scholarly journals Influence of psychostimulants and opioids on epigenetic modification of class III histone deacetylase (HDAC)-sirtuins in glial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalaiselvi Sivalingam ◽  
Mayur Doke ◽  
Mansoor A. Khan ◽  
Thangavel Samikkannu
Keyword(s):  
Histone Deacetylase ◽  
Energy Homeostasis ◽  
Epigenetic Modification ◽  
Genome Integrity ◽  
Class Iii ◽  
Neuronal Function ◽  
Nootropic Drug ◽  
The Central Nervous System ◽  
Behavioral Impairments ◽  
Global Health Problem

AbstractSubstance abuse affects the central nervous system (CNS) and remains a global health problem. Psychostimulants, such as cocaine and methamphetamine (METH), and opioids affect neuronal function and lead to behavioral impairments via epigenetic modification. Epigenetic changes occur via classical pathways, especially the class III histone deacetylase (HDAC)-sirtuin (SIRT) family, that act as cellular sensors to regulate energy homeostasis and coordinate cellular responses to maintain genome integrity. However, SIRT family (1–7)-associated neurodegeneration has not been elucidated in the context of energy metabolism. The present study examined the effects of psychostimulants, such as cocaine and METH, and opioids, such as morphine, on SIRT family (1–7) [class I, II, III and IV] expression and cellular translocation-mediated dysfunction in astrocytes and microglial cells. The “nootropic” drug piracetam played a preventative role against psychostimulant- and opioid-induced SIRT (1–7) expression in astrocytes. These results indicate that cocaine, METH, and morphine affected deacetylation and cellular function, and these changes were prevented by piracetam in astrocytes.

Abstract 236: Sirt6 Heterozygosity Exacerbates Atherosclerosis in Apolipoprotein E Deficient Mice

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
De-Pei Liu ◽  
Zhu-Qin Zhang ◽  
Si-Cong Ren ◽  
Zuo-Zhi Li ◽  
Ying Tan ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Apolipoprotein E ◽  
Histone Deacetylase ◽  
Epigenetic Modification ◽  
Atherosclerotic Plaques ◽  
Nkg2d Ligand ◽  
Class Iii ◽  
Ligand Expression ◽  
Atherosclerosis Development ◽  
Deficient Mice

Sirt6 is a member of the class III histone deacetylase family and is reported to promote longevity. Whether Sirt6 is involved in atherosclerosis, one aging associated disease and the major cause of cardiovascular diseases, is unknown. We investigated effects of Sirt6 on atherosclerosis development. We found that in human atherosclerotic plaques, Sirt6 expression was decreased. Sirt6+/-ApoE-/- mice exhibited increased atherosclerosis development and decreased plaque stability than ApoE-/- mice. We found that Sirt6 downregulation showed increased expression of NKG2D ligands (H60b in mice and MICA/B in human). Sirt6 bound to promoters of these genes and regulated the H3K9 acetylation levels. Thus, atherosclerosis development was promoted by Sirt6 heterozygosity and epigenetic modification of NKG2D ligand expression is involved in this process.

scholarly journals Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes

2020 ◽  
Vol 10 (9) ◽  
pp. 611
Author(s):  
Kalaiselvi Sivalingam ◽  
Thangavel Samikkannu
Keyword(s):  
Dna Methylation ◽  
Nuclear Dna ◽  
Epigenetic Modification ◽  
Neuroprotective Effect ◽  
Dna Methyltransferases ◽  
Epigenetic Changes ◽  
Nootropic Drug ◽  
The Central Nervous System ◽  
Tet Enzymes ◽  
The Impact

Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining genomic integrity in the central nervous system (CNS). However, the impact of cocaine-mediated epigenetic changes in astrocytes has not yet been elucidated. In this study, we explored the neuroprotective effect of piracetam against cocaine-induced epigenetic changes in DNA methylation in astrocytes. To study our hypothesis, we exposed human astrocytes to cocaine alone or in combination with the nootropic drug piracetam. We examined the expression of the DNA methyltransferases (DNMTs) DNMT-1, DNMT-3A, and DNMT-3B; global DNA methylation levels of 5-methycytosine (5-mC); and induction of ten–eleven translocation (TET) enzymes in astrocytes. In addition, we analyzed mtDNA methylation by targeted next-generation bisulfite sequencing. Our data provide evidence that cocaine impairs DNMT activity and thereby has impacts on mtDNA, which might contribute to the neurodegeneration observed in cocaine users. These effects might be at least partially prevented by piracetam, allowing neuronal function to be maintained.

scholarly journals Psychostimulants and opioids differentially influence the epigenetic modification of histone acetyltransferase and histone deacetylase in astrocytes

