concept has emerged as an interdisciplinary framework that explores how early-life events shape long-term health and disease risk. Rooted in the Thrifty Phenotype hypothesis proposed by Barker and Hales, DOHaD builds upon centuries of philosophical and scientific thought. Central to DOHaD is the concept of phenotypic plasticity, which explains how organisms adapt their biological characteristics in response to environmental stimuli, particularly during critical developmental periods. In this context, this review aims to analyze the historical evolution of phenotypic plasticity, its theoretical foundations, and its role in health and disease. After reviewing the literature on scope, we summarize key contributions from evolutionary biology, genetics, and epigenetics, examining theories from Lamarck, Darwin, Mendel, and Waddington to contemporary perspectives in DOHaD. Understanding that early-life events can lead to adaptations which may have short-term benefits but potentially increase the likelihood of diseases in adulthood highlights the importance of targeted preventive interventions. Additionally, individual variations in response to environmental stimuli reinforce the complexity of adaptive mechanisms. Thus, understanding the intricate relationship between phenotypic plasticity, early-life exposures, and disease risk is essential for developing preventive interventions and public health strategies. The challenge remains in translating these findings into effective healthcare policies and clinical applications, ensuring improved quality of life and disease prevention across generations.
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Affiliation(s)
- Joaci Pereira Dos Santos Júnior
- Graduate Program in Nutrition, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil
| | - Osmar Henrique Dos Santos Júnior
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Nursing Unit, Vitória Academic Center, Federal University of Pernambuco, Vitória de Santo Antão, Pernambuco 55608-680, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil.
| | - Eulália Rebeca Silva-Araujo
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
| | - Henrique José Cavalcanti Bezerra Gouveia
- Graduate Program in Nutrition, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil
| | - Diego Cabral Lacerda
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
| | - Diego Bulcão Visco
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program of Health Sciences, Laboratory of Neurofunctional, Department of Biological Sciences and Health, Federal University of Amapá, Macapá, Brazil
| | - Paula Brielle Pontes Silva
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
| | - Erika Vanessa Cadena-Burbano
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
| | - Isla Ariadny Amaral de Souza Gonzaga Paz
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
| | - Sandra Lopes de Souza
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
| | - Raul Manhães de Castro
- Graduate Program in Nutrition, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-420, Brazil; Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco 50670-901, Brazil
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Bhardwaj I, Singh S, Ansari AH, Rai SP, Singh D. Effect of stress on neuronal cell: Morphological to molecular approach. PROGRESS IN BRAIN RESEARCH 2025; 291:469-502. [PMID: 40222791 DOI: 10.1016/bs.pbr.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Stress can be characterized as any perceived or actual threat that necessitates compensatory actions to maintain homeostasis. It can alter an organism's behavior over time by permanently altering the composition and functionality of brain circuitry. The amygdala and prefrontal cortex are two interrelated brain regions that have been the focus of initial research on stress and brain structural and functional plasticity, with the hippocampus serving as the entry point for most of this knowledge. Prolonged stress causes significant morphological alterations in important brain regions such as the hippocampus, amygdala, and prefrontal cortex. Memory, learning, and emotional regulation are among the cognitive functions that are adversely affected by these changes, including neuronal shrinkage, dendritic retraction, and synaptic malfunction. Stress perturbs the equilibrium of neurotransmitters, neuronal plasticity, and mitochondrial function at the molecular level. On the other hand, chronic stress negatively impacts physiology and can result in neuropsychiatric diseases. Recent molecular research has linked various epigenetic processes, such as DNA methylation, histone modifications, and noncoding RNAs, to the dysregulation of genes in the impacted brain circuits responsible for the pathophysiology of chronic stress. Numerous disorders, including neurodegenerative diseases (NDDs) including Alzheimer's, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, multiple sclerosis, and Parkinson's disease, have been linked to oxidative stress as a possible cause.
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Affiliation(s)
- Ishita Bhardwaj
- Department of Zoology, S.S. Khanna Girls' Degree College, Prayagraj (A Constituent College of University of Allahabad, Prayagraj), Uttar Pradesh, India
| | - Sippy Singh
- Department of Zoology, S.S. Khanna Girls' Degree College, Prayagraj (A Constituent College of University of Allahabad, Prayagraj), Uttar Pradesh, India
| | - Atifa Haseeb Ansari
- Department of Zoology, S.S. Khanna Girls' Degree College, Prayagraj (A Constituent College of University of Allahabad, Prayagraj), Uttar Pradesh, India
| | - Swayam Prabha Rai
- Department of Zoology, S.S. Khanna Girls' Degree College, Prayagraj (A Constituent College of University of Allahabad, Prayagraj), Uttar Pradesh, India
| | - Durgesh Singh
- Department of Zoology, S.S. Khanna Girls' Degree College, Prayagraj (A Constituent College of University of Allahabad, Prayagraj), Uttar Pradesh, India.
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Funahashi Y, Dwivedi Y. Epigenetics and suicidal behavior in adolescents: a critical review. Epigenomics 2025; 17:247-262. [PMID: 39819344 PMCID: PMC11853622 DOI: 10.1080/17501911.2025.2453415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/10/2025] [Indexed: 01/19/2025] Open
Abstract
Suicide continues to be a significant public health issue globally, claiming over 700,000 lives annually. It is, therefore, important to assess the suicide risk properly and provide intervention in a timely fashion. While the heritability of suicidal behavior is around 50%, it does not explain the factors involved in causality. Recent evidence suggests that gene x environment interaction plays a vital role in suicidal behavior. In this paper, we critically evaluate the association between adolescent suicidal behavior and epigenetic modifications, including DNA methylation, histone modification, and non-coding RNAs, as well as epigenetic-based treatment options. It was noted that the prevalence of suicidal behavior in adolescents varied by age and sex and the presence of psychiatric disorders. Childhood adversity was closely associated with suicidal behavior. Studies show that alterations in epigenetic modifications may increase the risk of suicidal behavior independent of mental illnesses. Because epigenetic factors are reversible, environmental enrichment or the use of pharmacological agents that can target specific epigenetic modulation may be able to reduce suicidal behavior in this population.
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Affiliation(s)
- Yu Funahashi
- Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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Catanese MC, Klingl YE, Gilbert TM, Strebl-Bantillo MG, Hartigan CR, Schenone M, Hooker JM. Chemoproteomics Sheds Light on Epigenetic Targets of [ 11C]Martinostat in the Human Brain. ACS Chem Neurosci 2025; 16:723-731. [PMID: 39912892 DOI: 10.1021/acschemneuro.4c00781] [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] [Indexed: 02/07/2025] Open
Abstract
Initiation of research programs to investigate binding specificity based on in vivo positron emission tomography (PET) imaging results can provide rich opportunities to improve data interpretation, gain biological insight, and inform hypothesis development. Here, we profile the binding specificity of the neuroepigenetic imaging probe, [11C]Martinostat. In vivo neuroimaging studies using [11C]Martinostat have uncovered differential regional uptake in relation to age and biological sex and in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and low-back pain compared to healthy controls. Previous studies using recombinant proteins and thermal shift assays in postmortem tissue indicate that [11C]Martinostat engages class I and putatively class IIb histone deacetylases (HDACs). While HDACs serve multiple functions, including regulation of chromatin remodeling and gene transcription, it is not known how differences in HDAC expression may arise across brain regions. HDACs functionally interact with a diverse array of multisubunit complexes, and engagement with associated binding partners may contribute to these differences. To further assess target engagement of [11C]Martinostat, we designed a synthetic probe based on the inhibitor structural scaffold for use in competition experiments followed by proteomic analysis in postmortem tissue. The synthetic probe, called Compound 4, appears to interact with the class I HDAC paralog HDAC2 and the class IIb paralog HDAC6 in a robust manner. We also uncovered unique interacting partners, including synaptic proteins from the synaptotagmin (SYT) family of proteins and neuronal pentraxin 2 (NPTX2). Further work to investigate HDAC associations with interacting proteins across regions of the human brain is needed to better understand neuroepigenetic dysregulation in psychiatric and neurological conditions.
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Affiliation(s)
- Mary C Catanese
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Yvonne E Klingl
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Tonya M Gilbert
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
| | - Martin G Strebl-Bantillo
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
| | - Christina R Hartigan
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Monica Schenone
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Jacob M Hooker
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
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Antrobus MR, Desai T, Young D, Machado L, Ribbans WJ, El Khoury LY, Brazier J. Epigenetics of concussion: A systematic review. Gene 2025; 935:149046. [PMID: 39490707 DOI: 10.1016/j.gene.2024.149046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 10/14/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Concussion is the most common neurological disorder affecting millions of people globally each year. Identifying epigenetic mechanisms influencing concussion incidence, severity and recovery could provide diagnostic and prognostic insight into this injury. OBJECTIVES This systematic review aims to identify the epigenetic mechanisms underpinning concussion. METHODS Seven electronic databases; PubMed, MEDLINE, CINAHL, Cochrane library, SPORTDiscus, Scopus and Web of Science were searched for studies that investigated the epigenetic mechanisms of concussion and its underlying neuropathology. RESULTS Based on inclusion and exclusion criteria, 772 titles were independently analysed by two of the authors to a final list of 28 studies that totaled 3042 participants. We observed separate associations between sncRNAs, methylation, histone modification and concussion. Overall, 204 small non-coding RNAs were significantly dysregulated between concussed participants and controls or between concussion participants with no post-concussive symptoms and those with post-concussive symptoms. From these, 37 were reported in more than one study and 23 of these were expressed in a consistent direction with at least one further study. Ingenuity pathway analysis identified 10 miRNAs known to regulate 15 genes associated with human neurological pathologies. Two studies found significant changes in global methylation in concussed participants and one study found a decrease in H3K27Me3 in the context of DNA damage and concussion. CONCLUSIONS The review findings suggest that epigenetic mechanisms may play an important role in the pathophysiological mechanisms that could influence outcome, recovery, and potential long-term consequences of concussion for individuals.
