Mojgan Rastegar - Academia.edu (original) (raw)

Papers by Mojgan Rastegar

Cells

Eukaryotic gene expression is controlled at multiple levels, including gene transcription and pro... more Eukaryotic gene expression is controlled at multiple levels, including gene transcription and protein translation initiation. One molecule with key roles in both regulatory mechanisms is methyl CpG binding protein 2 (MeCP2). MECP2 gain- and loss-of-function mutations lead to Rett Syndrome and MECP2 Duplication Syndrome, respectively. To study MECP2 gain-of-function, we generated stably transduced human brain cells using lentiviral vectors for both MECP2E1 and MECP2E2 isoforms. Stable overexpression was confirmed by Western blot and immunofluorescence. We assessed the impact of MeCP2E1-E2 gain-of-function on the MeCP2 homeostasis regulatory network (MECP2E1/E2-BDNF/BDNF-miR-132), mTOR-AKT signaling, ribosome biogenesis, markers of chromatin structure, and protein translation initiation. We observed that combined co-transduction of MeCP2 isoforms led to protein degradation of MeCP2E1. Proteosome inhibition by MG132 treatment recovered MeCP2E1 protein within an hour, suggesting its ind...

Journal of Drug Delivery Science and Technology, 2022

Contemporary Clinical Neuroscience, 2017

Epigenetic mechanisms regulate cellular identity and organ morphology via controlling the gene ex... more Epigenetic mechanisms regulate cellular identity and organ morphology via controlling the gene expression program of specific cell types. Such mechanisms are not directly controlled by genomic DNA sequences and can be largely influenced by environmental factors. Epigenetic mechanisms include modification of DNA and DNA-bound proteins (histones), action of large and short regulatory RNA molecules, cross talk between DNA and histone marks, nucleosome positioning, chromatin removdeling, enhancer-promoter interactions, as well as three-dimensional chromatin structure that is in part controlled by global regulators and insulator proteins. Research on epigenetic mechanisms is an emerging hot topic today that may very well be due to the potential reversibility of epigenetic marks. Such characteristics of epigenetic modifications have brought them into the front row of research for cutting-edge therapeutic strategies. The challenge would be of course the very large number of genes that will be targeted by most epigenetic drugs that are capable of global modulation of epigenetic marks and a purposeful management of selectively targeting disease-associated genes in balance with global effects of these drugs.

Analytical Biochemistry, 2021

Fluorescence resonance energy transfer (FRET)-based biosensors are effective analytical tools ext... more Fluorescence resonance energy transfer (FRET)-based biosensors are effective analytical tools extensively used in fields of biomedicine, pharmacology, toxicology, and food sciences. Ratiometric imaging of substantial cellular processes, molecular components, and biological interactions is widely performed by these biosensors. A variety of FRET-based biosensors have provided comprehensive insights into underlying mechanisms of pathological conditions in live cells, tissues, and organisms. Moreover, integration of FRET-based biosensors with the current bioanalytical techniques allows for accurate, rapid, and sensitive diagnosis and proposes the advanced strategies for treatment. Precise analysis of ligand-receptor interactions by FRET-based biosensors has presented a basis for determination of novel therapeutic agents. Therefore, this study was designed to review the recent developments in FRET-based biosensors and their biomedical applications. In addition, characteristics, challenges, and outlooks of these biosensors were discussed.

Frontiers in Genetics, 2021

Ageing research reviews, 2018

Melatonin research has been experiencing hyper growth in the last two decades; this relates to it... more Melatonin research has been experiencing hyper growth in the last two decades; this relates to its numerous physiological functions including anti-inflammation, oncostasis, circadian and endocrine rhythm regulation, and its potent antioxidant activity. Recently, a large number of studies have focused on the role of melatonin in the regeneration of cells or tissues after their partial loss. In this review, we discuss the recent findings on the molecular involvement of melatonin in the regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others.