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252895
Author(s):  
Mayur Doke ◽  
Gurudutt Pendyala ◽  
Thangavel Samikkannu
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Chromatin Remodeling ◽  
Protein Modification ◽  
Illicit Drugs ◽  
Histone Acetyltransferase ◽  
Epigenetic Modification ◽  
Epigenetic Changes ◽  
Nootropic Drug ◽  
The Impact

Illicit drugs are known to affect central nervous system (CNS). Majorly psychostimulants such as cocaine, methamphetamine (METH) and opioids such as morphine are known to induce epigenetic changes of histone modifications and chromatin remodeling which are mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Aberrant changes in histone acetylation-deacetylation process further exacerbate dysregulation of gene expression and protein modification which has been linked with neuronal impairments including memory formation and synaptic plasticity. In CNS, astrocytes play a pivotal role in cellular homeostasis. However, the impact of psychostimulants and opioid mediated epigenetic changes of HAT/HADCs in astrocytes has not yet been fully elucidated. Therefore, we have investigated the effects of the psychostimulants and opioid on the acetylation-regulating enzymes- HAT and HDACs role in astrocytes. In this study, Class I and II HDACs and HATs gene expression, protein changes and global level changes of acetylation of H3 histones at specific lysines were analyzed. In addition, we have explored the neuroprotective “nootropic” drug piracetam were exposed with or without psychostimulants and opioid in the human primary astrocytes. Results revealed that psychostimulants and opioid upregulated HDAC1, HDAC4 and p300 expression, while HDAC5 and GCN5 expression were downregulated. These effects were reversed by piracetam coexposure. Psychostimulants and opioid exposure upregulated global acetylation levels of all H3Ks, except H3K14. These results suggest that psychostimulants and opioids differentially influence HATs and HDACs.

Central Histamine, the H3-Receptor and Obesity Therapy

2019 ◽  
Vol 18 (7) ◽  
pp. 516-522
Author(s):  
Néstor F. Díaz ◽  
Héctor Flores-Herrera ◽  
Guadalupe García-López ◽  
Anayansi Molina-Hernández
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Animal Studies ◽  
Energy Homeostasis ◽  
Receptor Activation ◽  
Receptor Ligands ◽  
Histaminergic System ◽  
H3 Receptor ◽  
Weight One ◽  
The Central Nervous System

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

scholarly journals The Role of the Innate Immune System in Alzheimer’s Disease and Frontotemporal Lobar Degeneration: An Eye on Microglia

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Elisa Ridolfi ◽  
Cinzia Barone ◽  
Elio Scarpini ◽  
Daniela Galimberti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Lobar Degeneration ◽  
Environmental Changes ◽  
Current Evidence ◽  
Neuronal Function ◽  
Immune Effector ◽  
Effector Cells ◽  
The Central Nervous System

In the last few years, genetic and biomolecular mechanisms at the basis of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) have been unraveled. A key role is played by microglia, which represent the immune effector cells in the central nervous system (CNS). They are extremely sensitive to the environmental changes in the brain and are activated in response to several pathologic events within the CNS, including altered neuronal function, infection, injury, and inflammation. While short-term microglial activity has generally a neuroprotective role, chronic activation has been implicated in the pathogenesis of neurodegenerative disorders, including AD and FTLD. In this framework, the purpose of this review is to give an overview of clinical features, genetics, and novel discoveries on biomolecular pathogenic mechanisms at the basis of these two neurodegenerative diseases and to outline current evidence regarding the role played by activated microglia in their pathogenesis.

Pain and immunity

2021 ◽  
pp. 67-71
Author(s):  
Simon Beggs
Keyword(s):  
Nervous System ◽  
Immune System ◽  
Early Life ◽  
System Development ◽  
Later Life ◽  
Nervous System Development ◽  
Neuronal Function ◽  
Neuronal Homeostasis ◽  
Neuroimmune Interactions ◽  
The Central Nervous System

The central nervous system (CNS) and immune system are inextricably linked. The complexity of their interactions is still being unraveled, but the list of processes mediated wholly or in part by neuroimmune interactions continues to grow. The influence of the immune system is crucial for normal nervous system development both pre- and postnatally, for maintaining neuronal homeostasis in the mature CNS and modulating synaptic plasticity. Aberrations in this crosstalk have been implicated in many neurodevelopmental and psychiatric disorders. It is not feasible to explore neuronal function at any point in the lifespan, in health or disease, without considering the influence of the immune system. In the adult animal it is now well established that pain chronicity is maintained by immune influence upon the neuronal nociceptive system, although, fascinatingly, there is now evidence for a marked sexual dimorphism in how the immune and nervous systems interact. This holds true for pain in early life, where the two still-developing systems provide a very different environment to mediate nociception and pain. Of particular interest is how the immune system and sex interact to early life painful events to prime pain responses in later life.