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Affiliation(s)
- Mark R Antrobus
- Centre for Physical Activity and Life Sciences, University of Northampton, Northampton NN1 5PH, UK.
| | - Terun Desai
- Institute of Sport, Exercise & Health, Division of Surgery & Interventional Science, University College London, W1T 7HA, UK
| | - David Young
- Centre for Physical Activity and Life Sciences, University of Northampton, Northampton NN1 5PH, UK
| | - Lee Machado
- Centre for Physical Activity and Life Sciences, University of Northampton, Northampton NN1 5PH, UK
| | - William J Ribbans
- Centre for Physical Activity and Life Sciences, University of Northampton, Northampton NN1 5PH, UK
| | - Louis Y El Khoury
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jon Brazier
- Department of Psychology, Geography and Sport, University of Hertfordshire, Hatfield AL10 9AB, UK
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Ding Y, Chen S. A comprehensive bibliographic study on mental illness. Acta Neuropsychiatr 2025; 37:e7. [PMID: 39881583 DOI: 10.1017/neu.2024.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
This study presents a comprehensive analysis of recent mental illness research by utilizing an advanced bibliographic method capable of analyzing up to 12,965 papers indexed in the Web of Science database, overcoming the limitations of traditional tools like VOSviewer, which typically analyze fewer than 1,000 papers. By examining a vast dataset, this study identifies key trends, significant keywords, and prominent contributors, including leading researchers, universities, and countries/regions, in the field of mental illness research. Additionally, the study highlights eight major contributors to mental health problems, offering critical insights into the field’s current state. The findings underscore the importance of advanced bibliographic methods in providing a more detailed and accurate overview of mental illness research. This analysis not only enhances the understanding of young scholars entering the field but also uncovers significant trends and identifies notable gaps in the literature. The study advocates for continued innovation and interdisciplinary collaboration to deepen understanding and address unresolved challenges in mental health research.
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Affiliation(s)
- Yuanzhao Ding
- Social Sciences Division, University of Oxford, Oxford, UK
| | - Shan Chen
- Science of Learning in Education Centre, National Institute of Education, Nanyang Technological University, Singapore
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Khatoon S, Kalam N. Mechanistic insight of curcumin: a potential pharmacological candidate for epilepsy. Front Pharmacol 2025; 15:1531288. [PMID: 39845785 PMCID: PMC11752882 DOI: 10.3389/fphar.2024.1531288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Recurrent spontaneous seizures with an extended epileptic discharge are the hallmarks of epilepsy. At present, there are several available anti-epileptic drugs (AEDs) in the market. Still no adequate treatment for epilepsy treatment is available. The main disadvantages of AEDs are their associated adverse effects. It is a challenge to develop new therapies that can reduce seizures by modulating the underlying mechanisms with no adverse effects. In the last decade, the neuromodulatory potential of phytoconstituents has sparked their usage in the treatment of central nervous system disorders. Curcumin is an active polyphenolic component that interacts at cellular and molecular levels. Curcumin's neuroprotective properties have been discovered in recent preclinical and clinical studies due to its immunomodulatory effects. Curcumin has the propensity to modulate signaling pathways involved in cell survival and manage oxidative stress, apoptosis, and inflammatory mechanisms. Further, curcumin can persuade epigenetic alterations, including histone modifications (acetylation/deacetylation), which are the changes responsible for the altered expression of genes facilitating the process of epileptogenesis. The bioavailability of curcumin in the brain is a concern that needs to be tackled. Therefore, nanonization has emerged as a novel drug delivery system to enhance the pharmacokinetics of curcumin. In the present review, we reviewed curcumin's modulatory effects on potential biomarkers involved in epileptogenesis including dendritic cells, T cell subsets, cytokines, chemokines, apoptosis mediators, antioxidant mechanisms, and cognition impairment. Also, we have discussed the nanocarrier systems for encapsulating curcumin, offering a promising approach to enhance bioavailability of curcumin.
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Affiliation(s)
- Saima Khatoon
- Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Nida Kalam
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Bandar Sunway, Malaysia
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Mackert S, Niemeyer C, Mecdad Y, Ebert T, Bajaj T, Durand S, Hofer SJ, Zellner A, Besteher B, Engelmann J, Gisabella B, Kempf V, Heckmann LA, Laakmann M, Newman EL, Sokn C, Heinz DE, Junglas E, Uribe-Marino A, Magnes C, Klengel C, Müller A, Opriessnig L, Meinitzer A, Lennarz M, Martin KMW, Albatarni R, Brockherde M, Lieb K, Rohner H, Stoffel-Wagner B, Philipsen A, Kuster B, Kölle M, Ressler KJ, Opel N, Schmidt MV, Pantazopoulos H, Müller MB, Kroemer G, Eisenberg T, Hartmann J, Madeo F, Gassen NC. Spermidine alleviates depression via control of the stress response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.04.626625. [PMID: 39677641 PMCID: PMC11642883 DOI: 10.1101/2024.12.04.626625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.
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Li N, Liu T, Wang YY, Xu T, Shi HJ, Chang L, Zhu LJ. Hippocampal HDAC5-mediated histone acetylation underlies stress susceptibility in mice exposed to chronic social defeat stress. Neuroscience 2024; 557:89-99. [PMID: 39127342 DOI: 10.1016/j.neuroscience.2024.08.010] [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: 02/23/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
Chronic stress leads to social avoidance and anhedonia in susceptible individuals, a phenomenon that has been observed in both human and animal models. Nevertheless, the underlying molecular mechanisms underpinning stress susceptibility and resilience remain largely unclear. There is growing evidence that epigenetic histone deacetylase (HDAC) mediated histone acetylation is involved in the modulation of depressive-related behaviors. We hypothesized that histone deacetylase 5 (HDAC5), which is associated with stress-related behaviors and antidepressant response, may play a vital role in the susceptibility to chronic stress. In the current study, we detected the levels of HDAC5 and acetylation of histone 4 (H4) in the hippocampus subsequent to chronic social defeat stress (CSDS) in C57BL/6J mice. We found that CSDS induces a notable increase in HDAC5 expression, concomitant with a reduction in the acetylation of histone H4 at lysine 12 (H4K12) in the hippocampus of susceptible mice. Meanwhile, intrahippocampal infusion of HDAC5 shRNA or HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) both reversed the depression susceptibility in susceptible mice that subjected to CSDS. Furthermore, HDAC5 overexpression was sufficient to induce depression susceptibility following microdefeat stress, accompanied by a significant reduction in H4K12 level within the hippocampus of mice. Additionally, the Morris water maze (MWM) results indicated that neither CSDS nor HDAC5 exerted significant effects on spatial memory function in mice. Taken together, these investigations indicated that HDAC5-modulated histone acetylation is implicated in regulating the depression susceptibility, and may be serve as potential preventive targets for susceptible individuals.
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Affiliation(s)
- Na Li
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China
| | - Ting Liu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China
| | - Yu-Ye Wang
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China
| | - Tong Xu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China
| | - Hu-Jiang Shi
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China
| | - Lei Chang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
| | - Li-Juan Zhu
- Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China.
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Wani SN, Grewal AK, Khan H, Singh TG. Elucidating the molecular symphony: unweaving the transcriptional & epigenetic pathways underlying neuroplasticity in opioid dependence and withdrawal. Psychopharmacology (Berl) 2024; 241:1955-1981. [PMID: 39254835 DOI: 10.1007/s00213-024-06684-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024]
Abstract
The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal.
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Affiliation(s)
- Shahid Nazir Wani
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Aman Pharmacy College, Dholakhera, Udaipurwati, Jhunjhunu, Rajasthan, 333307, India
| | - Amarjot Kaur Grewal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
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Du Y, He Z, Jin S, Jin G, Wang K, Yang F, Zhang J. Targeting histone methylation and demethylation for non-alcoholic fatty liver disease. Bioorg Chem 2024; 151:107698. [PMID: 39126869 DOI: 10.1016/j.bioorg.2024.107698] [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: 05/28/2024] [Revised: 07/16/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, facing increasing challenges in terms of prevention and treatment. The methylation of lysine and arginine residues on histone proteins is dynamically controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs), regulating chromatin structure and gene transcription. Mutations, genetic translocations, and altered gene expression involving HMTs and HDMs are frequently observed in NAFLD. HMTs and HDMs are receiving increasing attention in regulating NALFD. Targeting specific HMTs and HDMs for drug development is becoming a new strategy for treating NAFLD. This review provides a comprehensive summary of the regulatory mechanism of histone methylation/demethylation in NAFLD. Additionally, we discuss the potential applications of HMTs and HDMs inhibitors in preventing NAFLD, which may provide a scientific basis for the treatment of NAFLD.
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Affiliation(s)
- Yuanbing Du
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Zhangxu He
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
| | - Sasa Jin
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Gang Jin
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Kaiyue Wang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Feifei Yang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
| | - Jingyu Zhang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
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Menculini G, Cirimbilli F, Raspa V, Scopetta F, Cinesi G, Chieppa AG, Cuzzucoli L, Moretti P, Balducci PM, Attademo L, Bernardini F, Erfurth A, Sachs G, Tortorella A. Insights into the Effect of Light Pollution on Mental Health: Focus on Affective Disorders-A Narrative Review. Brain Sci 2024; 14:802. [PMID: 39199494 PMCID: PMC11352354 DOI: 10.3390/brainsci14080802] [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: 07/17/2024] [Revised: 08/04/2024] [Accepted: 08/08/2024] [Indexed: 09/01/2024] Open
Abstract
The presence of artificial light at night has emerged as an anthropogenic stressor in recent years. Various sources of light pollution have been shown to affect circadian physiology with serious consequences for metabolic pathways, possibly disrupting pineal melatonin production with multiple adverse health effects. The suppression of melatonin at night may also affect human mental health and contribute to the development or exacerbation of psychiatric disorders in vulnerable individuals. Due to the high burden of circadian disruption in affective disorders, it has been hypothesized that light pollution impacts mental health, mainly affecting mood regulation. Hence, the aim of this review was to critically summarize the evidence on the effects of light pollution on mood symptoms, with a particular focus on the role of circadian rhythms in mediating this relationship. We conducted a narrative review of the literature in the PubMed, Scopus, and Web of Science datasets. After the screening process, eighteen papers were eligible for inclusion. The results clearly indicate a link between light pollution and the development of affective symptoms, with a central role of sleep disturbances in the emergence of mood alterations. Risk perception also represents a crucial topic, possibly modulating the development of affective symptoms in response to light pollution. The results of this review should encourage a multidisciplinary approach to the design of healthier environments, including lighting conditions among the key determinants of human mental health.
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Affiliation(s)
- Giulia Menculini
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Federica Cirimbilli
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Veronica Raspa
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Francesca Scopetta
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Gianmarco Cinesi
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Anastasia Grazia Chieppa
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Lorenzo Cuzzucoli
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Patrizia Moretti
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
| | - Pierfrancesco Maria Balducci
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
- CSM Terni, Department of Mental Health, Local Health Unit USL Umbria 2, 05100 Terni, Italy
| | - Luigi Attademo
- Department of Mental Health, North West Tuscany Local Health Authority, 57023 Cecina, Italy;
| | - Francesco Bernardini
- SPDC Pordenone, Department of Mental Health, AsFO Friuli Occidentale, 33170 Pordenone, Italy;
| | - Andreas Erfurth
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, 1090 Vienna, Austria; (A.E.); (G.S.)