Current Topics in Medicinal Chemistry, 2017

Epigenetics control the gene expression program and cellular identity of individual cells in our ... more Epigenetics control the gene expression program and cellular identity of individual cells in our body via molecular mechanisms that are not directly reflected by the genomic DNA [1]. This includes different types of DNA methylation, histone post-translational modifications (PTMs), the cross-talk of DNA methylation and histone PTMs, chromatin remodeling, and the activity of non-coding and small micro RNAs. Recent discoveries have highlighted the importance of epigenetics and neuroepigenetics in the development, function, and diseases of the central nervous system. An important feature of epigenetic mechanisms is their reversibility. In contrast to genetic mutations, which are irreversible, there is a great potential to develop therapeutic strategies that target epigenetics. This thematic issue will cover recent advances in the field of "NeuroEpigenetics and Neurodevelopmental Disorders". In this special issue, I have gathered a collection of review articles on epigenetic mechanisms and neuroepigenetics, with a clear focus on neurodevelopmental disorders. The contributing authors have highlighted the impact of epigenetics in neuronal plasticity; as well as neural stem cell self-renewal and cell differentiation potencies in the context of neurodevelopmental disorders. The authors have further expanded the discussions on the cognitive neurodevelopmental diseases such as fetal alcohol spectrum disorders (FASD), reviewed the potential application of epigenetic drugs for neurodevelopmental disorders, discussed a well-studied neurodevelopmental disorder with genetic mutations in an epigenetic factor (Rett Syndrome), and ultimately provided an exciting series of recent discoveries in epigenetics that impact novel medicine. In the article "Epigenetic Basis of Neuronal and Synaptic Plasticity", contributed by Nina Karpova, Amanda Sales and Sâmia Joca, at the

Free Radical Biology and Medicine, 2016

Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after ... more Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions. Glutathione and thioredoxin systems provide reducing protons that can effectively reverse protein modifications and promote cell survival. The central role of Thioredoxin in inhibition of apoptosis is well identified. Additionally, its involvement in initiation of autophagy has been suggested recently. We therefore aimed to investigate the involvement of Thioredoxin system in autophagy-apoptosis processes. A model of serum deprivation in SH-SY5Y was used that is associated with autophagy and apoptosis. Using pharmacological and RNA-editing technology we show that Thioredoxin reductase deficiency in this model enhances oxidative stress and interrupts the early protective autophagy and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes as well as impairment in proteasome pathway. We further confirmed that the extent of oxidative stress is a determining factor in autophagy- apoptosis interplay, as upregulation of cellular reducing capacity by N-acetylcysteine prevented impairment in autophagy and proteasome systems thus promoted cell viability. Our study provides evidence that excessive oxidative stress inhibits protein degradation systems and affects the final stages of autophagy by inhibiting autolysosome maturation: a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis that can be applicable to neurodegenerative diseases.

ABSTRACT IntroductionChromatin Structure and Histone ModificationsDNA MethylationAnalyses of Epig... more ABSTRACT IntroductionChromatin Structure and Histone ModificationsDNA MethylationAnalyses of Epigenetic EventsEpigenetic Control of Stem Cell PluripotencyChromatin Structure in ES CellsPolycomb and Trithorax ProteinsDna Methylation and PluripotencyEpigenetics and Cellular ReprogrammingConclusion References

Biochemical Pharmacology, 2006

European Journal of Pharmacology, 2017

Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stres... more Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stress exposure. Early social isolation stress (SIS) is known to provoke a variety of psychiatric comorbidities as well as seizure risk. Psychiatric comorbidities present challenging dilemmas for treatment and management in people with seizure disorders. In this study, we aimed to investigate whether gabapentin (GBP) as an anti-epileptic drug is able to alleviate the seizure activity as well as comorbid behavioral abnormalities in socially isolated mice. Results showed that early SIS induced proconvulsant effects along with depressive, aggressive and anxiety-like behaviors. Whereas the administration of both acute and chronic GBP at sub-effective doses produced no alterations in the behavioral profile of socially conditioned counterparts the same treatments effectively reversed the seizure susceptibility to pentylenetetrazole and behavioral deficits in isolated mice. Results of the study indicate that 1) Early SIS could be considered as an animal model of psychosocial stress to investigate the psychiatric comorbidities in seizure disorders, 2) Chronic administration of low dose GBP prevented the shaping of behavioral abnormalities in adulthood, 3) Chronic administration of low dose GBP produced no negative behavioral effects in socially conditioned mice suggesting the safety of the drug, 4) Gabapentin at low doses may be considered as an agent for management of epilepsy in individuals with psychiatric comorbidities. Recently, we showed that early social isolation stress (SIS) provoked seizure risk along with affective behavioral dysfunctions in adult mice (Amiri et al., 2014). Early life stress is known to increase the risk of epileptogenesis and occurrence of psychiatric comorbidities (Huang, 2014; Jones et al., 2014). It has been suggested that applying animal

