1 4849 117 OPIOID-MEDIATED HIV-1 IMMUNOPATHOGENESIS. DESPITE THE ABILITY OF COMBINATION ANTIRETROVIRAL THERAPY TO DRAMATICALLY SUPPRESS VIREMIA, THE BRAIN CONTINUES TO BE A RESERVOIR OF HIV-1 LOW-LEVEL REPLICATION. ADDING FURTHER COMPLEXITY TO THIS IS THE COMORBIDITY OF DRUG ABUSE WITH HIV-1 ASSOCIATED NEUROCOGNITIVE DISORDERS AND NEUROHIV. AMONG SEVERAL ABUSED DRUGS, THE USE OF OPIATES IS HIGHLY PREVALENT IN HIV-1 INFECTED INDIVIDUALS, BOTH AS AN ABUSED DRUG AS WELL AS FOR PAIN MANAGEMENT. OPIOIDS AND THEIR RECEPTORS HAVE ATTAINED NOTABLE ATTENTION OWING TO THEIR ABILITY TO MODULATE IMMUNE FUNCTIONS, IN TURN, IMPACTING DISEASE PROGRESSION. VARIOUS CELL CULTURE, ANIMAL AND HUMAN STUDIES HAVE IMPLICATED THE ROLE OF OPIOIDS AND THEIR RECEPTORS IN MODULATING VIRAL REPLICATION AND VIRUS-MEDIATED PATHOLOGY BOTH POSITIVELY AND NEGATIVELY. FURTHER, THE COMBINATORIAL EFFECTS OF HIV-1/HIV-1 PROTEINS AND MORPHINE HAVE DEMONSTRATED ACTIVATION OF INFLAMMATORY SIGNALING IN THE HOST SYSTEM. HEREIN, WE SUMMARIZED THE CURRENT KNOWLEDGE ON THE ROLE OF OPIOIDS ON PERIPHERAL IMMUNOPATHOGENESIS, VIRAL IMMUNOPATHOGENESIS, EPIGENETIC PROFILES OF THE HOST AND VIRAL GENOME, NEUROPATHOGENESIS OF SIV/SHIV-INFECTED NON-HUMAN PRIMATES, BLOOD-BRAIN-BARRIER, HIV-1 VIRAL LATENCY, AND VIRAL REBOUND. OVERALL, THIS REVIEW PROVIDES RECENT INSIGHTS INTO THE ROLE OF OPIOIDS IN HIV-1 IMMUNOPATHOGENESIS. GRAPHICAL ABSTRACT. 2020 2 2073 32 EPIGENETIC CROSSTALK IN CHRONIC INFECTION WITH HIV-1. HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1) REPLICATES THROUGH THE INTEGRATION OF ITS VIRAL DNA INTO THE GENOME OF HUMAN IMMUNE TARGET CELLS. CHRONICALLY INFECTED INDIVIDUALS THUS CARRY A GENOMIC BURDEN OF VIRUS-DERIVED SEQUENCES THAT PERSISTS THROUGH ANTIRETROVIRAL THERAPY. THIS BURDEN CONSISTS OF A SMALL FRACTION OF INTACT, BUT TRANSCRIPTIONALLY SILENCED, I.E. LATENT, VIRAL GENOMES AND A DOMINANT FRACTION OF DEFECTIVE SEQUENCES. REMARKABLY, ALL VIRAL-DERIVED SEQUENCES ARE SUBJECT TO INTERACTION WITH HOST CELLULAR PHYSIOLOGY AT VARIOUS LEVELS. IN THIS REVIEW, WE FOCUS ON EPIGENETIC ASPECTS OF THIS INTERACTION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF HOW EPIGENETIC MECHANISMS CONTRIBUTE TO ESTABLISHMENT AND MAINTENANCE OF HIV-1 GENE REPRESSION DURING LATENCY. WE FURTHERMORE SUMMARIZE FINDINGS INDICATING THAT HIV-1 INFECTION LEADS TO CHANGES IN THE EPIGENOME OF TARGET AND BYSTANDER IMMUNE CELLS. FINALLY, WE DISCUSS HOW AN IMPROVED UNDERSTANDING OF EPIGENETIC FEATURES AND MECHANISMS INVOLVED IN HIV-1 INFECTION COULD BE EXPLOITED FOR CLINICAL USE. 2020 3 2580 33 EPIGENETICS OF MICRO-OPIOID RECEPTORS: INTERSECTION WITH HIV-1 INFECTION OF THE CENTRAL