1 3374 76 HISTONE POST-TRANSLATIONAL MODIFICATIONS AS POTENTIAL THERAPEUTIC TARGETS FOR PAIN MANAGEMENT. EFFECTIVE PHARMACOLOGICAL MANAGEMENT OF PAIN ASSOCIATED WITH TISSUE PATHOLOGY IS AN UNMET MEDICAL NEED. TRANSCRIPTIONAL MODIFICATIONS IN NOCICEPTIVE PATHWAYS ARE PIVOTAL FOR THE DEVELOPMENT AND THE MAINTENANCE OF PAIN ASSOCIATED WITH TISSUE DAMAGE. ACCUMULATING EVIDENCE HAS SHOWN THE IMPORTANCE OF THE EPIGENETIC CONTROL OF TRANSCRIPTION IN NOCICEPTIVE PATHWAYS VIA HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS). HENCE, HISTONE PTMS COULD BE TARGETS FOR NOVEL EFFECTIVE ANALGESICS. HERE, WE DISCUSS THE CURRENT UNDERSTANDING OF HISTONE PTMS IN THE MODULATION OF GENE EXPRESSION AFFECTING NOCICEPTION AND PAIN PHENOTYPES FOLLOWING TISSUE INJURY. WE ALSO PROVIDE A CRITICAL VIEW OF THE TRANSLATIONAL IMPLICATIONS OF PRECLINICAL MODELS AND DISCUSS OPPORTUNITIES AND CHALLENGES OF TARGETING HISTONE PTMS TO RELIEVE PAIN IN CLINICALLY RELEVANT TISSUE INJURIES. 2021 2 2459 14 EPIGENETIC THERAPIES FOR NON-ONCOLOGY INDICATIONS. CHRONIC AND DEGENERATIVE DISORDERS ARE A MAJOR, AND GROWING, HUMAN HEALTH BURDEN, AND CURRENT TREATMENTS ARE IN MANY CASES INADEQUATE OR VERY EXPENSIVE. EPIGENETIC THERAPIES ARE ATTRACTIVE OPTIONS FOR TREATING SUCH DISORDERS BECAUSE THEY MANIPULATE THE PROCESSES THAT MAINTAIN CELLS IN AN ABNORMAL TRANSCRIPTIONAL STATE. THE CHALLENGES LIE IN IDENTIFYING THE MOST APPROPRIATE DISEASES AND THE ENZYMES THAT SHOULD BE TARGETED. THIS REVIEW DESCRIBES THE DIFFERENT APPROACHES THAT CAN BE USED TO ADDRESS THIS PROBLEM, FOCUSING PARTICULARLY ON CNS DISORDERS (ESPECIALLY MENTAL RETARDATION, NEURODEGENERATIVE DISEASE, PSYCHIATRIC DISORDERS AND DRUG ADDICTION), DIABETES AND DIABETIC COMPLICATIONS, AND AUTOIMMUNITY AND INFLAMMATORY DISEASES. 2010 3 2498 29 EPIGENETICS AND EPILEPSY PREVENTION: THE THERAPEUTIC POTENTIAL OF ADENOSINE AND METABOLIC THERAPIES. PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE MOST URGENT NEED FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT. NOVEL CONCEPTUAL ADVANCES ARE REQUIRED TO MEANINGFULLY ADDRESS THIS FUNDAMENTAL CHALLENGE. MALADAPTIVE EPIGENETIC CHANGES, WHICH INCLUDE METHYLATION OF DNA AND ACETYLATION OF HISTONES - AMONG OTHER MECHANISMS, ARE NOW WELL RECOGNIZED TO PLAY A FUNCTIONAL ROLE IN THE DEVELOPMENT OF EPILEPSY AND ITS PROGRESSION. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN THIS CONTEXT, GLOBAL DNA HYPERMETHYLATION IS PARTICULARLY ASSOCIATED WITH CHRONIC EPILEPSY. LIKEWISE, ACETYLATION CHANGES OF HISTONES HAVE BEEN LINKED TO EPILEPSY DEVELOPMENT. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATE THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY METABOLIC AND BIOCHEMICAL MANIPULATIONS THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS REVIEW WILL DISCUSS EPIGENETIC MECHANISMS IMPLICATED IN EPILEPSY DEVELOPMENT AS WELL AS METABOLIC AND BIOCHEMICAL INTERACTIONS THOUGHT TO DRIVE EPILEPTOGENESIS. THEREFORE, METABOLIC AND BIOCHEMICAL MECHANISMS ARE IDENTIFIED AS NOVEL TARGETS FOR EPILEPSY PREVENTION. WE WILL SPECIFICALLY DISCUSS ADENOSINE BIOCHEMISTRY AS A NOVEL THERAPEUTIC STRATEGY TO RECONSTRUCT THE DNA METHYLOME AS ANTIEPILEPTOGENIC STRATEGY AS WELL AS METABOLIC MEDIATORS, SUCH AS BETA-HYDROXYBUTYRATE, WHICH AFFECT HISTONE ACETYLATION. FINALLY, METABOLIC DIETARY INTERVENTIONS (SUCH AS THE KETOGENIC DIET) WHICH HAVE THE UNIQUE POTENTIAL TO PREVENT EPILEPTOGENESIS THROUGH RECENTLY IDENTIFIED EPIGENETIC MECHANISMS WILL BE REVIEWED. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED 'NEW EPILEPSY THERAPIES FOR THE 21ST CENTURY - FROM ANTISEIZURE DRUGS TO PREVENTION, MODIFICATION AND CURE OF EPILEPSY'. 2020 4 5778 28 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015 5 3938 22 LNC(ING)RNAS TO THE "SHOCK AND KILL" STRATEGY FOR HIV-1 CURE. THE ADVENT OF ANTIRETROVIRAL THERAPY ALMOST 25 YEARS AGO HAS TRANSFORMED HIV-1 INFECTION INTO A MANAGEABLE CHRONIC CONDITION, ALBEIT STILL INCURABLE. THE INABILITY OF THE TREATMENT REGIMEN TO ELIMINATE LATENTLY INFECTED CELLS THAT HARBOR THE VIRUS IN AN EPIGENETICALLY SILENT STATE POSES A MAJOR HURDLE. CURRENT CURE APPROACHES ARE FOCUSED ON A "SHOCK AND KILL" STRATEGY THAT USES LATENCY-REVERSING AGENTS TO CHEMICALLY REVERSE THE PROVIRAL QUIESCENCE IN LATENTLY INFECTED CELLS, FOLLOWED BY IMMUNE-MEDIATED CLEARANCE OF REACTIVATED CELLS. TO DATE, HUNDREDS OF COMPOUNDS HAVE BEEN INVESTIGATED FOR VIRAL REACTIVATION, YET NONE HAS RESULTED IN A FUNCTIONAL CURE. THE INSUFFICIENCY OF THESE LATENCY-REVERSING AGENTS (LRAS) ALONE INDICATES A CRITICAL NEED FOR ADDITIONAL, ALTERNATE APPROACHES SUCH AS GENETIC MANIPULATION. LONG NON-CODING RNAS (LNCRNAS) ARE AN EMERGING CLASS OF REGULATORY RNAS WITH FUNCTIONAL ROLES IN MANY CELLULAR PROCESSES, INCLUDING EPIGENETIC MODULATION. A NUMBER OF LNCRNAS HAVE ALREADY BEEN IMPLICATED TO PLAY IMPORTANT ROLES IN HIV-1 LATENCY AND, AS SUCH, PHARMACOLOGICAL MODULATION OF LNCRNAS CONSTITUTES A RATIONAL ALTERNATIVE APPROACH IN HIV-1 CURE RESEARCH. IN THIS REVIEW, WE DISCUSS THE CURRENT STATE OF KNOWLEDGE OF THE ROLE OF LNCRNAS IN HIV-1 INFECTION AND EXPLORE THE SCOPE FOR A LNCRNA-MEDIATED GENETIC APPROACH WITHIN THE SHOCK AND KILL STRATEGY OF HIV-1 CURE. 2021 6 6712 21 VIRUS-HOST INTERPLAY IN HEPATITIS B VIRUS INFECTION AND EPIGENETIC TREATMENT STRATEGIES. WORLDWIDE, CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A