Neuroscience, 2017

Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction i... more Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the cooccurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2 mg/ mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24 h following STZ treatment. We observed that the co-occurrence of anxiety and depressivelike behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A 2 (cPLA 2) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation.

Neuroscience, Aug 7, 2016

Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a ke... more Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-lik...

Physiology & behavior, Sep 30, 2016

Mother-infant interactions are known to be associated with the psychological well-being of an ind... more Mother-infant interactions are known to be associated with the psychological well-being of an individual in adulthood. It is well accepted that emotional stress in early life, such as maternal separation (MS), leads to alterations in the neurotransmission systems of various brain regions, especially the mesolimbic dopaminergic system, and subsequently can increase the risk for development of psychiatric disorders including depression in adulthood. Selegiline is an irreversible monoamine oxidase (MAO) type B inhibitor which increases striatal dopamine levels and exerts an antidepressant effect. In this study, 180min of MS stress was applied to mice at postnatal day (PND) 2-14 followed by behavioral tests for determining depressive-like behaviors, such as forced swimming test (FST), splash test and sucrose preference test (SPT) in adult mice (PND 50). The open field test (OFT) also was applied to validate FST results. We used SCH23390 (D1 antagonist) and sulpiride (D2 antagonist) in o...

Epilepsy & Behavior, 2016

In this study, we tested whether acute administration of lithium mitigates the deleterious effect... more In this study, we tested whether acute administration of lithium mitigates the deleterious effect of adolescent social isolation stress (SIS) on seizure susceptibility. In comparison with socially conditioned (SC) mice, isolated conditioned (IC) mice exhibited an increase in seizure susceptibility to pentylenetetrazole. Acute administration of lithium (10 mg/kg) reversed the proconvulsant effect of SIS in IC mice, but this effect was not observed in SC mice. Coadministration of subthreshold doses of lithium (3 mg/kg) with nitric oxide synthase (NOS) inhibitors reversed the effect of SIS on seizure susceptibility and decreased hippocampal nitrite levels in IC animals. In addition, a subthreshold dose of a nitric oxide precursor reduced the protective effect of lithium on seizure susceptibility and increased nitrite levels in the hippocampus of IC mice. These results suggest that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS via a nitrergic system that includes activation of neuronal NOS in the hippocampus.

International Journal of Developmental Neuroscience, 2015

Introduction: MeCP2 is a major epigenetic modulator in brain. Mutations and expression deficits o... more Introduction: MeCP2 is a major epigenetic modulator in brain. Mutations and expression deficits of MeCP2 cause several neurodevelopmental disorders including Rett syndrome and Autism, which do not have any cure. Even though a thorough understanding of MeCP2 regulation in brain is required to design therapeutic strategies, mechanisms by which MeCP2 is regulated in brain remain elusive. Potential role of promoter DNA methylation in repressing MeCP2 expression in human autistic brains and stressed mouse brain have been shown before. Objectives: In this study, we investigated the role of DNA methylation at the Mecp2 regulatory elements (REs) within the Mecp2 promoter and intron 1 in regulating Mecp2/MeCP2 expression in vitro and in vivo. We used an established in vitro model of neurogenesis [differentiating neural stem cells (NSCs)] and adult mouse brain regions. Further, we aimed to test the ability of an FDA approved epigenetic drug to induce the Mecp2/MeCP2 expression through DNA methylation changes during neurogenesis. Methods: We studied DNA methylation by using bisulfite pyrosequencing in differentiating NSCs and seven brain regions in the adult mouse. We treated the differentiating NSC with the epigenetic drug Decitabine at the onset of NSC differentiation and studied changes in Mecp2/MeCP2 expression and DNA methylation. Results: Our results show dynamic DNA methylation profiles at the Mecp2 REs which correlated with Mecp2 expression at different stages of NSC differentiation and in the studied brain regions. The Decitabine treatment of NSCs significantly induced Mecp2/MeCP2 expression both at transcript and protein levels in association with DNA demethylation of the Mecp2 REs. Conclusions: Our studies provide evidence for the epigenetic regulation of Mecp2 expression by DNA methylation during neurogenesis and in adult brain. The ability of Decitabine to induce Mecp2/MeCP2 expression during neurogenesis provides insights on potential drug therapy to restore or induce Mecp2/MeCP2 expression in MeCP2 deficiency-related neurodevelopmental disorders.