NERVOUS SYSTEM. THE ABUSE OF INTRAVENOUS DRUGS, SUCH AS HEROIN, HAS BECOME A MAJOR PUBLIC HEALTH CONCERN DUE TO THE INCREASED RISK OF HIV-1 INFECTION. OPIOIDS SUCH AS HEROIN WERE ORIGINALLY IDENTIFIED AND SUBSEQUENTLY ABUSED FOR THEIR ANALGESIC EFFECTS. HOWEVER, MANY INVESTIGATIONS HAVE FOUND ADDITIONAL EFFECTS OF OPIOIDS, INCLUDING REGULATION OF THE IMMUNE SYSTEM. AS SUCH, CHRONIC OPIOID ABUSE HAS BEEN SHOWN TO PROMOTE HIV-1 PATHOGENESIS AND FACILITATE HIV-1-ASSOCIATED NEUROCOGNITIVE DYSFUNCTION. CLINICAL OPIOIDS, SUCH AS MORPHINE AND METHADONE, AS WELL AS ILLICIT OPIOIDS, SUCH AS HEROIN, EXERT THEIR EFFECTS PRIMARILY THROUGH INTERACTIONS WITH THE MICRO-OPIOID RECEPTOR (MOR). HOWEVER, THE MECHANISMS BY WHICH OPIOIDS ENHANCE NEUROCOGNITIVE DYSFUNCTION THROUGH MOR-MEDIATED SIGNALING PATHWAYS ARE NOT COMPLETELY UNDERSTOOD. NEW FINDINGS IN THE REGULATION OF MOR EXPRESSION, PARTICULARLY EPIGENETIC AND TRANSCRIPTIONAL REGULATION AS WELL AS ALTERNATIVE SPLICING, SHEDS NEW INSIGHTS INTO POSSIBLE MECHANISMS OF HIV-1 AND OPIATE SYNERGY. IN THIS REVIEW, WE IDENTIFY MECHANISMS REGULATING MOR EXPRESSION AND PROPOSE NOVEL MECHANISMS BY WHICH OPIOIDS AND HIV-1 MAY MODULATE THIS REGULATION. ADDITIONALLY, WE SUGGEST THAT DIFFERENTIAL REGULATION OF NEWLY IDENTIFIED MOR ISOFORMS BY OPIOIDS AND HIV-1 HAS FUNCTIONAL CONSEQUENCE IN ENHANCING HIV-1 NEUROCOGNITIVE DYSFUNCTION. 2012 4 1796 34 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 5 3938 29 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 5926 30 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. CHRONIC PAIN IS A MULTIFACETED AND COMPLEX CONDITION. BROADLY CLASSIFIED INTO SOMATIC, VISCERAL, OR NEUROPATHIC PAIN, IT IS POORLY MANAGED DESPITE ITS PREVALENCE. CURRENT DRUGS USED FOR THE TREATMENT OF CHRONIC PAIN ARE LIMITED BY TOLERANCE WITH LONG-TERM USE, ABUSE POTENTIAL, AND MULTIPLE ADVERSE SIDE EFFECTS. THE PERSISTENT NATURE OF PAIN SUGGESTS THAT EPIGENETIC MACHINERY MAY BE A CRITICAL FACTOR DRIVING CHRONIC PAIN. IN THIS REVIEW, WE DISCUSS THE LATEST INSIGHTS INTO EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, AND WE DESCRIBE THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF CHRONIC PAIN AND WHETHER EPIGENETIC MODIFICATIONS COULD BE APPLIED AS FUTURE THERAPEUTIC TARGETS FOR CHRONIC PAIN. WE PROVIDE EVIDENCE FROM EXPERIMENTAL MODELS AND TRANSLATIONAL RESEARCH IN HUMAN TISSUE THAT HAVE ENHANCED OUR UNDERSTANDING OF EPIGENETIC PROCESSES MEDIATING NOCICEPTION, AND WE THEN SPECULATE ON THE POTENTIAL FUTURE USE OF MORE SPECIFIC AND SELECTIVE AGENTS THAT TARGET EPIGENETIC MECHANISMS TO ATTENUATE PAIN. 2016 7 1686 30 DRUGGING THE PAIN EPIGENOME. MORE THAN 20% OF