MAJOR HEALTH PROBLEM AND NO CURE EXISTS. IMPORTANTLY, HEPATOCYTE INTRUSION BY HBV PARTICLES RESULTS IN A COMPLEX DEREGULATION OF BOTH VIRAL AND HOST CELLULAR GENETIC AND EPIGENETIC PROCESSES. AMONG THE ATTEMPTS TO DEVELOP NOVEL THERAPEUTIC APPROACHES AGAINST HBV INFECTION, SEVERAL OPTIONS TARGETING THE EPIGENOMIC REGULATION OF HBV REPLICATION ARE GAINING ATTENTION. THESE INCLUDE THE EXPERIMENTAL TREATMENT WITH 'EPIDRUGS'. MOREOVER, AS A TARGETED APPROACH, THE PRINCIPLE OF 'EPIGENETIC EDITING' RECENTLY IS BEING EXPLOITED TO CONTROL VIRAL REPLICATION. SILENCING OF HBV BY SPECIFIC REWRITING OF EPIGENETIC MARKS MIGHT DIMINISH VIRAL REPLICATION, VIREMIA, AND INFECTIVITY, EVENTUALLY CONTROLLING THE DISEASE AND ITS COMPLICATIONS. ADDITIONALLY, EPIGENETIC EDITING CAN BE USED AS AN EXPERIMENTAL TOOL TO INCREASE OUR LIMITED UNDERSTANDING REGARDING THE ROLE OF EPIGENETIC MODIFICATIONS IN VIRAL INFECTIONS. AIMING FOR PERMANENT EPIGENETIC REPROGRAMMING OF THE VIRAL GENOME WITHOUT UNSPECIFIC SIDE EFFECTS, THIS BREAKTHROUGH MAY PAVE THE ROADS FOR AN AMBITIOUS TECHNOLOGICAL PURSUIT: TO START DESIGNING A CURATIVE APPROACH UTILIZING MANIPULATIVE MOLECULAR THERAPIES FOR VIRAL INFECTIONS IN VIVO. 2017 7 6802 20 [EPIGENETIC MECHANISMS IN MODELS OF CHRONIC PAIN - A TARGET FOR NOVEL THERAPY?]. EVIDENCE OF EPIGENETICS' ROLE IN PAIN RESPONSE IS ACCUMULATING IN RECENT YEARS. TIGHTLY REGULATED EPIGENETIC ALTERATIONS ON DNA AND HISTONES IN THE SENSORY CIRCUIT SHAPE THE PHYSIOLOGICAL RESPONSE TO INJURY. ALTERING THOSE EPIGENETIC PROCESSES HINDERS THERAPEUTIC POTENTIAL IN PAIN. THIS REVIEW PROVIDES AN OVERVIEW OF EPIGENOMIC MODIFICATION IN THE DEVELOPMENT OF CHRONIC PAIN, AND SUMMARIZES THE THERAPEUTIC POTENTIAL TO ALTER EPIGENETIC PROCESSES. 2018 8 6024 28 THE BIOCHEMISTRY AND EPIGENETICS OF EPILEPSY: FOCUS ON ADENOSINE AND GLYCINE. EPILEPSY, ONE OF THE MOST PREVALENT NEUROLOGICAL CONDITIONS, PRESENTS AS A COMPLEX DISORDER OF NETWORK HOMEOSTASIS CHARACTERIZED BY SPONTANEOUS NON-PROVOKED SEIZURES AND ASSOCIATED COMORBIDITIES. CURRENTLY USED ANTIEPILEPTIC DRUGS HAVE BEEN DESIGNED TO SUPPRESS NEURONAL HYPEREXCITABILITY AND THEREBY TO SUPPRESS EPILEPTIC SEIZURES. HOWEVER, THE CURRENT ARMAMENTARIUM OF ANTIEPILEPTIC DRUGS IS NOT EFFECTIVE IN OVER 30% OF PATIENTS, DOES NOT AFFECT THE COMORBIDITIES OF EPILEPSY, AND DOES NOT PREVENT THE DEVELOPMENT AND PROGRESSION OF EPILEPSY (EPILEPTOGENESIS). PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE HOLY GRAIL FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT, REQUIRING NOVEL CONCEPTUAL ADVANCES TO FIND A SOLUTION TO THIS URGENT MEDICAL NEED. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN PARTICULAR, GLOBAL DNA HYPERMETHYLATION APPEARS TO BE ASSOCIATED WITH CHRONIC EPILEPSY. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATES THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY BIOCHEMICAL MANIPULATIONS AND THOSE THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS MINI-REVIEW WILL DISCUSS, EPIGENETIC MECHANISMS IMPLICATED IN EPILEPTOGENESIS AND BIOCHEMICAL INTERACTIONS BETWEEN ADENOSINE AND GLYCINE AS A CONCEPTUAL ADVANCE TO UNDERSTAND THE CONTRIBUTION OF MALADAPTIVE CHANGES IN BIOCHEMISTRY AS A MAJOR CONTRIBUTING FACTOR TO THE DEVELOPMENT OF EPILEPSY. NEW FINDINGS BASED ON BIOCHEMICAL MANIPULATION OF THE DNA METHYLOME SUGGEST THAT: (I) EPIGENETIC MECHANISMS PLAY A FUNCTIONAL ROLE IN EPILEPTOGENESIS; AND (II) THERAPEUTIC RECONSTRUCTION OF THE EPIGENOME IS AN EFFECTIVE ANTIEPILEPTOGENIC THERAPY. 2016 9 2254 24 EPIGENETIC MODULATION: RESEARCH PROGRESS ON HISTONE ACETYLATION LEVELS IN MAJOR DEPRESSIVE DISORDERS. 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. 2023 10 2250 30 EPIGENETIC MODULATION OF OPIOID RECEPTORS BY DRUGS OF ABUSE. CHRONIC EXPOSURE TO DRUGS OF ABUSE PRODUCES PROFOUND CHANGES IN GENE EXPRESSION AND NEURAL ACTIVITY ASSOCIATED WITH DRUG-SEEKING AND TAKING BEHAVIOR. DYSREGULATION OF OPIOID RECEPTOR GENE EXPRESSION IS COMMONLY OBSERVED ACROSS A VARIETY OF ABUSED SUBSTANCES INCLUDING OPIOIDS, COCAINE, AND ALCOHOL. EARLY STUDIES IN CULTURED CELLS SHOWED THAT THE SPATIAL AND TEMPORAL GENE EXPRESSION OF OPIOID RECEPTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA AND HISTONE MODIFICATIONS AND NON-CODING RNAS. ACCUMULATING EVIDENCE INDICATE THAT DRUGS OF ABUSE CAN MODULATE OPIOID RECEPTOR GENE EXPRESSION BY TARGETING VARIOUS EPIGENETIC REGULATORY NETWORKS. BASED ON CURRENT CELLULAR AND ANIMAL MODELS OF SUBSTANCE USE DISORDER AND CLINICAL EVIDENCE, THIS REVIEW SUMMARIZES HOW CHRONIC DRUG EXPOSURE ALTERS THE GENE EXPRESSION OF MU, DELTA, KAPPA, AND NOCICEPTIN RECEPTORS VIA DNA AND HISTONE MODIFICATIONS. THE INFLUENCE OF DRUGS OF ABUSE ON EPIGENETIC MODULATORS, SUCH AS NON-CODING RNAS AND TRANSCRIPTION FACTORS, IS ALSO PRESENTED. FINALLY, THE THERAPEUTIC POTENTIAL OF MANIPULATING EPIGENETIC PROCESSES AS AN AVENUE TO TREAT SUBSTANCE USE DISORDER IS DISCUSSED. 