1 2868 88 FUNCTIONAL CONSEQUENCES OF CALCIUM-DEPENDENT SYNAPSE-TO-NUCLEUS COMMUNICATION: FOCUS ON TRANSCRIPTION-DEPENDENT METABOLIC PLASTICITY. IN THE NERVOUS SYSTEM, CALCIUM SIGNALS PLAY A MAJOR ROLE IN THE CONVERSION OF SYNAPTIC STIMULI INTO TRANSCRIPTIONAL RESPONSES. SIGNAL-REGULATED GENE TRANSCRIPTION IS FUNDAMENTAL FOR A RANGE OF LONG-LASTING ADAPTIVE BRAIN FUNCTIONS THAT INCLUDE LEARNING AND MEMORY, STRUCTURAL PLASTICITY OF NEURITES AND SYNAPSES, ACQUIRED NEUROPROTECTION, CHRONIC PAIN, AND ADDICTION. IN THIS REVIEW, WE SUMMARIZE THE DIVERSE MECHANISMS GOVERNING CALCIUM-DEPENDENT TRANSCRIPTIONAL REGULATION ASSOCIATED WITH CENTRAL NERVOUS SYSTEM PLASTICITY. WE FOCUS ON RECENT ADVANCES IN THE FIELD OF SYNAPSE-TO-NUCLEUS COMMUNICATION THAT INCLUDE STUDIES OF THE SIGNAL-REGULATED TRANSCRIPTOME IN HUMAN NEURONS, IDENTIFICATION OF NOVEL REGULATORY MECHANISMS SUCH AS ACTIVITY-INDUCED DNA DOUBLE-STRAND BREAKS, AND THE IDENTIFICATION OF NOVEL FORMS OF ACTIVITY- AND TRANSCRIPTION-DEPENDENT ADAPTATIONS, IN PARTICULAR, METABOLIC PLASTICITY. WE SUMMARIZE THE RECIPROCAL INTERACTIONS BETWEEN DIFFERENT KINDS OF NEUROADAPTATIONS AND HIGHLIGHT THE EMERGING ROLE OF ACTIVITY-REGULATED EPIGENETIC MODIFIERS IN GATING THE INDUCIBILITY OF SIGNAL-REGULATED GENES. 2020 2 1877 20 EMERGING ROLES OF EPIGENETIC MECHANISMS IN THE ENDURING EFFECTS OF EARLY-LIFE STRESS AND EXPERIENCE ON LEARNING AND MEMORY. EPIGENETIC MECHANISMS ARE INVOLVED IN PROGRAMMING GENE EXPRESSION THROUGHOUT DEVELOPMENT. IN ADDITION, THEY ARE KEY CONTRIBUTORS TO THE PROCESSES BY WHICH EARLY-LIFE EXPERIENCE FINE-TUNES THE EXPRESSION LEVELS OF KEY NEURONAL GENES, GOVERNING LEARNING AND MEMORY THROUGHOUT LIFE. HERE WE DESCRIBE THE LONG-LASTING, BI-DIRECTIONAL EFFECTS OF EARLY-LIFE EXPERIENCE ON LEARNING AND MEMORY. WE DISCUSS HOW ENRICHED POSTNATAL EXPERIENCE ENDURINGLY AUGMENTS SPATIAL LEARNING, AND HOW CHRONIC EARLY-LIFE STRESS RESULTS IN PERSISTENT AND PROGRESSIVE DEFICITS IN THE STRUCTURE AND FUNCTION OF HIPPOCAMPAL NEURONS. THE EXISTING AND EMERGING ROLES OF EPIGENETIC MECHANISMS IN THESE FUNDAMENTAL NEUROPLASTICITY PHENOMENA ARE ILLUSTRATED. 2011 3 4762 21 NRF2 SIGNALING AND THE SLOWED AGING PHENOTYPE: EVIDENCE FROM LONG-LIVED MODELS. STUDYING LONG-LIVED ANIMALS PROVIDES NOVEL INSIGHT INTO SHARED CHARACTERISTICS OF AGING AND REPRESENTS A UNIQUE MODEL TO ELUCIDATE APPROACHES TO PREVENT CHRONIC DISEASE. OXIDANT STRESS UNDERLIES MANY CHRONIC DISEASES AND RESISTANCE TO STRESS IS A POTENTIAL MECHANISM GOVERNING SLOWED AGING. THE