ADULTS WORLDWIDE EXPERIENCE DIFFERENT TYPES OF CHRONIC PAIN, WHICH ARE FREQUENTLY ASSOCIATED WITH SEVERAL COMORBIDITIES AND A DECREASE IN QUALITY OF LIFE. SEVERAL APPROVED PAINKILLERS ARE AVAILABLE, BUT CURRENT ANALGESICS ARE OFTEN HAMPERED BY INSUFFICIENT EFFICACY AND/OR SEVERE ADVERSE EFFECTS. CONSEQUENTLY, NOVEL STRATEGIES FOR SAFE, HIGHLY EFFICACIOUS TREATMENTS ARE HIGHLY DESIRABLE, PARTICULARLY FOR CHRONIC PAIN. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNAS (MIRNAS) STRONGLY AFFECT THE REGULATION OF GENE EXPRESSION, POTENTIALLY FOR LONG PERIODS OVER YEARS OR EVEN GENERATIONS, AND HAVE BEEN ASSOCIATED WITH PATHOPHYSIOLOGICAL PAIN. SEVERAL STUDIES, MOSTLY IN ANIMALS, REVEALED THAT INHIBITORS OF DNA METHYLATION, ACTIVATORS AND INHIBITORS OF HISTONE MODIFICATION AND MODULATORS OF MIRNAS REVERSE A NUMBER OF PATHOLOGICAL CHANGES IN THE PAIN EPIGENOME, WHICH ARE ASSOCIATED WITH ALTERED EXPRESSION OF PAIN-RELEVANT GENES. THIS EPIGENETIC MODULATION MIGHT THEN REDUCE THE NOCICEPTIVE RESPONSE AND PROVIDE NOVEL THERAPEUTIC OPTIONS FOR ANALGESIC THERAPY OF CHRONIC PAIN STATES. HOWEVER, A NUMBER OF CHALLENGES, SUCH AS NONSPECIFIC EFFECTS AND POOR DELIVERY TO TARGET CELLS AND TISSUES, HINDER THE RAPID DEVELOPMENT OF SUCH ANALGESICS. IN THIS REVIEW, WE CRITICALLY SUMMARIZE DATA ON EPIGENETICS AND PAIN, FOCUSING ON CHALLENGES IN CLINICAL DEVELOPMENT AS WELL AS POSSIBLE NEW APPROACHES TO THE DRUG MODULATION OF THE PAIN EPIGENOME. 2017 8 2551 24 EPIGENETICS IN PAIN AND ANALGESIA: AN IMMINENT RESEARCH FIELD. HERITABLE PHENOTYPES RESULTING FROM ENVIRONMENT-CAUSED CHANGES IN A CHROMOSOME WITHOUT ALTERATIONS IN THE DNA SEQUENCE ARE INCREASINGLY RECOGNIZED AS A BASIS OF PERSONALIZED THERAPY. EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF THE DNA (METHYLATION) OR OF THE DNA-PACKAGING HISTONES (E.G., DEACETYLATION OR PHOSPHORYLATION). IN ADDITION, REGULATORY NON-CODING RNA MOLECULES (MICRO-RNAS) EXERT EPIGENETIC ACTIONS. THIS LEADS TO DISRUPTION OR OTHERWISE MODIFIED EXPRESSION OF GENES. ENVIRONMENTAL INFLUENCES SUCH AS NUTRITIONAL FACTORS, EXPOSURE TO CHEMICALS OR DRUGS, BUT ALSO SOCIAL FACTORS APPEAR TO EXERT EPIGENETIC ACTIONS. HISTONE MODIFICATIONS AND DNA METHYLATION ARE ASSOCIATED WITH THE SUBJECT'S AGE. EPIGENETIC MECHANISMS CAN SILENCE THE EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. TO THE EPIGENETIC CONTROL OF NOCICEPTION ADDS ITS CONTROL OF THE PHARMACODYNAMICS OR PHARMACOKINETICS OF ANALGESICS BY EPIGENETIC CONTROL OF DRUG TARGETS AND ANALGESICS METABOLIZING ENZYMES. ALTHOUGH EPIGENETICS-BASED STRATEGIES FOR PAIN THERAPY ARE NOT YET AVAILABLE, EXPERIMENTS IN RODENTS SUGGEST THAT RNA INTERFERENCE