2022 11 4784 21 NUTRIMIROMICS: ROLE OF MICRORNAS AND NUTRITION IN MODULATING INFLAMMATION AND CHRONIC DISEASES. NUTRIMIROMICS STUDIES THE INFLUENCE OF THE DIET ON THE MODIFICATION OF GENE EXPRESSION DUE TO EPIGENETIC PROCESSES RELATED TO MICRORNAS (MIRNAS), WHICH MAY AFFECT THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASES. MIRNAS ARE A CLASS OF NON-CODING ENDOGENOUS RNA MOLECULES THAT ARE USUALLY INVOLVED IN POST-TRANSCRIPTIONAL GENE SILENCING BY INDUCING MRNA DEGRADATION OR TRANSLATIONAL REPRESSION BY BINDING TO A TARGET MESSENGER RNA. THEY CAN BE CONTROLLED BY ENVIRONMENTAL AND DIETARY FACTORS, PARTICULARLY BY ISOLATED NUTRIENTS OR BIOACTIVE COMPOUNDS, INDICATING THAT DIET MANIPULATION MAY HOLD PROMISE AS A THERAPEUTIC APPROACH IN MODULATING THE RISK OF CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE EVIDENCE REGARDING THE INFLUENCE OF NUTRIENTS AND BIOACTIVE COMPOUNDS ON THE EXPRESSION OF MIRNAS RELATED TO INFLAMMATION AND CHRONIC DISEASE IN SEVERAL MODELS (CELL CULTURE, ANIMAL MODELS, AND HUMAN TRIALS). 2017 12 2536 25 EPIGENETICS IN EPILEPSY. EPILEPSY AFFECTS OVER 50 MILLION INDIVIDUALS GLOBALLY, MAKING IT THE MOST PREVALENT CHRONIC AND SERIOUS NEUROLOGICAL CONDITION. A PRECISE THERAPEUTIC STRATEGY IS COMPLICATED BY POOR UNDERSTANDING OF THE PATHOLOGICAL CHANGES IN EPILEPSY THUS, 30% OF TLE PATIENTS ARE RESISTANT TO DRUG THERAPY. IN THE BRAIN, EPIGENETIC PROCESSES TRANSLATE INFORMATION FROM TRANSIENT CELLULAR IMPULSES AND ADJUSTMENTS IN NEURONAL ACTIVITY INTO LONG-LASTING IMPACTS ON GENE EXPRESSION. RESEARCH SUGGESTS THAT EPIGENETIC PROCESSES CAN BE MANIPULATED IN THE FUTURE TO TREAT OR PREVENT EPILEPSY AS EPIGENETICS HAS BEEN SHOWN TO HAVE A PROFOUND INFLUENCE ON HOW GENES ARE EXPRESSED IN EPILEPSY. AS WELL AS BEING POTENTIAL BIOMARKERS FOR EPILEPSY DIAGNOSIS, EPIGENETIC CHANGES CAN ALSO BE USED AS PROGNOSTIC INDICATORS OF TREATMENT RESPONSE. IN THIS CHAPTER, WE REVIEW THE MOST RECENT FINDINGS IN SEVERAL MOLECULAR PATHWAYS LINKED WITH THE PATHOGENESIS OF TLE THAT ARE CONTROLLED BY EPIGENETIC MECHANISMS HIGHLIGHTING THEIR POTENTIAL UTILITY AS BIOMARKERS FOR UPCOMING TREATMENT STRATEGIES. 2023 13 4765 28 NRSF AND ITS EPIGENETIC EFFECTORS: NEW TREATMENTS FOR NEUROLOGICAL DISEASE. THE NEURON RESTRICTIVE SILENCER FACTOR (NRSF) IS THE WELL-KNOWN MASTER TRANSCRIPTIONAL REPRESSOR OF THE NEURONAL PHENOTYPE. RESEARCH TO DATE HAS SHOWN THAT IT IS AN IMPORTANT PLAYER IN THE GROWTH AND DEVELOPMENT OF THE NERVOUS SYSTEM. ITS ROLE IN THE MATURATION OF NEURAL PRECURSOR CELLS TO ADULT NEURONS HAS BEEN WELL CHARACTERIZED IN STEM CELL MODELS. WHILE MUCH HAS BEEN CHARACTERIZED FROM A DEVELOPMENTAL PERSPECTIVE, RESEARCH IS REVEALING THAT NRSF PLAYS A ROLE IN VARIOUS NEUROLOGICAL DISEASES, RANGING FROM NEURODEGENERATIVE, NEUROPSYCHIATRIC, TO CANCER. DYSREGULATION OF NRSF ACTIVITY DISRUPTS DOWNSTREAM GENE EXPRESSION THAT IS RESPONSIBLE FOR NEURONAL CELL HOMEOSTASIS IN SEVERAL MODELS THAT CONTRIBUTE TO PATHOLOGIC STATES. INTERESTINGLY, IT IS NOW BECOMING APPARENT THAT THE DYSREGULATION OF NRSF CONTRIBUTES TO