scholarly journals Neuroprotective Mechanisms of PPARδ: Modulation of Oxidative Stress and Inflammatory Processes

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Caroline I. Schnegg ◽  
Mike E. Robbins
Keyword(s):  
Energy Homeostasis ◽  
Peroxisome Proliferator ◽  
Cellular Processes ◽  
Wide Range ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Chronic Injuries ◽  
Neuroprotective Efficacy ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARα,δ, andγ) are ligand-activated transcription factors that regulate a wide range of cellular processes, including inflammation, proliferation, differentiation, metabolism, and energy homeostasis. All three PPAR subtypes have been identified in the central nervous system (CNS) of rodents. While PPARαand PPARγare expressed in more restricted areas of the CNS, PPARδis ubiquitously expressed and is the predominant subtype. Although data regarding PPARδare limited, studies have demonstrated that administration of PPARδagonists confers neuroprotection following various acute and chronic injuries to the CNS, such as stroke, multiple sclerosis, and Alzheimer's disease. The antioxidant and anti-inflammatory properties of PPARδagonists are thought to underly their neuroprotective efficacy. This review will focus on the putative neuroprotective benefits of therapeutically targeting PPARδin the CNS, and specifically, highlight the antioxidant and anti-inflammatory functions of PPARδagonists.

scholarly journals Remarkable response of a patient with secondary glioblastoma to a histone deacetylase inhibitor

2020 ◽  
Vol 2020 (3) ◽  
Author(s):  
Saumya S Gurbani ◽  
Brent D Weinberg ◽  
Eric Salgado ◽  
Alfredo Voloschin ◽  
Jose Enrique Velazquez Vega ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Epigenetic Modification ◽  
Life Outcomes ◽  
Standard Regimen ◽  
Secondary Glioblastoma ◽  
Epigenetic Drug ◽  
Deacetylase Inhibitor

Abstract Secondary glioblastoma is a rare brain tumor characterized by a mutation in isocitrate dehydrogenase, which is reported to lead to epigenetic modification. Patients with secondary glioblastoma experience poor survival and quality-of-life outcomes due to the disease’s aggressiveness and a lack of targeted therapies. In this report, a patient with a secondary glioblastoma was treated with a histone deacetylase inhibitor, an epigenetic drug with potent anti-inflammatory properties, in addition to the standard regimen. The patient showed very favorable survival and quality-of-life measures, and a restoration of several neuro-metabolites as measured by spectroscopic magnetic resonance imaging.

scholarly journals Monosodium Glutamate in the Diet Does Not Raise Brain Glutamate Concentrations or Disrupt Brain Functions

2018 ◽  
Vol 73 (Suppl. 5) ◽  
pp. 43-52 ◽  
Author(s):  
John D. Fernstrom
Keyword(s):  
Monosodium Glutamate ◽  
Safety Evaluation ◽  
The Body ◽  
Neuronal Function ◽  
Excitatory Neurotransmitter ◽  
Brain Functions ◽  
The Central Nervous System ◽  
Experimental Findings ◽  
The Brain ◽  
Amino Acid Glutamate

The non-essential amino acid glutamate participates in numerous metabolic pathways in the body. It also performs important physiologic functions, which include a sensory role as one of the basic tastes (as monosodium glutamate [MSG]), and a role in neuronal function as the dominant excitatory neurotransmitter in the central nervous system. Its pleasant taste (as MSG) has led to its inclusion as a flavoring agent in foods for centuries. Glutamate’s neurotransmitter role was discovered only in the last 60 years. Its inclusion in foods has necessitated its safety evaluation, which has raised concerns about its transfer into the blood ultimately increasing brain glutamate levels, thereby causing functional disruptions because it is a neurotransmitter. This concern, originally raised almost 50 years ago, has led to an extensive series of scientific studies to examine this issue, conducted primarily in rodents, non-human primates, and humans. The key findings have been that (a) the ingestion of MSG in the diet does not produce appreciable increases in glutamate concentrations in blood, except when given experimentally in amounts vastly in excess of normal intake levels; and (b) the blood-brain barrier effectively restricts the passage of glutamate from the blood into the brain, such that brain glutamate levels only rise when blood glutamate concentrations are raised experimentally via non-physiologic means. These and related discoveries explain why the ingestion of MSG in the diet does not lead to an increase in brain glutamate concentrations, and thus does not produce functional disruptions in brain. This article briefly summarizes key experimental findings that evaluate whether MSG in the diet poses a threat to brain function.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

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