Current Topics in Medicinal Chemistry, 2017

Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects ... more Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects and neurodevelopmental deficits referred to as "Fetal Alcohol Spectrum Disorders (FASD)". The more visible phenotypes caused by PAE include growth retardation, and characteristic craniofacial abnormalities associated with functional and structural damage to the central nervous system. Ethanol is a teratogenic agent itself; but it can also alter gene expression. These changes may contribute to the spectrum of effects and different phenotypes that are dependent on alcohol metabolism, as well as the timing and duration of alcohol exposure. Evidence from both human patients and animal models show that genetic factors and epigenetic mechanisms such as DNA methylation, histone post-translational modifications and noncoding RNAs, contribute to the gene expression changes caused by ethanol. Not all embryos that are exposed to alcohol during development exhibit FASD symptoms after birth. FASD patients may present severe birth defects, while others are normal in physical appearance but present a variety of cognitive and behavioral difficulties. It has been hypothesized that maternal and paternal genetic factors may contribute to the sensitivity, resistance or vulnerability of the fetus to alcohol. Moreover, the epigenome is highly sensitive to a multitude of environmental insults including PAE. Studies also show 'transgenerational' effects of alcohol. In such cases, maternal or paternal preconception alcohol consumption could lead to FASD-like phenotypes in the newborn. Thus, the phenotypes in FASD can be modified by interplay between maternal/paternal genetic factors and epigenetic mechanisms. This current review summarizes the contribution of genetic and epigenetic mechanisms in FASD pathobiology, and how this information could be utilized for prevention, early diagnosis and potentially treatment of the affected individuals.

Biochemical Journal, 1998

Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a family of tissue-specific transcription... more Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a family of tissue-specific transcription factors characterized by a bipartite DNA-binding domain consisting of a single cut domain and a novel type of homeodomain. We have previously cloned rat cDNA species coding for two isoforms, HNF-6α (465 residues) and β (491 residues), which differ only by the length of the spacer between the two DNA-binding domains. We have now localized the rat Hnf6 gene to chromosome 8q24–q31 by Southern blotting of DNA from somatic cell hybrids and by fluorescence in situhybridization. Cloning and sequencing of the rat gene showed that the two HNF-6 isoforms are generated by alternative splicing of three exons that are more than 10 kb apart from each other. Exon 1 codes for the N-terminal part and the cut domain, exon 2 codes for the 26 HNF-6β-specific amino acids, and exon 3 codes for the homeodomain and the C-terminal amino acids. The transcription initiation site was mapped by ribonuclease protect...

Epilepsy & Behavior, 2015

Experiencing early-life stress has been considered as a potent risk factor for the development of... more Experiencing early-life stress has been considered as a potent risk factor for the development of many of brain disorders, including seizures. Intervening mechanisms through which neonatal maternal separation (MS) alters the seizure susceptibility in adulthood have not been well studied. In the current study, by applying 180 min of MS stress (PND 2-14), we determined the seizure susceptibility and considered the role of the opioid system. Maternal separation increased the seizure threshold, and administration of anticonvulsant/proconvulsant doses of morphine (1 and 30 mg/kg, respectively) reversed the impact of MS. Using tail flick and hot plate tests, we exposed animals to 30 min Restraint stress (RS) and found that MS decreased the pain threshold, suggesting the hyporesponsiveness of the opioid system. These results supported the abnormal seizure activity observed in the MS mice and suggested that abnormalities in the opioid system following MS alter seizure susceptibility in later life.