MAY BECOME A NEW THERAPY APPROACH FOR NEUROPATHIC AND OTHER PAIN. ANOTHER EPIGENETIC APPROACH TO ANALGESIC TREATMENT EMPLOYS INHIBITORS OF HISTONE DEACETYLASE THAT ACT ON THE EPIGENOME BY INDIRECTLY REMODELING THE SPATIAL CONFORMATION OF THE CHROMATIN. FINALLY, EPIGENETIC TECHNIQUES SUCH AS RNA INTERFERENCE HAVE BEEN EMPLOYED IN PAIN RESEARCH TO PROOF THE CONTRIBUTION OF CERTAIN PROTEINS TO NOCICEPTION. THUS, THE NEW FIELD OF EPIGENETICS BECOMES INCREASINGLY USED IN RESEARCH AND MANAGEMENT OF PAIN AND WILL COMPLEMENT GENETICS. THIS ARTICLE INTRODUCES EPIGENETICS TO PAIN AND SUMMARIZES THE CURRENT AND FUTURE UTILITY. 2011 9 5038 22 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 10 2250 29 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 5928 18 TARGETING EPIGENETIC MECHANISMS FOR PAIN RELIEF. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS TO CHROMATIN THAT MODULATE GENE ACTIVITY WITHOUT ALTERING THE DNA SEQUENCE. WHILE RESEARCH ON EPIGENETICS HAS GROWN EXPONENTIALLY OVER THE PAST FEW YEARS, VERY FEW STUDIES HAVE INVESTIGATED EPIGENETIC MECHANISMS IN RELATION TO PAIN STATES. HOWEVER, EPIGENETIC MECHANISMS ARE CRUCIAL TO MEMORY FORMATION THAT REQUIRES SIMILAR SYNAPTIC PLASTICITY TO PAIN PROCESSING, INDICATING THAT THEY MAY PLAY A KEY ROLE IN THE CONTROL OF PAIN STATES. THIS ARTICLE REVIEWS THE EARLY EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS ARE ENGAGED AFTER INJURY AND IN CHRONIC PAIN STATES, AND THAT DRUGS USED CLINICALLY TO TARGET THE EPIGENETIC MACHINERY FOR THE TREATMENT OF CANCER MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. 2012 12 405 21 ANALYSIS OF EPIGENETIC MECHANISMS REGULATING OPIOID RECEPTOR GENE TRANSCRIPTION. OPIOID DRUGS ARE GENERALLY USED FOR MODERATE AND SEVERE PAIN REDUCTIONS WHICH ACT THROUGH OPIOID RECEPTORS. STUDIES ON TRANSCRIPTIONAL REGULATION OF OPIOID RECEPTORS ARE STILL INVALUABLE BECAUSE NOT ONLY TRANSCRIPTION IS THE FIRST STEP TO PRODUCE PROTEIN PRODUCTS IN CELLS, BUT THE RECEPTOR TRANSCRIPTION LEVELS ALSO AFFECT THE PAIN REDUCTION BY OPIOIDS, AS OBSERVED IN STUDIES OF HETEROZYGOUS OPIOID RECEPTOR KNOCKOUT MICE.THERE ARE GROWING EVIDENCES THAT EPIGENETIC REGULATION HAS PLAYED SIGNIFICANT ROLES IN TRANSCRIPTIONAL REGULATION OF GENES, INCLUDING OPIOID RECEPTORS. IN GENERAL, EPIGENETIC MECHANISMS INCLUDE THREE MAIN REGULATORY FACTORS: DNA METHYLATION, CHROMATIN MODIFICATION, AND NONCODING RNAS (SUCH AS MICRORNA). FROM PREVIOUS STUDIES OF OURS AND OTHERS ON OPIOID RECEPTORS, THOSE EPIGENETIC FACTORS WERE CLEARLY INVOLVED IN REGULATING OPIOID RECEPTOR EXPRESSION IN VIVO AND IN VITRO. IN THIS CHAPTER, AMONG THOSE THREE TECHNIQUES WE DESCRIBE MORE DETAILS OF DNA METHYLATION METHODS BECAUSE OF EMERGING CONCEPTS OF DNA METHYLATION WITH THE RECENT DISCOVERY OF 5-HYDROXYMETHYLCYTOSINE CONVERTING ENZYME, TET1. ANOTHER ANALYTICAL METHOD OF THE EPIGENETIC FACTORS, CHROMATIN MODIFICATION, WILL BE DESCRIBED BRIEFLY AND INFORMATION OF ANALYZING NONCODING RNAS IS BRIEFLY MENTIONED IN SUBHEADING 1. 