NEUROLOGICAL DISEASE THROUGH EPIGENETIC MECHANISMS. ALTHOUGH NRSF ITSELF IS A TRANSCRIPTION FACTOR, ITS MAJOR EFFECTORS ARE CHROMATIN MODIFIERS. AT THE LEVEL OF EPIGENETICS, CHANGES IN NRSF ACTIVITY HAVE BEEN WELL CHARACTERIZED IN MODELS OF NEUROPATHIC PAIN AND EPILEPSY. BETTER UNDERSTANDING OF THE EPIGENETIC BASIS OF BRAIN DISEASES HAS LED TO DESIGN AND USE OF SMALL MOLECULES THAT CAN PREVENT NRSF FROM REPRESSING GENE EXPRESSION BY NEUTRALIZING ITS INTERACTIONS WITH ITS CHROMATIN REMODELERS. THIS REVIEW WILL ADDRESS THE BASIC FUNCTION OF NRSF AND ITS COFACTORS, INVESTIGATE THEIR MECHANISMS, THEN EXPLORE HOW THEIR DYSFUNCTION CAN CAUSE DISEASE STATES. THIS REVIEW WILL ALSO ADDRESS RESEARCH ON NRSF AS A THERAPEUTIC TARGET AND DELVE INTO NEW THERAPEUTIC STRATEGIES THAT FOCUS ON DISRUPTING NRSF'S ABILITY TO RECRUIT CHROMATIN REMODELERS. 2018 14 4049 25 MAKING MEMORIES THAT LAST A LIFETIME: HERITABLE FUNCTIONS OF SELF-RENEWING MEMORY CD8 T CELLS. CLONAL EXPANSION OF VIRUS-SPECIFIC NAIVE T CELLS DURING AN ACUTE VIRAL INFECTION RESULTS IN THE FORMATION OF MEMORY CD8 T CELLS THAT PROVIDE THE HOST WITH LONG-TERM PROTECTIVE IMMUNITY AGAINST THE PATHOGEN. MEMORY CD8 T CELLS DISPLAY ENHANCED EFFECTOR FUNCTIONS COMPARED WITH THEIR NAIVE PRECURSORS, ALLOWING THEM TO RESPOND MORE RAPIDLY AND EFFECTIVELY TO ANTIGEN RE-ENCOUNTER. THE ENHANCED FUNCTIONS OF MEMORY CD8 T CELLS ARE MEDIATED BY HERITABLE CHANGES IN GENE REGULATION. EXPRESSION OF SELECT TRANSCRIPTION FACTORS ALONG WITH LOCUS-SPECIFIC EPIGENETIC MODIFICATIONS ARE COUPLED TO AND ARE ESSENTIAL IN THE FORMATION OF MEMORY-SPECIFIC GENE EXPRESSION PATTERNS. HERE, WE WILL REVIEW THE CHANGES IN GENE EXPRESSION THAT ACCOMPANY DEVELOPMENT OF MEMORY CD8 T CELLS AND DISCUSS CHROMATIN MODIFICATIONS AS A POTENTIAL MEANS FOR HERITABLE PROPAGATION OF THESE CHANGES DURING HOMEOSTATIC CELL DIVISION OF SELF-RENEWING MEMORY CD8 T CELLS. ALSO, WE WILL DISCUSS THERAPIES THAT MANIPULATE HERITABLE GENE REGULATION AS A POTENTIAL MECHANISM TO RESTORE FUNCTION TO NON-FUNCTIONAL MEMORY CD8 T CELLS TO COMBAT CHRONIC VIRAL INFECTION. 2010 15 2292 19 EPIGENETIC REGULATION IN SUBSTANCE USE DISORDERS. SUBSTANCE USE DISORDER IS A CHRONIC CONDITION OF COMPULSIVE DRUG SEEKING AND USE THAT IS MEDIATED BY STABLE CHANGES IN CENTRAL REWARD PATHWAYS. REPEATED USE OF ABUSED DRUGS CAUSES PERSISTENT ALTERATIONS IN GENE EXPRESSION RESPONSIBLE FOR THE LONG-TERM BEHAVIORAL AND STRUCTURAL CHANGES. RECENTLY, IT HAS BEEN SUGGESTED THAT EPIGENETIC MECHANISMS ARE RESPONSIBLE IN PART FOR THESE DRUG-INDUCED CHANGES IN GENE EXPRESSION. ONE OF THE ALLURING ASPECTS OF EPIGENETIC REGULATION OF GENE EXPRESSION IS THAT EPIGENETIC