TRANSCRIPTION FACTOR NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 IS THE "MASTER REGULATOR" OF CELLULAR ANTIOXIDANT DEFENSES. NRF2 IS UPREGULATED BY SOME LONGEVITY PROMOTING INTERVENTIONS AND MAY PLAY A ROLE IN REGULATING SPECIES LONGEVITY. HOWEVER, NRF2 EXPRESSION AND ACTIVITY IN LONG-LIVED MODELS HAVE NOT BEEN WELL DESCRIBED. HERE, WE REVIEW EVIDENCE FOR ALTERED NRF2 SIGNALING IN A VARIETY OF SLOWED AGING MODELS THAT ACCOMPLISH LIFESPAN EXTENSION VIA PHARMACOLOGICAL, NUTRITIONAL, EVOLUTIONARY, GENETIC, AND PRESUMABLY EPIGENETIC MEANS. 2015 4 6214 24 THE INTRACELLULAR SIGNALING PATHWAYS GOVERNING MACROPHAGE ACTIVATION AND FUNCTION IN HUMAN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY LIPID ACCUMULATION AND PLAQUE FORMATION IN ARTERIAL VESSEL WALLS. ATHEROSCLEROTIC PLAQUES NARROW THE ARTERIAL LUMEN TO INCREASE THE RISK OF HEART ATTACKS, ISCHEMIC STROKE AND PERIPHERAL VASCULAR DISEASE, WHICH ARE MAJOR AND WORLDWIDE HEALTH AND ECONOMIC BURDENS. MACROPHAGE ACCUMULATION WITHIN PLAQUES IS CHARACTERISTIC OF ALL STAGES OF ATHEROSCLEROSIS AND THEIR PRESENCE IS A POTENTIAL MARKER OF DISEASE ACTIVITY AND PLAQUE STABILITY. MACROPHAGES ENGULF LIPIDS AND MODIFIED LIPOPROTEINS TO FORM FOAM CELLS THAT EXPRESS PRO-INFLAMMATORY AND CHEMOTACTIC EFFECTOR MOLECULES, STRESS INDUCING FACTORS AND REACTIVE OXYGEN SPECIES. THEY CONTROL PLAQUE STABILITY AND RUPTURE THROUGH SECRETION OF METALLOPROTEINASES AND EXTRACELLULAR MATRIX DEGRADATION. ALTHOUGH MACROPHAGES CAN WORSEN DISEASE BY PROPAGATING INFLAMMATION, THEY CAN STABILIZE ATHEROSCLEROTIC PLAQUES THROUGH TISSUE REMODELING, PROMOTING THE FORMATION OF A FIBROUS CAP, CLEARING APOPTOTIC CELLS TO PREVENT NECROTIC CORE FORMATION AND THROUGH VASCULAR REPAIR. IN ATHEROSCLEROSIS, MACROPHAGES RESPOND TO DYSLIPIDAEMIA, CYTOKINES, DYING CELLS, METABOLIC FACTORS, LIPIDS, PHYSICAL STIMULI AND EPIGENETIC FACTORS AND EXHIBIT HETEROGENEITY IN THEIR ACTIVATION DEPENDING ON THE STIMULI THEY RECEIVE. UNDERSTANDING THESE SIGNALS AND THE PATHWAYS DRIVING MACROPHAGE FUNCTION WITHIN DEVELOPING AND ESTABLISHED PLAQUES AND HOW THEY CAN BE PHARMACOLOGICALLY MODULATED, REPRESENTS A STRATEGY FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS. THIS REVIEW FOCUSSES ON THE CURRENT UNDERSTANDING OF FACTORS CONTROLLING MACROPHAGE HETEROGENEITY AND FUNCTION IN ATHEROSCLEROSIS. PARTICULAR ATTENTION IS GIVEN TO THE MACROPHAGE INTRACELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS ACTIVATED BY BIOCHEMICAL AND BIOPHYSICAL STIMULI WITHIN PLAQUES, AND HOW THEY ARE INTEGRATED TO REGULATE PLAQUE FORMATION AND STABILITY. 