2015 13 6130 25 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 14 2600 21 EPIGENETICS REGULATION DURING VIRUS-HOST INTERACTION AND THEIR EFFECTS ON THE VIRUS AND HOST CELL. EPIGENETICS, A FIELD OF STUDY FOCUSED ON CELLULAR GENE REGULATION INDEPENDENT OF DNA SEQUENCE ALTERATIONS, ENCOMPASSES DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA MODIFICATION. EPIGENETICS PROCESSES PLAY A PIVOTAL ROLE IN GOVERNING THE LIFE CYCLES OF VIRUSES, ENABLING THEIR TRANSMISSION, PERSISTENCE, AND MAINTENANCE WITH IN HOST ORGANISMS. THIS REVIEW EXAMINES THE EPIGENETICS REGULATION OF DIVERSE VIRUS INCLUDING ORTHOMOXYVIRUSES, CORONAVIRUS, RETROVIRIDAE, MONONEGAVIRALES, AND POXVIRUSES AMONG OTHERS. THE INVESTIGATION ENCOMPASSES TEN REPRESENTATIVE VIRUSES FROM THESE FAMILIES. DETAILED EXPLORATION OF THE EPIGENETIC MECHANISMS UNDERLYING EACH VIRUS TYPE, INVOLVING MIRNA MODIFICATION, HISTONE MODIFICATION AND DNA METHYLATION, SHEDS LIGHT ON THE INTRICATE AND MULTIFACETED EPIGENETIC INTERPLAY BETWEEN VIRUSES AND THEIR HOSTS. FURTHERMORE, THIS REVIEW INVESTIGATES THE INFLUENCE OF THESE EPIGENETIC PROCESSES ON INFECTION CYCLES, EMPHASIZING THE UTILIZATION OF EPIGENETICS BY VIRUSES SUCH AS EPSTEIN-BARR VIRUS AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) TO REGULATE GENE EXPRESSION DURING CHRONIC OR LATENT INFECTIONS, CONTROL LATENCY, AND TRANSITION TO LYTIC INFECTION. FINALLY, THE PAPER EXPLORES THE NOVEL TREATMENTS POSSIBILITIES STEMMING FROM THIS EPIGENETIC UNDERSTANDING. 2023 15 2611 26 EPIGENETICS: A PROMISING PARADIGM FOR BETTER UNDERSTANDING AND MANAGING PAIN. EPIGENETIC REGULATION OF GENE EXPRESSION IS A RAPIDLY GROWING AREA OF RESEARCH. CONSIDERING THE LONGEVITY AND PLASTICITY OF NEURONS, THE STUDIES ON EPIGENETIC PATHWAYS IN THE NERVOUS SYSTEM SHOULD BE OF SPECIAL INTEREST FOR BOTH EPIGENETICISTS AND NEUROSCIENTISTS. ACTIVATION OR INACTIVATION OF DIFFERENT EPIGENETIC PATHWAYS BECOMES MORE PRONOUNCED WHEN THE CELLS EXPERIENCE RAPID CHANGES IN THEIR ENVIRONMENT, AND SUCH CHANGES CAN BE EASILY CAUSED BY INJURY AND INFLAMMATION, RESULTING IN PAIN PERCEPTION OR DISTORTION OF PAIN PERCEPTION (EG, HYPERALGESIA). THEREFORE, IN THIS REGARD, THE FIELD OF PAIN IS AT AN ADVANTAGE TO STUDY THE EPIGENETIC PATHWAYS. MORE IMPORTANTLY, UNDERSTANDING PAIN FROM AN EPIGENETICS POINT OF VIEW WOULD PROVIDE