Cells

Eukaryotic gene expression is controlled at multiple levels, including gene transcription and pro... more Eukaryotic gene expression is controlled at multiple levels, including gene transcription and protein translation initiation. One molecule with key roles in both regulatory mechanisms is methyl CpG binding protein 2 (MeCP2). MECP2 gain- and loss-of-function mutations lead to Rett Syndrome and MECP2 Duplication Syndrome, respectively. To study MECP2 gain-of-function, we generated stably transduced human brain cells using lentiviral vectors for both MECP2E1 and MECP2E2 isoforms. Stable overexpression was confirmed by Western blot and immunofluorescence. We assessed the impact of MeCP2E1-E2 gain-of-function on the MeCP2 homeostasis regulatory network (MECP2E1/E2-BDNF/BDNF-miR-132), mTOR-AKT signaling, ribosome biogenesis, markers of chromatin structure, and protein translation initiation. We observed that combined co-transduction of MeCP2 isoforms led to protein degradation of MeCP2E1. Proteosome inhibition by MG132 treatment recovered MeCP2E1 protein within an hour, suggesting its ind...

Journal of Drug Delivery Science and Technology, 2022

Contemporary Clinical Neuroscience, 2017

Epigenetic mechanisms regulate cellular identity and organ morphology via controlling the gene ex... more Epigenetic mechanisms regulate cellular identity and organ morphology via controlling the gene expression program of specific cell types. Such mechanisms are not directly controlled by genomic DNA sequences and can be largely influenced by environmental factors. Epigenetic mechanisms include modification of DNA and DNA-bound proteins (histones), action of large and short regulatory RNA molecules, cross talk between DNA and histone marks, nucleosome positioning, chromatin removdeling, enhancer-promoter interactions, as well as three-dimensional chromatin structure that is in part controlled by global regulators and insulator proteins. Research on epigenetic mechanisms is an emerging hot topic today that may very well be due to the potential reversibility of epigenetic marks. Such characteristics of epigenetic modifications have brought them into the front row of research for cutting-edge therapeutic strategies. The challenge would be of course the very large number of genes that will be targeted by most epigenetic drugs that are capable of global modulation of epigenetic marks and a purposeful management of selectively targeting disease-associated genes in balance with global effects of these drugs.

Analytical Biochemistry, 2021

Fluorescence resonance energy transfer (FRET)-based biosensors are effective analytical tools ext... more Fluorescence resonance energy transfer (FRET)-based biosensors are effective analytical tools extensively used in fields of biomedicine, pharmacology, toxicology, and food sciences. Ratiometric imaging of substantial cellular processes, molecular components, and biological interactions is widely performed by these biosensors. A variety of FRET-based biosensors have provided comprehensive insights into underlying mechanisms of pathological conditions in live cells, tissues, and organisms. Moreover, integration of FRET-based biosensors with the current bioanalytical techniques allows for accurate, rapid, and sensitive diagnosis and proposes the advanced strategies for treatment. Precise analysis of ligand-receptor interactions by FRET-based biosensors has presented a basis for determination of novel therapeutic agents. Therefore, this study was designed to review the recent developments in FRET-based biosensors and their biomedical applications. In addition, characteristics, challenges, and outlooks of these biosensors were discussed.

Frontiers in Genetics, 2021

Ageing research reviews, 2018

Melatonin research has been experiencing hyper growth in the last two decades; this relates to it... more Melatonin research has been experiencing hyper growth in the last two decades; this relates to its numerous physiological functions including anti-inflammation, oncostasis, circadian and endocrine rhythm regulation, and its potent antioxidant activity. Recently, a large number of studies have focused on the role of melatonin in the regeneration of cells or tissues after their partial loss. In this review, we discuss the recent findings on the molecular involvement of melatonin in the regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others.