2022 5 4655 32 NEUROTROPHIN MEDIATED HPA AXIS DYSREGULATION IN STRESS INDUCED GENESIS OF PSYCHIATRIC DISORDERS: ORCHESTRATION BY EPIGENETIC MODIFICATIONS. APART FROM THEIR ESTABLISHED ROLE IN EMBRYONIC DEVELOPMENT, NEUROTROPHINS (NTS) HAVE DIVERSE FUNCTIONS IN THE NERVOUS SYSTEM. THEIR ROLE IN THE INTEGRATION OF PHYSIOLOGICAL AND BIOCHEMICAL ASPECTS OF THE NERVOUS SYSTEM IS CURRENTLY ATTRACTING MUCH ATTENTION. BASED ON A SYSTEMATIC ANALYSIS OF THE LITERATURE, WE HERE PROPOSE A NEW PARADIGM THAT, BY EXPLOITING A NOVEL ROLE OF NTS, MAY HELP EXPLAIN THE GENESIS OF STRESS-RELATED PSYCHIATRIC DISORDERS, OPENING NEW AVENUES FOR BETTER MANAGEMENT OF THE SAME. WE HYPOTHESIZE THAT NTS AS AN INTEGRATED NETWORK PLAY A CRUCIAL ROLE IN MAINTAINING AN INDIVDUAL'S PSYCHOLOGICAL WELLBEING. GIVEN THE EVIDENCE THAT STRESS CAN INDUCE CHRONIC DISRUPTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS WHICH, IN TURN, IS CAUSALLY LINKED TO SEVERAL PSYCHIATRIC DISORDERS, THIS FUNCTION MAY BE MEDIATED THROUGH THE HOMEOSTATIC MECHANISMS GOVERNING REGULATION OF THIS AXIS. IN FACT, NTS, SUCH AS NERVE GROWTH FACTOR (NGF) AND BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) ARE KNOWN TO PARTICIPATE IN NEUROENDOCRINE REGULATION. RECENT STUDIES SUGGEST EPIGENETIC MODIFICATION OF NT-HPA AXIS INTERPLAY IN THE PRECIPITATION OF PSYCHIATRIC DISORDERS. OUR ARTICLE HIGHLIGHTS WHY THIS NEW KNOWLEDGE REGARDING NTS SHOULD BE CONSIDERED IN THE ETIOGENESIS AND TREATMENT OF STRESS-INDUCED PSYCHOPATHOLOGY. 2019 6 1872 21 EMERGING ROLE OF LONG NON-CODING RNAS IN ENDOTHELIAL DYSFUNCTION AND THEIR MOLECULAR MECHANISMS. LONG NON-CODING RNAS (LNCRNAS) ARE THE NOVEL CLASS OF TRANSCRIPTS INVOLVED IN TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL REGULATION OF PHYSIOLOGY AND THE PATHOLOGY OF DISEASES. STUDIES HAVE EVIDENCED THAT THE IMPAIRMENT OF ENDOTHELIUM IS A CRITICAL EVENT IN THE PATHOGENESIS OF ATHEROSCLEROSIS AND ITS COMPLICATIONS. ENDOTHELIAL DYSFUNCTION IS CHARACTERIZED BY AN IMBALANCE IN VASODILATION AND VASOCONSTRICTION, OXIDATIVE STRESS, PROINFLAMMATORY FACTORS, AND NITRIC OXIDE BIOAVAILABILITY. DISRUPTION OF THE ENDOTHELIAL BARRIER PERMEABILITY, THE FIRST STEP IN DEVELOPING ATHEROSCLEROTIC LESIONS IS A CONSEQUENCE OF ENDOTHELIAL DYSFUNCTION. THOUGH SEVERAL FACTORS INTERFERE WITH THE NORMAL FUNCTIONING OF THE ENDOTHELIUM, INTRINSIC EPIGENETIC MECHANISMS GOVERNING ENDOTHELIAL FUNCTION ARE REGULATED BY LNCRNAS AND PERTURBATIONS