- Klinik Hietzing, 1st Department of Psychiatry and Psychotherapeutic Medicine, 1130 Vienna, Austria
| | - Gabriele Sachs
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, 1090 Vienna, Austria; (A.E.); (G.S.)
| | - Alfonso Tortorella
- Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (F.C.); (V.R.); (F.S.); (G.C.); (A.G.C.); (L.C.); (P.M.); (P.M.B.); (A.T.)
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13
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Woo MS, Engler JB, Friese MA. The neuropathobiology of multiple sclerosis. Nat Rev Neurosci 2024; 25:493-513. [PMID: 38789516 DOI: 10.1038/s41583-024-00823-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2024] [Indexed: 05/26/2024]
Abstract
Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials.
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Affiliation(s)
- Marcel S Woo
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Broder Engler
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Manuel A Friese
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
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14
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Riyahi J, Taslimi Z, Gelfo F, Petrosini L, Haghparast A. Trans-generational effects of parental exposure to drugs of abuse on offspring memory functions. Neurosci Biobehav Rev 2024; 160:105644. [PMID: 38548003 DOI: 10.1016/j.neubiorev.2024.105644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/10/2024] [Accepted: 03/22/2024] [Indexed: 04/01/2024]
Abstract
Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring's complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol.
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Affiliation(s)
- Javad Riyahi
- Department of Cognitive and Behavioral Science and Technology in Sport, Faculty of Sport Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | - Zahra Taslimi
- Behavioral Disorders and Substance Abuse Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Fertility and Infertility Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Francesca Gelfo
- IRCCS Santa Lucia Foundation, Rome, Italy; Department of Human Sciences, Guglielmo Marconi University, Rome, Italy
| | | | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran.
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15
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Hilal FF, Jeanblanc J, Deschamps C, Naassila M, Pierrefiche O, Ben Hamida S. Epigenetic drugs and psychedelics as emerging therapies for alcohol use disorder: insights from preclinical studies. J Neural Transm (Vienna) 2024; 131:525-561. [PMID: 38554193 DOI: 10.1007/s00702-024-02757-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/22/2024] [Indexed: 04/01/2024]
Abstract
Alcohol use disorder (AUD) is a public health issue that affects millions of people worldwide leading to physical, mental and socio-economic consequences. While current treatments for AUD have provided relief to individuals, their effectiveness on the long term is often limited, leaving a number of affected individuals without sustainable solutions. In this review, we aim to explore two emerging approaches for AUD: psychedelics and epigenetic drugs (i.e., epidrugs). By examining preclinical studies, different animal species and procedures, we delve into the potential benefits of each of these treatments in terms of addictive behaviors (alcohol drinking and seeking, motivation to drink alcohol and prevention of relapse). Because psychedelics and epidrugs may share common and complementary mechanisms of action, there is an exciting opportunity for exploring synergies between these approaches and their parallel effectiveness in treating AUD and the diverse associated psychiatric conditions.
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Affiliation(s)
- Fahd François Hilal
- INSERM UMR 1247-Research Group on Alcohol and Pharmacodependences (GRAP), Université de Picardie Jules Verne, Chemin du Thil - Centre Universitaire de Recherche en Santé, 80025, Amiens, France
| | - Jerome Jeanblanc
- INSERM UMR 1247-Research Group on Alcohol and Pharmacodependences (GRAP), Université de Picardie Jules Verne, Chemin du Thil - Centre Universitaire de Recherche en Santé, 80025, Amiens, France
| | - Chloé Deschamps
- INSERM UMR 1247-Research Group on Alcohol and Pharmacodependences (GRAP), Université de Picardie Jules Verne, Chemin du Thil - Centre Universitaire de Recherche en Santé, 80025, Amiens, France
| | - Mickael Naassila
- INSERM UMR 1247-Research Group on Alcohol and Pharmacodependences (GRAP), Université de Picardie Jules Verne, Chemin du Thil - Centre Universitaire de Recherche en Santé, 80025, Amiens, France.
| | - Olivier Pierrefiche
- INSERM UMR 1247-Research Group on Alcohol and Pharmacodependences (GRAP), Université de Picardie Jules Verne, Chemin du Thil - Centre Universitaire de Recherche en Santé, 80025, Amiens, France
| | - Sami Ben Hamida
- INSERM UMR 1247-Research Group on Alcohol and Pharmacodependences (GRAP), Université de Picardie Jules Verne, Chemin du Thil - Centre Universitaire de Recherche en Santé, 80025, Amiens, France.
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16
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Cao L, Zhou Y, Gao L, Yin H, Zhang M, Zhang H, Ju P, Dou K, Ai S. Ascorbic Acid Induced the Improved Oxygen Vacancy Defects of Bi 4O 5Br 2 and Its Application on Photoelectrochemical Detection of DNA Demethylase MBD2 with Improved Detection Sensitivity. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306365. [PMID: 38009777 DOI: 10.1002/smll.202306365] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/20/2023] [Indexed: 11/29/2023]
Abstract
Oxygen vacancy defects (OVs) are one of the main strategies for nanomaterials modification to improve the photoactivity, but current methods for fabricating OVs are usually complicated and harsh. It is important to develop simple, rapid, safe, and mild methods to fabricate OVs. By studying the effects of different weak reducing agents, the concentration of the reducing agent and the reaction time on fabrication of OVs, it is found that L-ascorbic acid (AA) gently and rapidly induces the increase of OVs in Bi4O5Br2 at room temperature. The increased OVs not only improve the adsorption of visible light, but also enhance the photocurrent response. Based on this, the preparation of OVs in Bi4O5Br2 is employed to the development of a photoelectrochemical biosensor for the detection of DNA demethylase of methyl-CpG binding domain protein 2 (MBD2). The biosensor shows a wide linear range of 0.1-400 ng mL-1 and a detection limit as low as 0.03 ng mL-1 (3σ). In addition, the effect of plasticizers on MBD2 activity is evaluated using this sensor. This work not only provides a novel method to prepare OVs in bismuth rich materials, but also explores a new novel evaluation tool for studying the ecotoxicological effects of contaminants.
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Affiliation(s)
- LuLu Cao
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
| | - Yunlei Zhou
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
| | - Lanlan Gao
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
| | - Huanshun Yin
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
| | - Miao Zhang
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
| | - Haowei Zhang
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
| | - Peng Ju
- Key Laboratory of Marine Eco-Environmental Science and Technology, Marine Bioresource and Environment Research Center, First Institute of Oceanography, Ministry of Natural Resources, Qingdao, 266061, P. R. China
| | - Kunpeng Dou
- College of Information Science and Engineering, Ocean University of China, Qingdao, 266061, P. R. China
| | - Shiyun Ai
- College of Chemistry and Material Science, Key Laboratory of Low-Carbon and Green Agriculture Chemistry in Universities of Shandong, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Shandong Agricultural University, Tai'an, 271018, P. R. China
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17
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Li H, Kawatake-Kuno A, Inaba H, Miyake Y, Itoh Y, Ueki T, Oishi N, Murai T, Suzuki T, Uchida S. Discrete prefrontal neuronal circuits determine repeated stress-induced behavioral phenotypes in male mice. Neuron 2024; 112:786-804.e8. [PMID: 38228137 DOI: 10.1016/j.neuron.2023.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/26/2023] [Accepted: 12/11/2023] [Indexed: 01/18/2024]
Abstract
Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.
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Affiliation(s)
- Haiyan Li
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Ayako Kawatake-Kuno
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiromichi Inaba
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yuka Miyake
- SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Yukihiro Itoh
- SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Takatoshi Ueki
- Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
| | - Naoya Oishi
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Toshiya Murai
- Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Takayoshi Suzuki
- SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
| | - Shusaku Uchida
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan; Kyoto University Medical Science and Business Liaison Organization, Medical Innovation Center, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
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18
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Dirven BCJ, van Melis L, Daneva T, Dillen L, Homberg JR, Kozicz T, Henckens MJAG. Hippocampal Trauma Memory Processing Conveying Susceptibility to Traumatic Stress. Neuroscience 2024; 540:87-102. [PMID: 38220126 DOI: 10.1016/j.neuroscience.2024.01.007] [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: 02/27/2023] [Revised: 12/04/2023] [Accepted: 01/10/2024] [Indexed: 01/16/2024]
Abstract
While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted-Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma-related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal parvalbuminneuronal density and a relatively lower activity of parvalbumininterneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.
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Affiliation(s)
- Bart C J Dirven
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands; Department of Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
| | - Lennart van Melis
- Department of Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
| | - Teya Daneva
- Department of Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
| | - Lieke Dillen
- Department of Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
| | - Judith R Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
| | - Tamas Kozicz
- Department of Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands; Center for Individualized Medicine, Department of Clinical Genomics, and Biochemical Genetics Laboratory, Mayo Clinic, Rochester, MN 55905, USA; University of Pecs Medical School, Department of Anatomy, Pecs, Hungary
| | - Marloes J A G Henckens
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
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19
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Radhakrishnan M, Vijay V, Supraja Acharya B, Basuthakur P, Patel S, Soren K, Kumar A, Chakravarty S. Uncovering Sex-Specific Epigenetic Regulatory Mechanism Involving H3k9me2 in Neural Inflammation, Damage, and Recovery in the Internal Carotid Artery Occlusion Mouse Model. Neuromolecular Med 2024; 26:3. [PMID: 38407687 DOI: 10.1007/s12017-023-08768-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/01/2023] [Indexed: 02/27/2024]
Abstract
Cerebral ischemic stroke is one of the foremost global causes of death and disability. Due to inadequate knowledge in its sequential disease mechanisms, therapeutic efforts to mitigate acute ischemia-induced brain injury are limited. Recent studies have implicated epigenetic mechanisms, mostly histone lysine acetylation/deacetylation, in ischemia-induced neural damage and death. However, the role of lysine methylation/demethylation, another prevalent epigenetic mechanism in cerebral ischemia has not undergone comprehensive investigation, except a few recent reports, including those from our research cohort. Considering the impact of sex on post-stroke outcomes, we studied both male and female mice to elucidate molecular details using our recently developed Internal Carotid Artery Occlusion (ICAO) model, which induces mild to moderate cerebral ischemia, primarily affecting the striatum and ventral hippocampus. Here, we demonstrate for the first time that female mice exhibit faster recovery than male mice following ICAO, evaluated through neurological deficit score and motor coordination assessment. Furthermore, our investigation unveiled that dysregulated histone lysine demethylases (KDMs), particularly kdm4b/jmjd2b are responsible for the sex-specific variance in the modulation of inflammatory genes. Building upon our prior reportage blocking KDMs by DMOG (Dimethyloxalylglycine) and thus preventing the attenuation in H3k9me2 reduced the post-ICAO transcript levels of the inflammatory molecules and neural damage, our present study delved into investigating the differential role of H3k9me2 in the regulation of pro-inflammatory genes in female vis-à-vis male mice underlying ICAO-induced neural damage and recovery. Overall, our results reveal the important role of epigenetic mark H3k9me2 in mediating sex-specific sequential events in inflammatory response, elicited post-ICAO.