Current Topics in Medicinal Chemistry, 2017

Epigenetics control the gene expression program and cellular identity of individual cells in our ... more Epigenetics control the gene expression program and cellular identity of individual cells in our body via molecular mechanisms that are not directly reflected by the genomic DNA [1]. This includes different types of DNA methylation, histone post-translational modifications (PTMs), the cross-talk of DNA methylation and histone PTMs, chromatin remodeling, and the activity of non-coding and small micro RNAs. Recent discoveries have highlighted the importance of epigenetics and neuroepigenetics in the development, function, and diseases of the central nervous system. An important feature of epigenetic mechanisms is their reversibility. In contrast to genetic mutations, which are irreversible, there is a great potential to develop therapeutic strategies that target epigenetics. This thematic issue will cover recent advances in the field of "NeuroEpigenetics and Neurodevelopmental Disorders". In this special issue, I have gathered a collection of review articles on epigenetic mechanisms and neuroepigenetics, with a clear focus on neurodevelopmental disorders. The contributing authors have highlighted the impact of epigenetics in neuronal plasticity; as well as neural stem cell self-renewal and cell differentiation potencies in the context of neurodevelopmental disorders. The authors have further expanded the discussions on the cognitive neurodevelopmental diseases such as fetal alcohol spectrum disorders (FASD), reviewed the potential application of epigenetic drugs for neurodevelopmental disorders, discussed a well-studied neurodevelopmental disorder with genetic mutations in an epigenetic factor (Rett Syndrome), and ultimately provided an exciting series of recent discoveries in epigenetics that impact novel medicine. In the article "Epigenetic Basis of Neuronal and Synaptic Plasticity", contributed by Nina Karpova, Amanda Sales and Sâmia Joca, at the

Free Radical Biology and Medicine, 2016

Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after ... more Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions. Glutathione and thioredoxin systems provide reducing protons that can effectively reverse protein modifications and promote cell survival. The central role of Thioredoxin in inhibition of apoptosis is well identified. Additionally, its involvement in initiation of autophagy has been suggested recently. We therefore aimed to investigate the involvement of Thioredoxin system in autophagy-apoptosis processes. A model of serum deprivation in SH-SY5Y was used that is associated with autophagy and apoptosis. Using pharmacological and RNA-editing technology we show that Thioredoxin reductase deficiency in this model enhances oxidative stress and interrupts the early protective autophagy and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes as well as impairment in proteasome pathway. We further confirmed that the extent of oxidative stress is a determining factor in autophagy- apoptosis interplay, as upregulation of cellular reducing capacity by N-acetylcysteine prevented impairment in autophagy and proteasome systems thus promoted cell viability. Our study provides evidence that excessive oxidative stress inhibits protein degradation systems and affects the final stages of autophagy by inhibiting autolysosome maturation: a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis that can be applicable to neurodegenerative diseases.

ABSTRACT IntroductionChromatin Structure and Histone ModificationsDNA MethylationAnalyses of Epig... more ABSTRACT IntroductionChromatin Structure and Histone ModificationsDNA MethylationAnalyses of Epigenetic EventsEpigenetic Control of Stem Cell PluripotencyChromatin Structure in ES CellsPolycomb and Trithorax ProteinsDna Methylation and PluripotencyEpigenetics and Cellular ReprogrammingConclusion References

Biochemical Pharmacology, 2006

European Journal of Pharmacology, 2017

Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stres... more Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stress exposure. Early social isolation stress (SIS) is known to provoke a variety of psychiatric comorbidities as well as seizure risk. Psychiatric comorbidities present challenging dilemmas for treatment and management in people with seizure disorders. In this study, we aimed to investigate whether gabapentin (GBP) as an anti-epileptic drug is able to alleviate the seizure activity as well as comorbid behavioral abnormalities in socially isolated mice. Results showed that early SIS induced proconvulsant effects along with depressive, aggressive and anxiety-like behaviors. Whereas the administration of both acute and chronic GBP at sub-effective doses produced no alterations in the behavioral profile of socially conditioned counterparts the same treatments effectively reversed the seizure susceptibility to pentylenetetrazole and behavioral deficits in isolated mice. Results of the study indicate that 1) Early SIS could be considered as an animal model of psychosocial stress to investigate the psychiatric comorbidities in seizure disorders, 2) Chronic administration of low dose GBP prevented the shaping of behavioral abnormalities in adulthood, 3) Chronic administration of low dose GBP produced no negative behavioral effects in socially conditioned mice suggesting the safety of the drug, 4) Gabapentin at low doses may be considered as an agent for management of epilepsy in individuals with psychiatric comorbidities. Recently, we showed that early social isolation stress (SIS) provoked seizure risk along with affective behavioral dysfunctions in adult mice (Amiri et al., 2014). Early life stress is known to increase the risk of epileptogenesis and occurrence of psychiatric comorbidities (Huang, 2014; Jones et al., 2014). It has been suggested that applying animal