MECHANISMS MAY PROVIDE TRANSIENT AND POTENTIALLY STABLE CONDITIONS THAT IN TURN MAY ULTIMATELY PARTICIPATE IN THE MOLECULAR MECHANISMS REQUIRED FOR NEURONAL CHANGES SUBSERVING LONG-LASTING CHANGES IN BEHAVIOR. THIS REVIEW DESCRIBES EPIGENETIC MECHANISMS OF GENE REGULATION AND THEN DISCUSSES THE EMERGING ROLE OF EPIGENETICS IN DRUG-INDUCED PLASTICITY AND BEHAVIOR. UNDERSTANDING THESE MECHANISMS THAT ESTABLISH AND MAINTAIN DRUG-DEPENDENT PLASTICITY CHANGES MAY LEAD TO DEEPER UNDERSTANDING OF SUBSTANCE USE DISORDERS AS WELL AS NOVEL APPROACHES TO TREATMENT. 2010 16 2415 22 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS: STRESS AND DEPRESSION. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL DISORDERS INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS PLAY A ROLE IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION, ADDICTION, AND SCHIZOPHRENIA, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY POINT TO THE IMPORTANCE OF ADDITIONAL FACTORS. ENVIRONMENTAL FACTORS, SUCH AS STRESS, PLAY A MAJOR ROLE IN THE PSYCHIATRIC DISORDERS BY INDUCING STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR. INSULTS AT THE DEVELOPMENTAL STAGE AND IN ADULTHOOD APPEAR TO INDUCE DISTINCT MALADAPTATIONS. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND ASSOCIATED ABERRANT EPIGENETIC REGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. ASPECTS OF DEPRESSION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS, AND THESE STUDIES CAN PROVIDE A MORE GENERAL UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSYCHIATRIC DISORDERS. UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS IS PROVIDING NEW INSIGHTS INTO DISEASE MECHANISMS IN HUMANS. 2014 17 2141 34 EPIGENETIC INTERVENTIONS FOR EPILEPTOGENESIS: A NEW FRONTIER FOR CURING EPILEPSY. THIS ARTICLE HIGHLIGHTS THE EMERGING THERAPEUTIC POTENTIAL OF SPECIFIC EPIGENETIC MODULATORS AS PROMISING ANTIEPILEPTOGENIC OR DISEASE-MODIFYING AGENTS FOR CURING EPILEPSY. CURRENTLY, THERE IS AN UNMET NEED FOR ANTIEPILEPTOGENIC AGENTS THAT TRULY PREVENT THE DEVELOPMENT OF EPILEPSY IN PEOPLE AT RISK. THERE IS STRONG EVIDENCE THAT EPIGENETIC SIGNALING, WHICH EXERTS HIGH FIDELITY REGULATION OF GENE EXPRESSION, PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF EPILEPTOGENESIS AND CHRONIC EPILEPSY. THESE MODIFICATIONS ARE NOT HARD-WIRED INTO THE GENOME AND ARE CONSTANTLY REPROGRAMMED BY ENVIRONMENTAL INFLUENCES. THE POTENTIAL EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, MICRORNA-BASED TRANSCRIPTIONAL CONTROL, AND BROMODOMAIN READING ACTIVITY, CAN DRASTICALLY ALTER THE NEURONAL GENE EXPRESSION PROFILE BY EXERTING THEIR SUMMATIVE EFFECTS IN A COORDINATED