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Affiliation(s)
- Mydhili Radhakrishnan
- Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Vincy Vijay
- Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - B Supraja Acharya
- Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India
| | - Papia Basuthakur
- Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shashikant Patel
- Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Kalyani Soren
- Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Arvind Kumar
- Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
| | - Sumana Chakravarty
- Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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20
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Bigio B, Azam S, Mathé AA, Nasca C. The neuropsychopharmacology of acetyl-L-carnitine (LAC): basic, translational and therapeutic implications. DISCOVER MENTAL HEALTH 2024; 4:2. [PMID: 38169018 PMCID: PMC10761640 DOI: 10.1007/s44192-023-00056-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/15/2023] [Indexed: 01/05/2024]
Abstract
Mitochondrial metabolism can contribute to nuclear histone acetylation among other epigenetic mechanisms. A central aspect of this signaling pathway is acetyl-L-carnitine (LAC), a pivotal mitochondrial metabolite best known for its role in fatty acid oxidation. Work from our and other groups suggested LAC as a novel epigenetic modulator of brain plasticity and a therapeutic target for clinical phenotypes of depression linked to childhood trauma. Aberrant mitochondrial metabolism of LAC has also been implicated in the pathophysiology of Alzheimer's disease. Furthermore, mitochondrial dysfunction is linked to other processes implicated in the pathophysiology of both major depressive disorders and Alzheimer's disease, such as oxidative stress, inflammation, and insulin resistance. In addition to the rapid epigenetic modulation of glutamatergic function, preclinical studies showed that boosting mitochondrial metabolism of LAC protects against oxidative stress, rapidly ameliorates insulin resistance, and reduces neuroinflammation by decreasing proinflammatory pathways such as NFkB in hippocampal and cortical neurons. These basic and translational neuroscience findings point to this mitochondrial signaling pathway as a potential target to identify novel mechanisms of brain plasticity and potential unique targets for therapeutic intervention targeted to specific clinical phenotypes.
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Affiliation(s)
- Benedetta Bigio
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA
| | - Shofiul Azam
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA
- Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
| | - Aleksander A Mathé
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Carla Nasca
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.
- Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USA.
- Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA.
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21
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Golubeva E, Zeltser A, Zorkina Y, Ochneva A, Tsurina A, Andreyuk D, Kostyuk G, Morozova A. Epigenetic Alterations in Post-Traumatic Stress Disorder: Comprehensive Review of Molecular Markers. Complex Psychiatry 2024; 10:71-107. [PMID: 39564465 PMCID: PMC11573359 DOI: 10.1159/000541822] [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: 06/18/2024] [Accepted: 10/03/2024] [Indexed: 11/21/2024] Open
Abstract
Background Post-traumatic stress disorder (PTSD) can occur after a traumatic event. PTSD is characterized by nightmares, flashbacks and avoidance of stressors. It currently affects 2-8% of the population, with military personnel particularly susceptible. Studies show that environmental stressors can induce various epigenetic changes that shape the PTSD phenotype. Despite the significant impact of epigenetic factors on PTSD symptoms and susceptibility, they have not been widely discussed in the literature. This review focuses on describing epigenetic mechanisms in PTSD, especially DNA methylation, chromatin regulation, and noncoding RNA. Summary The article includes relevant studies published from 2013 to 2023, excluding non-English-language studies or studies with insufficient data. This review investigated gene methylation changes in association with PTSD, including those related to the hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, neurotransmitters, and immune system functioning, as well as the role of histones and regulatory noncoding RNAs. Key Messages Epigenetic alterations play a crucial role in shaping PTSD susceptibility, symptomatology, and long-term outcomes, highlighting their potential as important markers and therapeutic targets. Understanding these alterations can aid in developing clinical strategies to better predict, prevent, and treat PTSD. However, further large-scale longitudinal studies are needed to establish the temporal relationship between epigenetic changes and the onset of PTSD, as well as to classify other potential epigenetic mechanisms.
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Affiliation(s)
- Elizaveta Golubeva
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Angelina Zeltser
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
| | - Yana Zorkina
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
- V. Serbsky National Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
| | | | - Anna Tsurina
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - Denis Andreyuk
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
- M. V. Lomonosov Moscow State University, Moscow, Russia
| | - Georgiy Kostyuk
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- M. V. Lomonosov Moscow State University, Moscow, Russia
- Federal State Budgetary Educational Institution of Higher Education Russian Biotechnological University, Moscow, Russia
| | - Anna Morozova
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Moscow, Russia
- V. Serbsky National Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
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22
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Li N, Xiao X, Zhang H, Bai Z, Li M, Sun J, Dong Y, Zhu W, Fei Z, Sun X, Xiao P, Gao Y, Zhou D. Sterile soil mitigates the intergenerational loss of gut microbial diversity and anxiety-like behavior induced by antibiotics in mice. Brain Behav Immun 2024; 115:179-190. [PMID: 37848098 DOI: 10.1016/j.bbi.2023.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 10/10/2023] [Accepted: 10/14/2023] [Indexed: 10/19/2023] Open
Abstract
The decline in gut microbial diversity in modern humans is closely associated with the rising prevalence of various diseases. It is imperative to investigate the underlying causes of gut microbial loss and restoring methods. Although the impact of non-perinatal antibiotic use on gut microbiota has been recognized, its intergenerational effects remain unexplored. Our previous research has highlighted soil in the farm environment as a key factor for gut microbiome health by restoring gut microbial diversity and balance. In this study, we investigated the intergenerational consequences of antibiotic exposure and the therapeutic potential of sterile soil. We treated C57BL/6 mice with vancomycin and streptomycin for 2 weeks continuously, followed by a 4-8 week withdrawal period before breeding. The process was repeated across 3 generations. Half of the mice in each generation received an oral sterile soil intervention. We assessed gut microbial diversity, anxiety behavior, microglial reactivity, and gut barrier integrity across generations. Antibiotic exposure led to a decrease in gut microbial diversity over generations, along with aggravated anxiety behavior, microgliosis, and altered intestinal tight junction protein expression. Oral sterile soil intervention restored gut microbial diversity in adult mice across generations, concomitantly rescuing abnormalities in behavior, microgliosis, and intestinal barrier integrity. In conclusion, this study simulated an important process of the progressive loss of gut microbiota diversity in modern humans and demonstrated the potential of sterile soil to reverse this process. This study provides a theoretical and experimental basis for research and interventions targeting multiple modern chronic diseases related to intestinal microorganisms.
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Affiliation(s)
- Na Li
- Key Laboratory of Child Development and Learning Science of Department of Education, Southeast University, Nanjing 210096, China
| | - Xiaoao Xiao
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Honglin Zhang
- College of Food Science, Nanjing Xiaozhuang University, Nanjing 211171, China
| | - Zhimao Bai
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210009, China
| | - Mengjie Li
- Key Laboratory of Child Development and Learning Science of Department of Education, Southeast University, Nanjing 210096, China
| | - Jia Sun
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Yangyang Dong
- Key Laboratory of Child Development and Learning Science of Department of Education, Southeast University, Nanjing 210096, China
| | - Wenyong Zhu
- State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China
| | - Zhongjie Fei
- State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China
| | - Xiao Sun
- State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China
| | - Pengfeng Xiao
- State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China
| | - Yuanqing Gao
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
| | - Dongrui Zhou
- Key Laboratory of Child Development and Learning Science of Department of Education, Southeast University, Nanjing 210096, China.
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23
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Bhatia P, Yang L, Luo JXJ, Xu M, Renthal W. Epigenomic profiling of mouse nucleus accumbens at single-cell resolution. Mol Cell Neurosci 2023; 126:103857. [PMID: 37137383 PMCID: PMC10525004 DOI: 10.1016/j.mcn.2023.103857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/21/2023] [Accepted: 04/26/2023] [Indexed: 05/05/2023] Open
Abstract
The nucleus accumbens (NAc) is a key brain region involved in reward processing and is linked to multiple neuropsychiatric conditions such as substance use disorder, depression, and chronic pain. Recent studies have begun to investigate NAc gene expression at a single-cell resolution, however, our understanding of the cellular heterogeneity of the NAc epigenomic landscape remains limited. In this study, we utilize single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) to map cell-type-specific differences in chromatin accessibility in the NAc. Our findings not only reveal the transcription factors and putative gene regulatory elements that may contribute to these cell-type-specific epigenomic differences but also provide a valuable resource for future studies investigating epigenomic changes that occur in neuropsychiatric disorders.
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Affiliation(s)
- Parth Bhatia
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Lite Yang
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Jay X J Luo
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Mengyi Xu
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, USA
| | - William Renthal
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, USA.
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24
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Gershoni M. Transgenerational transmission of environmental effects in livestock in the age of global warming. Cell Stress Chaperones 2023; 28:445-454. [PMID: 36715961 PMCID: PMC10468476 DOI: 10.1007/s12192-023-01325-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 01/10/2023] [Accepted: 01/22/2023] [Indexed: 01/31/2023] Open
Abstract
Recent decades provide mounting evidence for the continual increase in global temperatures, now termed "global warming," to the point of drastic worldwide change in the climate. Climatic change is a long-term shift in temperatures and weather patterns, including increased frequency and intensity of extreme environmental events such as heat waves accompanied by extreme temperatures and high humidity. Climate change and global warming put several challenges to the livestock industry by directly affecting the animal's production, reproduction, health, and welfare. The broad impact of global warming, and in particular heat stress, on-farm animals' performance has been comprehensively studied. It has been estimated that the US livestock industry's loss caused by heat stress is up to $2.4 billion annually. However, the long-term intergenerational and transgenerational effects of climatic change and global warming on farm animals are sparse. Transgenerational effects, which are mediated by epigenetic mechanisms, can affect the animal's performance regardless of its immediate environment by altering its phenotypic expression to fit its ancestors' environment. In many animal species, environmental effects are epigenetically encoded within a narrow time interval during the organism's gametogenesis, and these epigenetic modifications can then be intergenerationally transmitted. Several epigenetic mechanisms mediate intergenerational transmission of environmental effects, typically in a parent-dependent manner. Therefore, exposure of the animal to an extreme climatic event and other environmental stressors during gametogenesis can undergo epigenetic stabilization in the germline and be passed to the offspring. As a result, the offspring might express a phenotype adjusted to fit the stressors experienced by their ancestors, regardless of their direct environment. The purpose of this perspective is to review current evidence for intergenerational and transgenerational transmission of environmental stress effects, specifically in the context of global warming and climate change, and to offer viewpoints on the possible impacts on the livestock industry.