Neuroscience, 2017

Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction i... more Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the cooccurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2 mg/ mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24 h following STZ treatment. We observed that the co-occurrence of anxiety and depressivelike behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A 2 (cPLA 2) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation.

Neuroscience, Aug 7, 2016

Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a ke... more Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-lik...

Physiology & behavior, Sep 30, 2016

Mother-infant interactions are known to be associated with the psychological well-being of an ind... more Mother-infant interactions are known to be associated with the psychological well-being of an individual in adulthood. It is well accepted that emotional stress in early life, such as maternal separation (MS), leads to alterations in the neurotransmission systems of various brain regions, especially the mesolimbic dopaminergic system, and subsequently can increase the risk for development of psychiatric disorders including depression in adulthood. Selegiline is an irreversible monoamine oxidase (MAO) type B inhibitor which increases striatal dopamine levels and exerts an antidepressant effect. In this study, 180min of MS stress was applied to mice at postnatal day (PND) 2-14 followed by behavioral tests for determining depressive-like behaviors, such as forced swimming test (FST), splash test and sucrose preference test (SPT) in adult mice (PND 50). The open field test (OFT) also was applied to validate FST results. We used SCH23390 (D1 antagonist) and sulpiride (D2 antagonist) in o...

Epilepsy & Behavior, 2016

In this study, we tested whether acute administration of lithium mitigates the deleterious effect... more In this study, we tested whether acute administration of lithium mitigates the deleterious effect of adolescent social isolation stress (SIS) on seizure susceptibility. In comparison with socially conditioned (SC) mice, isolated conditioned (IC) mice exhibited an increase in seizure susceptibility to pentylenetetrazole. Acute administration of lithium (10 mg/kg) reversed the proconvulsant effect of SIS in IC mice, but this effect was not observed in SC mice. Coadministration of subthreshold doses of lithium (3 mg/kg) with nitric oxide synthase (NOS) inhibitors reversed the effect of SIS on seizure susceptibility and decreased hippocampal nitrite levels in IC animals. In addition, a subthreshold dose of a nitric oxide precursor reduced the protective effect of lithium on seizure susceptibility and increased nitrite levels in the hippocampus of IC mice. These results suggest that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS via a nitrergic system that includes activation of neuronal NOS in the hippocampus.

International Journal of Developmental Neuroscience, 2015

Introduction: MeCP2 is a major epigenetic modulator in brain. Mutations and expression deficits o... more Introduction: MeCP2 is a major epigenetic modulator in brain. Mutations and expression deficits of MeCP2 cause several neurodevelopmental disorders including Rett syndrome and Autism, which do not have any cure. Even though a thorough understanding of MeCP2 regulation in brain is required to design therapeutic strategies, mechanisms by which MeCP2 is regulated in brain remain elusive. Potential role of promoter DNA methylation in repressing MeCP2 expression in human autistic brains and stressed mouse brain have been shown before. Objectives: In this study, we investigated the role of DNA methylation at the Mecp2 regulatory elements (REs) within the Mecp2 promoter and intron 1 in regulating Mecp2/MeCP2 expression in vitro and in vivo. We used an established in vitro model of neurogenesis [differentiating neural stem cells (NSCs)] and adult mouse brain regions. Further, we aimed to test the ability of an FDA approved epigenetic drug to induce the Mecp2/MeCP2 expression through DNA methylation changes during neurogenesis. Methods: We studied DNA methylation by using bisulfite pyrosequencing in differentiating NSCs and seven brain regions in the adult mouse. We treated the differentiating NSC with the epigenetic drug Decitabine at the onset of NSC differentiation and studied changes in Mecp2/MeCP2 expression and DNA methylation. Results: Our results show dynamic DNA methylation profiles at the Mecp2 REs which correlated with Mecp2 expression at different stages of NSC differentiation and in the studied brain regions. The Decitabine treatment of NSCs significantly induced Mecp2/MeCP2 expression both at transcript and protein levels in association with DNA demethylation of the Mecp2 REs. Conclusions: Our studies provide evidence for the epigenetic regulation of Mecp2 expression by DNA methylation during neurogenesis and in adult brain. The ability of Decitabine to induce Mecp2/MeCP2 expression during neurogenesis provides insights on potential drug therapy to restore or induce Mecp2/MeCP2 expression in MeCP2 deficiency-related neurodevelopmental disorders.