FASHION. SUCH AN EPIGENETIC INTERVENTION APPEARS MORE RATIONAL STRATEGY FOR PREVENTING EPILEPSY BECAUSE IT TARGETS THE PRIMARY PATHWAY THAT INITIALLY TRIGGERS THE NUMEROUS DOWNSTREAM CELLULAR AND MOLECULAR EVENTS MEDIATING EPILEPTOGENESIS. AMONG CURRENTLY APPROVED EPIGENETIC DRUGS, THE MAJORITY ARE ANTICANCER DRUGS WITH WELL-ESTABLISHED PROFILES IN CLINICAL TRIALS AND PRACTICE. EVIDENCE FROM PRECLINICAL STUDIES SUPPORTS THE PREMISE THAT THESE DRUGS MAY BE APPLIED TO A WIDE RANGE OF BRAIN DISORDERS. TARGETING HISTONE DEACETYLATION BY INHIBITING HISTONE DEACETYLASE ENZYMES APPEARS TO BE ONE PROMISING EPIGENETIC THERAPY SINCE CERTAIN INHIBITORS HAVE BEEN SHOWN TO PREVENT EPILEPTOGENESIS IN ANIMAL MODELS. HOWEVER, DEVELOPING NEURONAL SPECIFIC EPIGENETIC MODULATORS REQUIRES RATIONAL, PATHOPHYSIOLOGY-BASED OPTIMIZATION TO EFFICIENTLY INTERCEPT THE UPSTREAM PATHWAYS IN EPILEPTOGENESIS. OVERALL, EPIGENETIC AGENTS HAVE BEEN WELL POSITIONED AS NEW FRONTIER TOOLS TOWARDS THE NATIONAL GOAL OF CURING EPILEPSY. 2017 18 3855 22 IS THERE ANY THERAPEUTIC VALUE FOR THE USE OF HISTONE DEACETYLASE INHIBITORS FOR CHRONIC PAIN? CHRONIC PAIN IS A COMPLEX CLINICAL CONDITION THAT REDUCES THE QUALITY OF LIFE FOR BILLIONS OF PEOPLE. IN RECENT YEARS, THE ROLE OF EPIGENETIC MODULATION IN THE CONTROL OF LONG-TERM NEURONAL PLASTICITY HAS ATTRACTED THE ATTENTION OF PAIN RESEARCHERS. THE EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF DNA AND/OR HISTONE PROTEINS. MOUNTING EVIDENCE SUGGESTS THAT THE ACTIVITY OF HISTONE DEACETYLASES (HDACS) AND LEVELS OF HISTONE ACETYLATION ARE DYNAMIC AND THAT THESE ENZYMES MODULATE PAIN-RELATED SYNAPTIC PLASTICITY. THEREFORE, HDACS PLAY ESSENTIAL ROLES IN CHRONIC PAIN DEVELOPMENT AND MAINTENANCE. IN THIS MINI REVIEW, WE WILL DISCUSS THE ROLE OF HDACS IN THE PATHOGENESIS OF CHRONIC PAIN AND WILL CONSIDER THE THERAPEUTIC VALUE OF HDAC INHIBITORS IN TREATING CHRONIC PAIN. 2016 19 2414 21 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION AND ADDICTION, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS OR PRIOR DRUG EXPOSURE ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. SUCH EXPOSURE TO ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL AND ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND ASSOCIATED ABERRANT EPIGENETIC REGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. ASPECTS OF DEPRESSION AND ADDICTION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS (E.G., CHRONIC STRESS, DRUG ADMINISTRATION). UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS REVEALS NEW INSIGHT INTO DISEASE MECHANISMS IN HUMANS. 2014 20 2259 21 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY. 2018