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Affiliation(s)
- Moran Gershoni
- Institute of Animal Science, Agricultural Research Organization, Volcani Center, 7505101, Rishon LeZion, Israel.
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25
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Dogaru BG, Munteanu C. The Role of Hydrogen Sulfide (H 2S) in Epigenetic Regulation of Neurodegenerative Diseases: A Systematic Review. Int J Mol Sci 2023; 24:12555. [PMID: 37628735 PMCID: PMC10454626 DOI: 10.3390/ijms241612555] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
This review explores the emerging role of hydrogen sulfide (H2S) in modulating epigenetic mechanisms involved in neurodegenerative diseases. Accumulating evidence has begun to elucidate the multifaceted ways in which H2S influences the epigenetic landscape and, subsequently, the progression of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. H2S can modulate key components of the epigenetic machinery, such as DNA methylation, histone modifications, and non-coding RNAs, impacting gene expression and cellular functions relevant to neuronal survival, inflammation, and synaptic plasticity. We synthesize recent research that positions H2S as an essential player within this intricate network, with the potential to open new therapeutic avenues for these currently incurable conditions. Despite significant progress, there remains a considerable gap in our understanding of the precise molecular mechanisms and the potential therapeutic implications of modulating H2S levels or its downstream targets. We conclude by identifying future directions for research aimed at exploiting the therapeutic potential of H2S in neurodegenerative diseases.
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Affiliation(s)
- Bombonica Gabriela Dogaru
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Clinical Rehabilitation Hospital, 400437 Cluj-Napoca, Romania
| | - Constantin Munteanu
- Teaching Emergency Hospital “Bagdasar-Arseni” (TEHBA), 041915 Bucharest, Romania
- Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa” Iași, 700454 Iași, Romania
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26
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Bi S, Tu Z, Chen D, Zhang S. Histone modifications in embryo implantation and placentation: insights from mouse models. Front Endocrinol (Lausanne) 2023; 14:1229862. [PMID: 37600694 PMCID: PMC10436591 DOI: 10.3389/fendo.2023.1229862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Embryo implantation and placentation play pivotal roles in pregnancy by facilitating crucial maternal-fetal interactions. These dynamic processes involve significant alterations in gene expression profiles within the endometrium and trophoblast lineages. Epigenetics regulatory mechanisms, such as DNA methylation, histone modification, chromatin remodeling, and microRNA expression, act as regulatory switches to modulate gene activity, and have been implicated in establishing a successful pregnancy. Exploring the alterations in these epigenetic modifications can provide valuable insights for the development of therapeutic strategies targeting complications related to pregnancy. However, our current understanding of these mechanisms during key gestational stages remains incomplete. This review focuses on recent advancements in the study of histone modifications during embryo implantation and placentation, while also highlighting future research directions in this field.
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Affiliation(s)
- Shilei Bi
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
| | - Zhaowei Tu
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
| | - Dunjin Chen
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
| | - Shuang Zhang
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
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27
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Grezenko H, Ekhator C, Nwabugwu NU, Ganga H, Affaf M, Abdelaziz AM, Rehman A, Shehryar A, Abbasi FA, Bellegarde SB, Khaliq AS. Epigenetics in Neurological and Psychiatric Disorders: A Comprehensive Review of Current Understanding and Future Perspectives. Cureus 2023; 15:e43960. [PMID: 37622055 PMCID: PMC10446850 DOI: 10.7759/cureus.43960] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 08/26/2023] Open
Abstract
The burgeoning field of epigenetics offers transformative insights into the complex landscape of neurological and psychiatric disorders. By unraveling the intricate interplay between genetic, epigenetic, environmental, and lifestyle factors, this comprehensive review highlights the multifaceted nature of mental health. The exploration reveals the potential of epigenetic modifications to revolutionize our understanding, diagnosis, treatment, and prevention of these disorders. Emphasizing the importance of multidisciplinary collaborations, large-scale studies, technological advancements, and ethical considerations, the review asserts the promise of epigenetics as a vital tool for personalized medicine, early intervention, and public health strategies. While acknowledging the challenges in a still-emerging field, the review paints an optimistic picture of epigenetics as a groundbreaking approach that can reshape mental healthcare, offering hope for those affected by neurological and psychiatric conditions. The future trajectory of the field relies on interdisciplinary efforts, ethical diligence, innovative technologies, and translating scientific insights into real-world applications, thereby unlocking the vast potential of epigenetics in mental health.
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Affiliation(s)
- Han Grezenko
- Translational Neuroscience, Barrow Neurological Institute, Phoenix, USA
| | - Chukwuyem Ekhator
- Neuro-Oncology, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, USA
| | - Nkechi U Nwabugwu
- Public Health, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | | | - Maryam Affaf
- Internal Medicine, Women Medical College, Abbottabad, PAK
| | - Ali M Abdelaziz
- Internal Medicine, Alexandria University Faculty of Medicine, Alexandria, EGY
| | | | | | - Fatima A Abbasi
- Cardiology, Shifa International Hospital Islamabad, Islamabad, PAK
| | - Sophia B Bellegarde
- Pathology and Laboratory Medicine, American University of Antigua, St. John's, ATG
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28
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Marinho LSR, Chiarantin GMD, Ikebara JM, Cardoso DS, de Lima-Vasconcellos TH, Higa GSV, Ferraz MSA, De Pasquale R, Takada SH, Papes F, Muotri AR, Kihara AH. The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools. Semin Cell Dev Biol 2023; 144:67-76. [PMID: 36115764 DOI: 10.1016/j.semcdb.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/10/2022] [Accepted: 09/10/2022] [Indexed: 11/23/2022]
Abstract
The use of antidepressants during pregnancy benefits the mother's well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepressants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids - self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale transcriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids.
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Affiliation(s)
| | | | - Juliane Midori Ikebara
- Neurogenetics Laboratory, Universidade Federal do ABC, São Bernardo do Campo, SP 09606-045, Brazil
| | - Débora Sterzeck Cardoso
- Neurogenetics Laboratory, Universidade Federal do ABC, São Bernardo do Campo, SP 09606-045, Brazil
| | | | - Guilherme Shigueto Vilar Higa
- Neurogenetics Laboratory, Universidade Federal do ABC, São Bernardo do Campo, SP 09606-045, Brazil; Department of Physiology and Biophysics, Biomedical Sciences Institute I, São Paulo University, São Paulo, SP 05508-000, Brazil
| | | | - Roberto De Pasquale
- Department of Physiology and Biophysics, Biomedical Sciences Institute I, São Paulo University, São Paulo, SP 05508-000, Brazil
| | - Silvia Honda Takada
- Neurogenetics Laboratory, Universidade Federal do ABC, São Bernardo do Campo, SP 09606-045, Brazil
| | - Fabio Papes
- Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil; Center for Medicinal Chemistry, University of Campinas, Campinas, SP 13083-875, Brazil; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Alysson R Muotri
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Cellular & Molecular Medicine, University of California San Diego, School of Medicine, Center for Academic Research and Training in Anthropogeny, Kavli Institute for Brain and Mind, Archealization Center (ArchC), La Jolla, CA 92037, USA.
| | - Alexandre Hiroaki Kihara
- Neurogenetics Laboratory, Universidade Federal do ABC, São Bernardo do Campo, SP 09606-045, Brazil.
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29
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Çerçi B, Gök A, Akyol A. Brain-derived neurotrophic factor: Its role in energy balance and cancer cachexia. Cytokine Growth Factor Rev 2023; 71-72:105-116. [PMID: 37500391 DOI: 10.1016/j.cytogfr.2023.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 07/29/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) plays an important role in the development of the central and peripheral nervous system during embryogenesis. In the mature central nervous system, BDNF is required for the maintenance and enhancement of synaptic transmissions and the survival of neurons. Particularly, it is involved in the modulation of neurocircuits that control energy balance through food intake, energy expenditure, and locomotion. Regulation of BDNF in the central nervous system is complex and environmental factors affect its expression in murine models which may reflect to phenotype dramatically. Furthermore, BDNF and its high-affinity receptor tropomyosin receptor kinase B (TrkB), as well as pan-neurotrophin receptor (p75NTR) is expressed in peripheral tissues in adulthood and their signaling is associated with regulation of energy balance. BDNF/TrkB signaling is exploited by cancer cells as well and BDNF expression is increased in tumors. Intriguingly, previously demonstrated roles of BDNF in regulation of food intake, adipose tissue and muscle overlap with derangements observed in cancer cachexia. However, data about the involvement of BDNF in cachectic cancer patients and murine models are scarce and inconclusive. In the future, knock-in and/or knock-out experiments with murine cancer models could be helpful to explore potential new roles for BDNF in the development of cancer cachexia.
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Affiliation(s)
- Barış Çerçi
- Medical School, Hacettepe University, Ankara, Turkey.
| | - Ayşenur Gök
- Department of Stem Cell Sciences, Graduate School of Health Sciences, Hacettepe University, Ankara, Turkey; Hacettepe University Transgenic Animal Technologies Research and Application Center, Sıhhiye, Ankara 06100, Turkey
| | - Aytekin Akyol
- Departmant of Pathology, Medical School, Hacettepe University, Ankara, Turkey; Hacettepe University Transgenic Animal Technologies Research and Application Center, Sıhhiye, Ankara 06100, Turkey
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30
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Cao L, Zhou Y, Gao L, Zheng Y, Cui X, Yin H, Wang S, Zhang M, Zhang H, Ai S. Photoelectrochemical biosensor for DNA demethylase detection based on enzymatically induced double-stranded DNA digestion by endonuclease-exonuclease system and Bi 4O 5Br 2-Au/CdS photoactive material. Talanta 2023; 262:124670. [PMID: 37245429 DOI: 10.1016/j.talanta.2023.124670] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/22/2023] [Accepted: 05/12/2023] [Indexed: 05/30/2023]
Abstract
A novel photoelectrochemical (PEC) biosensor for the detection of DNA demethylase MBD2 was developed based on Bi4O5Br2-Au/CdS photosensitive material. Bi4O5Br2 was firstly modified with gold nanoparticles (AuNPs), following with the modification onto the ITO electrode with CdS to realize the strong photocurrent response as a result of AuNPs had good conductibility and the matched energy between CdS and Bi4O5Br2. In the presence of MBD2, double-stranded DNA (dsDNA) on the electrode surface was demethylated, which triggered the digestion activity of endonuclease HpaII to cleave dsDNA and induced the further cleavage of the dsDNA fragment by exonuclease III (Exo III), causing the release of biotin labeled dsDNA and inhibiting the immobilization of streptavidin (SA) onto the electrode surface. As a results, the photocurrent was increased greatly. However, in the absence of MBD2, HpaII digestion activity was inhibited by DNA methylation modification, which further caused the failure in the release of biotin, leading to the successful immobilization of SA onto the electrode to realize a low photocurrent. The sensor had a detection of 0.3-200 ng/mL and a detection limit was 0.09 ng/mL (3σ). The applicability of this PEC strategy was assessed by studying the effect of environmental pollutants on MBD2 activity.