Current Topics in Medicinal Chemistry, 2017

Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects ... more Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects and neurodevelopmental deficits referred to as "Fetal Alcohol Spectrum Disorders (FASD)". The more visible phenotypes caused by PAE include growth retardation, and characteristic craniofacial abnormalities associated with functional and structural damage to the central nervous system. Ethanol is a teratogenic agent itself; but it can also alter gene expression. These changes may contribute to the spectrum of effects and different phenotypes that are dependent on alcohol metabolism, as well as the timing and duration of alcohol exposure. Evidence from both human patients and animal models show that genetic factors and epigenetic mechanisms such as DNA methylation, histone post-translational modifications and noncoding RNAs, contribute to the gene expression changes caused by ethanol. Not all embryos that are exposed to alcohol during development exhibit FASD symptoms after birth. FASD patients may present severe birth defects, while others are normal in physical appearance but present a variety of cognitive and behavioral difficulties. It has been hypothesized that maternal and paternal genetic factors may contribute to the sensitivity, resistance or vulnerability of the fetus to alcohol. Moreover, the epigenome is highly sensitive to a multitude of environmental insults including PAE. Studies also show 'transgenerational' effects of alcohol. In such cases, maternal or paternal preconception alcohol consumption could lead to FASD-like phenotypes in the newborn. Thus, the phenotypes in FASD can be modified by interplay between maternal/paternal genetic factors and epigenetic mechanisms. This current review summarizes the contribution of genetic and epigenetic mechanisms in FASD pathobiology, and how this information could be utilized for prevention, early diagnosis and potentially treatment of the affected individuals.

Biochemical Journal, 1998

Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a family of tissue-specific transcription... more Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a family of tissue-specific transcription factors characterized by a bipartite DNA-binding domain consisting of a single cut domain and a novel type of homeodomain. We have previously cloned rat cDNA species coding for two isoforms, HNF-6α (465 residues) and β (491 residues), which differ only by the length of the spacer between the two DNA-binding domains. We have now localized the rat Hnf6 gene to chromosome 8q24–q31 by Southern blotting of DNA from somatic cell hybrids and by fluorescence in situhybridization. Cloning and sequencing of the rat gene showed that the two HNF-6 isoforms are generated by alternative splicing of three exons that are more than 10 kb apart from each other. Exon 1 codes for the N-terminal part and the cut domain, exon 2 codes for the 26 HNF-6β-specific amino acids, and exon 3 codes for the homeodomain and the C-terminal amino acids. The transcription initiation site was mapped by ribonuclease protect...

Epilepsy & Behavior, 2015

Experiencing early-life stress has been considered as a potent risk factor for the development of... more Experiencing early-life stress has been considered as a potent risk factor for the development of many of brain disorders, including seizures. Intervening mechanisms through which neonatal maternal separation (MS) alters the seizure susceptibility in adulthood have not been well studied. In the current study, by applying 180 min of MS stress (PND 2-14), we determined the seizure susceptibility and considered the role of the opioid system. Maternal separation increased the seizure threshold, and administration of anticonvulsant/proconvulsant doses of morphine (1 and 30 mg/kg, respectively) reversed the impact of MS. Using tail flick and hot plate tests, we exposed animals to 30 min Restraint stress (RS) and found that MS decreased the pain threshold, suggesting the hyporesponsiveness of the opioid system. These results supported the abnormal seizure activity observed in the MS mice and suggested that abnormalities in the opioid system following MS alter seizure susceptibility in later life.