A NEW PARADIGM FOR DEVELOPING DRUGS OR STRATEGIES FOR PAIN MANAGEMENT. IN THIS REVIEW, WE INTRODUCE BASIC CONCEPTS OF EPIGENETICS, INCLUDING CHROMATIN DYNAMICS, HISTONE MODIFICATIONS, DNA METHYLATION, AND RNA-INDUCED GENE SILENCING. IN ADDITION, WE PROVIDE EVIDENCE FROM PUBLISHED STUDIES SUGGESTING WIDE IMPLICATION OF DIFFERENT EPIGENETIC PATHWAYS WITHIN PAIN PATHWAYS. PERSPECTIVE: THIS ARTICLE PROVIDES A BRIEF OVERVIEW OF EPIGENETIC PATHWAYS FOR GENE REGULATION AND HIGHLIGHTS THEIR INVOLVEMENT IN PAIN. OUR GOAL IS TO EXPOSE THE READERS TO THESE CONCEPTS SO THAT PAIN-RELATED PHENOTYPES CAN BE INVESTIGATED FROM THE EPIGENETIC POINT OF VIEW. 2013 16 3379 27 HIV LATENCY AND THE NONCODING RNA THERAPEUTIC LANDSCAPE. THE HUMAN IMMUNODEFICIENCY VIRUS (HIV) BELONGS TO THE SUBFAMILY OF LENTIVIRUSES THAT ARE CHARACTERIZED BY LONG INCUBATION PERIODS AND CHRONIC, PERSISTENT INFECTION. THE VIRUS INTEGRATES INTO THE GENOME OF INFECTED CD4+ CELLS AND, IN A SUBPOPULATION OF CELLS, ADOPTS A TRANSCRIPTIONALLY SILENT STATE, A PROCESS REFERRED TO A VIRAL LATENCY. THIS PROPERTY MAKES IT EXCEEDINGLY DIFFICULT TO THERAPEUTICALLY TARGET THE VIRUS AND ERADICATE INFECTION. IF LEFT UNTREATED, THE INEXORABLE DEMISE OF THE INFECTED INDIVIDUAL'S IMMUNE SYSTEM ENSUES, A CAUSAL RESULT OF ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS). LATENTLY INFECTED CELLS PROVIDE A RESERVOIR THAT MAINTAINS VIRAL INFECTION INDEFINITELY. IN THIS CHAPTER WE EXPLORE THE ROLE OF NONCODING RNAS IN HIV INFECTION AND IN THE ESTABLISHMENT AND MAINTENANCE OF VIRAL LATENCY. BOTH SHORT AND LONG NONCODING RNAS ARE ENDOGENOUS MODULATORS OF EPIGENETIC REGULATION IN HUMAN CELLS AND PLAY AN ACTIVE ROLE IN GENE EXPRESSION. LASTLY, WE EXPLORE THERAPEUTIC MODALITIES BASED ON EXPRESSED RNAS THAT ARE CAPABLE OF COUNTERING INFECTION, TRANSCRIPTIONALLY REGULATING THE VIRUS, AND SUPPRESSING OR ACTIVATING THE LATENT STATE. 2015 17 789 36 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 18 834 21 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 19 2354 19 EPIGENETIC REGULATION OF PERSISTENT PAIN. PERSISTENT OR CHRONIC PAIN IS TIGHTLY ASSOCIATED WITH VARIOUS ENVIRONMENTAL CHANGES AND LINKED TO ABNORMAL GENE EXPRESSION WITHIN CELLS PROCESSING NOCICEPTIVE SIGNALING. EPIGENETIC REGULATION GOVERNS GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES. RECENT ANIMAL MODEL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OR MAINTENANCE OF PERSISTENT PAIN AND POSSIBLY THE TRANSITION OF ACUTE PAIN TO CHRONIC PAIN, THUS SHEDDING LIGHT IN A DIRECTION FOR DEVELOPMENT OF NEW THERAPEUTICS FOR PERSISTENT PAIN. 2015 20 2194 27 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015