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Affiliation(s)
- LuLu Cao
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Yunlei Zhou
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China.
| | - Lanlan Gao
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Yulin Zheng
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Xiaoting Cui
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Huanshun Yin
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China.
| | - Suo Wang
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Miao Zhang
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Haowei Zhang
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
| | - Shiyun Ai
- College of Chemistry and Material Science, Food Safety Analysis and Test Engineering Technology Research Center of Shandong Province, Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, Shandong Agricultural University, 271018, Taian, Shandong, People's Republic of China
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Ji J, Jing A, Geng T, Ma X, Liu W, Liu B. Editorial: Protein modifications in epigenetic dysfunctional diseases: mechanisms and potential therapeutic strategies. Front Cell Dev Biol 2023; 11:1216637. [PMID: 37255602 PMCID: PMC10225621 DOI: 10.3389/fcell.2023.1216637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 06/01/2023] Open
Affiliation(s)
- Jing Ji
- Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Aixin Jing
- Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Ting Geng
- Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Xinhui Ma
- Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Wei Liu
- School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States
| | - Bin Liu
- Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
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Cheng Y, Song H, Ming GL, Weng YL. Epigenetic and epitranscriptomic regulation of axon regeneration. Mol Psychiatry 2023; 28:1440-1450. [PMID: 36922674 PMCID: PMC10650481 DOI: 10.1038/s41380-023-02028-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/18/2023]
Abstract
Effective axonal regeneration in the adult mammalian nervous system requires coordination of elevated intrinsic growth capacity and decreased responses to the inhibitory environment. Intrinsic regenerative capacity largely depends on the gene regulatory network and protein translation machinery. A failure to activate these pathways upon injury is underlying a lack of robust axon regeneration in the mature mammalian central nervous system. Epigenetics and epitranscriptomics are key regulatory mechanisms that shape gene expression and protein translation. Here, we provide an overview of different types of modifications on DNA, histones, and RNA, underpinning the regenerative competence of axons in the mature mammalian peripheral and central nervous systems. We highlight other non-neuronal cells and their epigenetic changes in determining the microenvironment for tissue repair and axon regeneration. We also address advancements of single-cell technology in charting transcriptomic and epigenetic landscapes that may further facilitate the mechanistic understanding of differential regenerative capacity in neuronal subtypes. Finally, as epigenetic and epitranscriptomic processes are commonly affected by brain injuries and psychiatric disorders, understanding their alterations upon brain injury would provide unprecedented mechanistic insights into etiology of injury-associated-psychiatric disorders and facilitate the development of therapeutic interventions to restore brain function.
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Affiliation(s)
- Yating Cheng
- Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX, 77030, USA
- Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Hongjun Song
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Guo-Li Ming
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Yi-Lan Weng
- Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX, 77030, USA.
- Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA.
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Singer P, Yee BK. The adenosine hypothesis of schizophrenia into its third decade: From neurochemical imbalance to early life etiological risks. Front Cell Neurosci 2023; 17:1120532. [PMID: 36998267 PMCID: PMC10043328 DOI: 10.3389/fncel.2023.1120532] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 02/15/2023] [Indexed: 03/17/2023] Open
Abstract
The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions. This new strategy may offer hope for improving treatment, especially in alleviating negative symptoms and cognitive deficits of schizophrenia that do not respond to current medications. To date, however, the adenosine hypothesis has yet led to any significant therapeutic breakthroughs. Here, we address two possible reasons for the impasse. First, neither the presence of adenosine functional deficiency in people with schizophrenia nor its causal relationship to symptom production has been satisfactorily examined. Second, the lack of novel adenosine-based drugs also impedes progress. This review updates the latest preclinical and clinical data pertinent to the construct validity of the adenosine hypothesis and explores novel molecular processes whereby dysregulation of adenosine signaling could be linked to the etiology of schizophrenia. It is intended to stimulate and revitalize research into the adenosine hypothesis towards the development of a new and improved generation of antipsychotic drugs that has eluded us for decades.
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Affiliation(s)
- Philipp Singer
- Roche Diagnostics International AG, Rotkreuz, Switzerland
- *Correspondence: Philipp Singer Benjamin K. Yee
| | - Benjamin K. Yee
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- Mental Health Research Centre, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- *Correspondence: Philipp Singer Benjamin K. Yee
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Brocato ER, Wolstenholme JT. Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes. Front Mol Neurosci 2023; 16:1082104. [PMID: 36937047 PMCID: PMC10020663 DOI: 10.3389/fnmol.2023.1082104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 02/10/2023] [Indexed: 03/06/2023] Open
Abstract
Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4 g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA-and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis - a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.
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Affiliation(s)
- Emily R. Brocato
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Jennifer T. Wolstenholme
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, United States
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Jyothi AK, Thotakura B, Priyadarshini SC, Patil S, Poojari MS, Subramanian M. Paternal stress alters synaptic density and expression of GAP-43, GRIN1, M1 and SYP genes in the hippocampus and cortex of offspring of stress-induced male rats. Morphologie 2023; 107:67-79. [PMID: 35715368 DOI: 10.1016/j.morpho.2022.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/16/2022] [Accepted: 05/03/2022] [Indexed: 02/07/2023]
Abstract
Adverse experiences during pregnancy have a negative impact on the neuronal structure and behavior of offspring, but the effects of a father's life events on the outcome of progeny are scarce. The present study is intended to investigate whether paternal stress affects the offspring brain structure, especially those regions concerned with learning and formation of memory, namely the hippocampus (HC) and prefrontal cortex (PFC), and also the expression of certain genes linked to learning and memory in the offspring. Induced stress to male rats by five stressors, one per day followed by allowing them to mate with the normal, unstressed female. Synaptophysin immunoreactivity was assessed in the tissue sections of the HC and PFC as well as expression of genes concerned with learning and memory was evaluated by RT-PCR in the progeny of stress-received males. The progeny of stressed rats had reduced antisynaptophysin immunoreactivity in the HC and PFC. The synaptic density in HC was less in the A-S (Offspring of male rats who received stress during adulthood) and PA-S (offspring of male rats who received stress during both adolescence and adulthood) than in P-S (offspring of male rats who received stress during adolescence) and C-C (offspring of control) groups. Similar results were observed even in the PFC. The results of post hoc tests proved that the HC and PFC of the progeny of stress-exposed rats exhibited considerably less synaptic density than control (P<0.05), and the levels of expression of GAP-43, GRIN1, M1, and SYP genes in HC and PFC were down-regulated. This study concludes that paternal adverse experiences can affect the offspring's synaptic plasticity and also the genes, which can regulate learning and formation of memory.
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Affiliation(s)
- A K Jyothi
- Department of Anatomy, Basaveshwara Medical College and Hospital, 577502 Chitradurga, Karnataka, India
| | - B Thotakura
- Department of Anatomy, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chettinad Health City, 603103 Kanchipuram, Tamil Nadu, India.
| | - S C Priyadarshini
- Department of Anatomy, Tagore Medical College & Hospital, 600127 Chennai, Tamil Nadu, India
| | - S Patil
- Department of Anatomy, Basaveshwara Medical College and Hospital, 577502 Chitradurga, Karnataka, India
| | - M S Poojari
- Department of Anatomy, Basaveshwara Medical College and Hospital, 577502 Chitradurga, Karnataka, India
| | - M Subramanian
- Department of Anatomy, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chettinad Health City, 603103 Kanchipuram, Tamil Nadu, India
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Trangle SS, Rosenberg T, Parnas H, Levy G, Bar E, Marco A, Barak B. In individuals with Williams syndrome, dysregulation of methylation in non-coding regions of neuronal and oligodendrocyte DNA is associated with pathology and cortical development. Mol Psychiatry 2023; 28:1112-1127. [PMID: 36577841 DOI: 10.1038/s41380-022-01921-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/03/2022] [Accepted: 12/12/2022] [Indexed: 12/29/2022]
Abstract
Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer-promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type-specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS.
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Affiliation(s)
- Sari Schokoroy Trangle
- The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Tali Rosenberg
- Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel
| | - Hadar Parnas
- Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel
| | - Gilad Levy
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Ela Bar
- The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.,The School of Neurobiology, Biochemistry & Biophysics, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Asaf Marco
- Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel.
| | - Boaz Barak
- The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel. .,Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.
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Xia M, Yan R, Kim MH, Xu X. Tet Enzyme-Mediated Response in Environmental Stress and Stress-Related Psychiatric Diseases. Mol Neurobiol 2023; 60:1594-1608. [PMID: 36534335 DOI: 10.1007/s12035-022-03168-9] [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: 08/08/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022]
Abstract
Mental disorders caused by stress have become a worldwide public health problem. These mental disorders are often the results of a combination of genes and environment, in which epigenetic modifications play a crucial role. At present, the genetic and epigenetic mechanisms of mental disorders such as posttraumatic stress disorder or depression caused by environmental stress are not entirely clear. Although many epigenetic modifications affect gene regulation, the most well-known modification in eukaryotic cells is the DNA methylation of CpG islands. Stress causes changes in DNA methylation in the brain to participate in the neuronal function or mood-modulating behaviors, and these epigenetic modifications can be passed on to offspring. Ten-eleven translocation (Tet) enzymes are the 5-methylcytosine (5mC) hydroxylases of DNA, which recognize 5mC on the DNA sequence and oxidize it to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Tet regulates gene expression at the transcriptional level through the demethylation of DNA. This review will elaborate on the molecular mechanism and the functions of Tet enzymes in environmental stress-related disorders and discuss future research directions.
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Affiliation(s)
- Meiling Xia
- Departments of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou City, 215006, China.,Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul City, 03080, Korea
| | - Rui Yan
- Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Myoung-Hwan Kim
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul City, 03080, Korea.
| | - Xingshun Xu
- Departments of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou City, 215006, China. .,Institute of Neuroscience, Soochow University, Suzhou City, China. .,Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou City, China.
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Fu P, Luo S, Liu Z, Furuhara K, Tsuji T, Higashida H, Yokoyama S, Zhong J, Tsuji C. Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder. Brain Sci 2023; 13:brainsci13020316. [PMID: 36831858 PMCID: PMC9954495 DOI: 10.3390/brainsci13020316] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/16/2023] Open
Abstract
Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.
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Affiliation(s)
- Pinyue Fu
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
- Division of Socio-Cognitive-Neuroscience, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Kanazawa 920-8640, Japan
| | - Shuxin Luo
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
- Physiological Department, Guangxi University of Chinese Medicine, Nanning 530011, China
| | - Zhongyu Liu
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
- Physiological Department, Guangxi University of Chinese Medicine, Nanning 530011, China
| | - Kazumi Furuhara
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
| | - Takahiro Tsuji
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
- Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
- Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan
| | - Haruhiro Higashida
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
| | - Shigeru Yokoyama
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
- Division of Socio-Cognitive-Neuroscience, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Kanazawa 920-8640, Japan
| | - Jing Zhong
- Physiological Department, Guangxi University of Chinese Medicine, Nanning 530011, China
- Correspondence: (J.Z.); or (C.T.); Tel.: +81-(0)-76-265-2458 (C.T.)
| | - Chiharu Tsuji
- Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan
- Correspondence: (J.Z.); or (C.T.); Tel.: +81-(0)-76-265-2458 (C.T.)
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Meng Y, Du J, Liu N, Qiang Y, Xiao L, Lan X, Ma L, Yang J, Yu J, Lu G. Epigenetic modulation: Research progress on histone acetylation levels in major depressive disorders. J Drug Target 2023; 31:142-151. [PMID: 36112185 DOI: 10.1080/1061186x.2022.2125978] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Depression is a serious mental illness and a prevalent condition with multiple aetiologies. The impact of the current therapeutic strategies is limited and the pathogenesis of the illness is not well understood. According to previous studies, depression onset is influenced by a variety of environmental and genetic factors, including chronic stress, aberrant changes in gene expression, and hereditary predisposition. Transcriptional regulation in eukaryotes is closely related to chromosome packing and is controlled by histone post-translational modifications. The development of new antidepressants may proceed along a new path with medications that target epigenetics. Histone deacetylase inhibitors (HDACis) are a class of compounds that interfere with the function of histone deacetylases (HDACs). This review explores the relationship between HDACs and depression and focuses on the current knowledge on their regulatory mechanism in depression and the potential therapeutic use of HDACis with antidepressant efficacy in preclinical research. Future research on inhibitors is also proposed and discussed.
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Affiliation(s)
- Yuan Meng
- Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, PR China.,Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Juan Du
- Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, PR China.,Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Ning Liu
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Yuanyuan Qiang
- Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, PR China
| | - Lifei Xiao
- Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, PR China
| | - Xiaobing Lan
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Lin Ma
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Jiamei Yang
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Jianqiang Yu
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, PR China
| | - Guangyuan Lu
- Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, PR China
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Wang Y, Yang L, Zhou H, Zhang K, Zhao M. Identification of miRNA-mediated gene regulatory networks in L-methionine exposure counteracts cocaine-conditioned place preference in mice. Front Genet 2023; 13:1076156. [PMID: 36744178 PMCID: PMC9893020 DOI: 10.3389/fgene.2022.1076156] [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: 10/21/2022] [Accepted: 12/27/2022] [Indexed: 01/20/2023] Open
Abstract
Background and Aims: Methionine has been proven to inhibit addictive behaviors of cocaine dependence. This study aimed to identify the potential mechanisms of MET relating to its inhibitory effects on cocaine induced cellular and behavioral changes. Methods: MRNA and miRNA high-throughput sequencing of the prefrontal cortex in a mouse model of cocaine conditioned place preference (CPP) combined with L-methionine was performed. Differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) regulated by cocaine and inhibited by L-methionine were identified. DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, the identified DEGs were subjected to the DAVID webserver for functional annotation. Finally, miRNA-mRNA regulatory network and miRNA-mRNA-TF regulatory networks were established to screen key DE-miRNAs and coregulation network in Cytoscape. Results: Sequencing data analysis showed that L-methionine reversely regulated genes and miRNAs affected by cocaine. Pathways associated with drug addiction only enriched in CS-down with MC-up genes targeted by DE-miRNAs including GABAergic synapse, Glutamatergic synapse, Circadian entrainment, Axon guidance and Calcium signaling pathway. Drug addiction associated network was formed of 22 DEGs including calcium channel (Cacna1c, Cacna1e, Cacna1g and Cacng8), ephrin receptor genes (Ephb6 and Epha8) and ryanodine receptor genes (Ryr1 and Ryr2). Calcium channel gene network were identified as a core gene network modulated by L-methionine in response to cocaine dependence. Moreover, it was predicted that Grin1 and Fosb presented in TF-miRNA-mRNA coregulation network with a high degree of interaction as hub genes and interacted calcium channels. Conclusion: These identified key genes, miRNA and coregulation network demonstrated the efficacy of L-methionine in counteracting the effects of cocaine CPP. To a certain degree, it may provide some hints to better understand the underlying mechanism on L-methionine in response to cocaine abuse.
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Affiliation(s)
- Yan Wang
- CAS Key Lab of Mental Health, Institute of Psychology, Beijing, China,Department of psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Lvyu Yang
- CAS Key Lab of Mental Health, Institute of Psychology, Beijing, China,Department of psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Hansheng Zhou
- Department of Pharmacy, Linyi People’s Hospital, Linyi, Shandong Province, China
| | - Kunlin Zhang
- CAS Key Lab of Mental Health, Institute of Psychology, Beijing, China
| | - Mei Zhao
- CAS Key Lab of Mental Health, Institute of Psychology, Beijing, China,Department of psychology, University of Chinese Academy of Sciences, Beijing, China,*Correspondence: Mei Zhao,
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Li CH, Chan MH, Chang YC, Hsiao M. Gold Nanoparticles as a Biosensor for Cancer Biomarker Determination. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28010364. [PMID: 36615558 PMCID: PMC9822408 DOI: 10.3390/molecules28010364] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023]
Abstract
Molecular biology applications based on gold nanotechnology have revolutionary impacts, especially in diagnosing and treating molecular and cellular levels. The combination of plasmonic resonance, biochemistry, and optoelectronic engineering has increased the detection of molecules and the possibility of atoms. These advantages have brought medical research to the cellular level for application potential. Many research groups are working towards this. The superior analytical properties of gold nanoparticles can not only be used as an effective drug screening instrument for gene sequencing in new drug development but also as an essential tool for detecting physiological functions, such as blood glucose, antigen-antibody analysis, etc. The review introduces the principles of biomedical sensing systems, the principles of nanomaterial analysis applied to biomedicine at home and abroad, and the chemical surface modification of various gold nanoparticles.
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Affiliation(s)
- Chien-Hsiu Li
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Ming-Hsien Chan
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 106, Taiwan
- Correspondence:
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Yin BK, Lázaro D, Wang ZQ. TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis. Comput Struct Biotechnol J 2022; 21:472-484. [PMID: 36618986 PMCID: PMC9804013 DOI: 10.1016/j.csbj.2022.12.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/15/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
The adult hippocampal neurogenesis plays a vital role in the function of the central nervous system (CNS), including memory consolidation, cognitive flexibility, emotional function, and social behavior. The deficiency of adult neural stem cells (aNSCs) in maintaining the quiescence and entering cell cycle, self-renewal and differentiation capacity is detrimental to the functional integrity of neurons and cognition of the adult brain. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) have been shown to modulate brain functionality and are important for embryonic neurogenesis via regulation of gene transcription. We showed previously that Trrap, an adapter for several HAT complexes, is required for Sp1 transcriptional control of the microtubule dynamics in neuronal cells. Here, we find that Trrap deletion compromises self-renewal and differentiation of aNSCs in mice and in cultures. We find that the acetylation status of lysine residues K16, K19, K703 and K639 all fail to overcome Trrap-deficiency-incurred instability of Sp1, indicating a scaffold role of Trrap. Interestingly, the deacetylation of Sp1 at K639 and K703 greatly increases Sp1 binding to the promoter of target genes, which antagonizes Trrap binding, and thereby elevates Sp1 activity. However, only deacetylated K639 is refractory to Trrap deficiency and corrects the differentiation defects of Trrap-deleted aNSCs. We demonstrate that the acetylation pattern at K639 by HATs dictates the role of Sp1 in the regulation of adult neurogenesis.
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Affiliation(s)
- Bo-Kun Yin
- Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
| | - David Lázaro
- Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
| | - Zhao-Qi Wang
- Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany,Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, Bachstrasse 18k, 07743 Jena, Germany,Corresponding author at: Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany,.
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Begum N, Mandhare A, Tryphena KP, Srivastava S, Shaikh MF, Singh SB, Khatri DK. Epigenetics in depression and gut-brain axis: A molecular crosstalk. Front Aging Neurosci 2022; 14:1048333. [PMID: 36583185 PMCID: PMC9794020 DOI: 10.3389/fnagi.2022.1048333] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022] Open
Abstract
Gut-brain axis is a dynamic, complex, and bidirectional communication network between the gut and brain. Changes in the microbiota-gut-brain axis are responsible for developing various metabolic, neurodegenerative, and neuropsychiatric disorders. According to clinical and preclinical findings, the gut microbiota is a significant regulator of the gut-brain axis. In addition to interacting with intestinal cells and the enteric nervous system, it has been discovered that microbes in the gut can modify the central nervous system through metabolic and neuroendocrine pathways. The metabolites of the gut microbiome can modulate a number of diseases by inducing epigenetic alteration through DNA methylation, histone modification, and non-coding RNA-associated gene silencing. Short-chain fatty acids, especially butyrate, are well-known histone deacetylases inhibitors. Similarly, other microbial metabolites such as folate, choline, and trimethylamine-N-oxide also regulate epigenetics mechanisms. Furthermore, various studies have revealed the potential role of microbiome dysbiosis and epigenetics in the pathophysiology of depression. Hence, in this review, we have highlighted the role of gut dysbiosis in epigenetic regulation, causal interaction between host epigenetic modification and the gut microbiome in depression and suggest microbiome and epigenome as a possible target for diagnosis, prevention, and treatment of depression.
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Affiliation(s)
- Nusrat Begum
- Cellular and Molecular Neuroscience Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Aniket Mandhare
- Cellular and Molecular Neuroscience Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Kamatham Pushpa Tryphena
- Cellular and Molecular Neuroscience Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India,*Correspondence: Saurabh Srivastava,
| | - Mohd Farooq Shaikh
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia,Mohd Farooq Shaikh,
| | - Shashi Bala Singh
- Cellular and Molecular Neuroscience Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Dharmendra Kumar Khatri
- Cellular and Molecular Neuroscience Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India,Dharmendra Kumar Khatri,
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Wang W, Tan T, Cao Q, Zhang F, Rein B, Duan WM, Yan Z. Histone Deacetylase Inhibition Restores Behavioral and Synaptic Function in a Mouse Model of 16p11.2 Deletion. Int J Neuropsychopharmacol 2022; 25:877-889. [PMID: 35907244 PMCID: PMC9593221 DOI: 10.1093/ijnp/pyac048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/21/2022] [Accepted: 07/27/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Microdeletion of the human 16p11.2 gene locus confers risk for autism spectrum disorders and intellectual disability. How 16p11.2 deletion is linked to these neurodevelopmental disorders and whether there are treatment avenues for the manifested phenotypes remain to be elucidated. Emerging evidence suggests that epigenetic aberrations are strongly implicated in autism. METHODS We performed behavioral and electrophysiological experiments to examine the therapeutic effects of epigenetic drugs in transgenic mice carrying 16p11.2 deletion (16p11del/+). RESULTS We found that 16p11del/+ mice exhibited a significantly reduced level of histone acetylation in the prefrontal cortex (PFC). A short (3-day) treatment with class I histone deacetylase (HDAC) inhibitor MS-275 or Romidepsin led to the prolonged (3-4 weeks) rescue of social and cognitive deficits in 16p11del/+ mice. Concomitantly, MS-275 treatment reversed the hypoactivity of PFC pyramidal neurons and the hyperactivity of PFC fast-spiking interneurons. Moreover, the diminished N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents and the elevated GABAA receptor-mediated synaptic currents in PFC pyramidal neurons of 16p11del/+ mice were restored to control levels by MS-275 treatment. CONCLUSIONS Our results suggest that HDAC inhibition provides a highly effective therapeutic strategy for behavioral deficits and excitation/inhibition imbalance in 16p11del/+ mice, likely via normalization of synaptic function in the PFC.
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Affiliation(s)
- Wei Wang
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Tao Tan
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Qing Cao
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Freddy Zhang
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Benjamin Rein
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Wei-Ming Duan
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Zhen Yan
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
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Changes in Stereotypies: Effects over Time and over Generations. Animals (Basel) 2022; 12:ani12192504. [PMID: 36230246 PMCID: PMC9559266 DOI: 10.3390/ani12192504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/06/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022] Open
Abstract
Simple Summary Herein, we propose that there should be discussion about the function and effects of stereotypies in relation to the time during which they are shown. In the first stages, stereotypies may help animals deal with challenges. However, behavior can potentially alter the brain, impairing its function due the absence of a diverse repertory, and change brain connections, neurophysiology and later neuroanatomy. The neuroanatomical changes in individuals showing stereotypies could be an effect rather than a cause of the stereotypy. As a consequence, studies showing different outcomes for animal welfare from stereotypy expression could be due to variation in a timeline of expression. Stereotypies are widely used as an animal welfare indicator, and their expression can tell us about psychological states. However, there are questions about the longer-term consequences if animals express stereotypies: do the stereotypies help in coping? During the prenatal period, stereotypic behavior expressed by the mother can change the phenotype of the offspring, especially regarding emotionality, one mechanism acting via methylation in the limbic system in the brain. Are individuals that show stereotypies for shorter or longer periods all better adjusted, and hence have better welfare, or is the later welfare of some worse than that of individuals that do not show the behavior? Abstract Stereotypies comprise a wide range of repeated and apparently functionless behaviors that develop in individuals whose neural condition or environment results in poor welfare. While stereotypies are an indicator of poor welfare at the time of occurrence, they may have various consequences. Environmental enrichment modifies causal factors and reduces the occurrence of stereotypies, providing evidence that stereotypies are an indicator of poor welfare. However, stereotypy occurrence and consequences change over time. Furthermore, there are complex direct and epigenetic effects when mother mammals that are kept in negative conditions do or do not show stereotypies. It is proposed that, when trying to deal with challenging situations, stereotypies might initially help animals to cope. After further time in the conditions, the performance of the stereotypy may impair brain function and change brain connections, neurophysiology and eventually neuroanatomy. It is possible that reported neuroanatomical changes are an effect of the stereotypy rather than a cause.
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Vasilopoulou F, Bellver-Sanchis A, Companys-Alemany J, Jarne-Ferrer J, Irisarri A, Palomera-Ávalos V, Gonzalez-Castillo C, Ortuño-Sahagún D, Sanfeliu C, Pallàs M, Griñán-Ferré C. Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice. Cells 2022; 11:cells11162603. [PMID: 36010679 PMCID: PMC9406492 DOI: 10.3390/cells11162603] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/14/2022] [Accepted: 08/19/2022] [Indexed: 11/21/2022] Open
Abstract
Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer’s Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model.
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Affiliation(s)
- Foteini Vasilopoulou
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Aina Bellver-Sanchis
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Júlia Companys-Alemany
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Júlia Jarne-Ferrer
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Alba Irisarri
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Verónica Palomera-Ávalos
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | | | - Daniel Ortuño-Sahagún
- Laboratorio de Neuroinmunología Molecular, Instituto de Investigación de Ciencias Biomédicas (IICB) CUCS, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Coral Sanfeliu
- Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain
- Correspondence:
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Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, Wagner I, Haferkamp U, Pless O, Merkler D, Engler JB, Friese MA. G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. SCIENCE ADVANCES 2022; 8:eabm5500. [PMID: 35930635 PMCID: PMC9355351 DOI: 10.1126/sciadv.abm5500] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 06/23/2022] [Indexed: 06/15/2023]
Abstract
Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.
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Affiliation(s)
- Nicola Rothammer
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Marcel S. Woo
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Simone Bauer
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Lars Binkle-Ladisch
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Giovanni Di Liberto
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Kristof Egervari
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Ingrid Wagner
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Undine Haferkamp
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany
| | - Ole Pless
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany
| | - Doron Merkler
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Jan Broder Engler
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Manuel A. Friese
- Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany
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Tsuji C, Furuhara K, Mizutani R, Minami K, Fu P, Zhong J, Higashida H, Yokoyama S, Tsuji T. Early-onset of social communication and locomotion activity in F2 pups of a valproic acid-induced mouse model of autism. Neurosci Lett 2022; 788:136827. [DOI: 10.1016/j.neulet.2022.136827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/18/2022] [Accepted: 08/03/2022] [Indexed: 10/15/2022]
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Watanabe T, Hayashi K, Takara T, Teratani T, Kitayama J, Kawahara T. Effect of Oral Administration of Lactiplantibacillus plantarum SNK12 on Temporary Stress in Adults: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19158936. [PMID: 35897310 PMCID: PMC9332698 DOI: 10.3390/ijerph19158936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 01/27/2023]
Abstract
Mouse studies have reported anti-stress effects of Lactiplantibacillus plantarum SNK12 (SNK). Specifically, oral SNK administration increased mRNA levels of hippocampal neurotrophic factor and gamma-aminobutyric acid receptor in mice with sub-chronic mild stress-induced social defeat; moreover, it improved depressive behavior. We aimed to evaluate the efficacy of SNK ingestion against stress in healthy adults. We used the Uchida–Kraepelin test for the stress load, with a low-dose (50 mg/day), high-dose (150 mg/day), and placebo groups (dextrin). The primary outcome was the psychological evaluation as measured by the Profile of Mood States 2nd Edition (POMS2) using total mood disturbance (TMD) scores. The secondary outcomes were the score of each POMS2 item, salivary cortisol as a stress marker, and autonomic balance with the low frequency (LF)/ high frequency (HF) ratio. Compared with the placebo group, the SNK ingestion group showed significantly lower TMD scores. Additionally, compared with the placebo group, the high-dose group showed significantly lower scores for Tension-Anxiety and Confusion-Bewilderment, while the low-dose group showed significantly lower Anger-Hostility scores, salivary cortisol levels, and LF/HF scores. Our findings suggest that SNK ingestion could relieve stress (negative feelings, anxiety, tension, embarrassment, confusion, anger, and hostility) resulting from the temporary load caused by work and study.
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Affiliation(s)
- Takumi Watanabe
- Division of Translational Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan; (T.T.); (J.K.)
- College of Life and Health Sciences, Chubu University, 1200 Matsumoto, Kasugai 487-8501, Aichi, Japan; (K.H.); (T.K.)
- Correspondence: ; Tel.: +81-42-978-7208
| | - Kyoko Hayashi
- College of Life and Health Sciences, Chubu University, 1200 Matsumoto, Kasugai 487-8501, Aichi, Japan; (K.H.); (T.K.)
| | - Tsuyoshi Takara
- Medical Corporation Seishinkai, Takara Clinic, 2-3-2-9, Higashigotanda, Shinagawa 141-0022, Tokyo, Japan;
| | - Takumi Teratani
- Division of Translational Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan; (T.T.); (J.K.)
| | - Joji Kitayama
- Division of Translational Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan; (T.T.); (J.K.)
| | - Toshio Kawahara
- College of Life and Health Sciences, Chubu University, 1200 Matsumoto, Kasugai 487-8501, Aichi, Japan; (K.H.); (T.K.)
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Epigenetic Studies for Evaluation of NPS Toxicity: Focus on Synthetic Cannabinoids and Cathinones. Biomedicines 2022; 10:biomedicines10061398. [PMID: 35740419 PMCID: PMC9219842 DOI: 10.3390/biomedicines10061398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 11/26/2022] Open
Abstract
In the recent decade, numerous new psychoactive substances (NPSs) have been added to the illicit drug market. These are synthetized to mimic the effects of classic drugs of abuse (i.e., cannabis, cocaine, etc.), with the purpose of bypassing substance legislations and increasing the pharmacotoxicological effects. To date, research into the acute pharmacological effects of new NPSs is ongoing and necessary in order to provide an appropriate contribution to public health. In fact, multiple examples of NPS-related acute intoxication and mortality have been recorded in the literature. Accordingly, several in vitro and in vivo studies have investigated the pharmacotoxicological profiles of these compounds, revealing that they can cause adverse effects involving various organ systems (i.e., cardiovascular, respiratory effects) and highlighting their potential increased consumption risks. In this sense, NPSs should be regarded as a complex issue that requires continuous monitoring. Moreover, knowledge of long-term NPS effects is lacking. Because genetic and environmental variables may impact NPS responses, epigenetics may aid in understanding the processes behind the harmful events induced by long-term NPS usage. Taken together, “pharmacoepigenomics” may provide a new field of combined study on genetic differences and epigenetic changes in drug reactions that might be predictive in forensic implications.
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