CONTRIBUTE TO THE PATHOGENESIS OF THE DISEASE. THIS REVIEW COMPREHENSIVELY ADDRESSES THE BIOGENESIS OF LNCRNA AND MOLECULAR MECHANISMS UNDERLYING AND REGULATION IN ENDOTHELIAL FUNCTION. AN INSIGHT CORRELATING LNCRNAS AND ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES CAN POSITIVELY IMPACT THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC TARGETS IN ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES AND TREATMENT STRATEGIES. 2022 7 375 17 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 8 2313 30 EPIGENETIC REGULATION OF ENDOTHELIAL CELL FUNCTION BY NUCLEIC ACID METHYLATION IN CARDIAC HOMEOSTASIS AND DISEASE. PATHOLOGICAL REMODELLING OF THE MYOCARDIUM, INCLUDING INFLAMMATION, FIBROSIS AND HYPERTROPHY, IN RESPONSE TO ACUTE OR CHRONIC INJURY IS CENTRAL IN THE DEVELOPMENT AND PROGRESSION OF HEART FAILURE (HF). WHILE BOTH RESIDENT AND INFILTRATING CARDIAC CELLS ARE IMPLICATED IN THESE PATHOPHYSIOLOGICAL PROCESSES, RECENT EVIDENCE HAS SUGGESTED THAT ENDOTHELIAL CELLS (ECS) MAY BE THE PRINCIPAL CELL TYPE RESPONSIBLE FOR ORCHESTRATING PATHOLOGICAL CHANGES IN THE FAILING HEART. EPIGENETIC MODIFICATION OF NUCLEIC ACIDS, INCLUDING DNA, AND MORE RECENTLY RNA, BY METHYLATION IS ESSENTIAL FOR PHYSIOLOGICAL DEVELOPMENT DUE TO THEIR CRITICAL REGULATION OF CELLULAR GENE EXPRESSION. AS ACCUMULATING EVIDENCE HAS HIGHLIGHTED ALTERED PATTERNS OF DNA AND RNA METHYLATION IN HF AT BOTH THE GLOBAL AND INDIVIDUAL GENE LEVELS, MUCH EFFORT HAS BEEN DIRECTED TOWARDS DEFINING THE PRECISE ROLE OF SUCH CELL-SPECIFIC EPIGENETIC CHANGES IN THE CONTEXT OF HF. CONSIDERING THE INCREASINGLY APPARENT CRUCIAL ROLE THAT ECS PLAY IN CARDIAC HOMEOSTASIS AND DISEASE, THIS ARTICLE WILL SPECIFICALLY FOCUS ON NUCLEIC ACID METHYLATION (BOTH DNA AND RNA) IN THE FAILING HEART, EMPHASISING THE KEY INFLUENCE OF THESE EPIGENETIC MECHANISMS IN GOVERNING EC FUNCTION. THIS REVIEW SUMMARISES CURRENT UNDERSTANDING OF DNA AND RNA METHYLATION ALTERATIONS IN HF, ALONG WITH THEIR SPECIFIC ROLE IN REGULATING EC FUNCTION IN RESPONSE TO STRESS (E.G. HYPERGLYCAEMIA, HYPOXIA). IMPROVED APPRECIATION OF THIS IMPORTANT RESEARCH AREA WILL AID IN FURTHER IMPLICATING DYSFUNCTIONAL ECS IN HF PATHOGENESIS, WHILST INFORMING DEVELOPMENT OF EC-TARGETED STRATEGIES AND ADVANCING POTENTIAL TRANSLATION OF EPIGENETIC-BASED THERAPIES FOR SPECIFIC TARGETING OF PATHOLOGICAL CARDIAC REMODELLING IN HF. 2021 9 6447 29 THERAPEUTIC PROSPECTS FOR EPIGENETIC MODULATION. INTRODUCTION: EPIGENETICS DESCRIBES THE PHENOMENON OF HERITABLE CHANGES IN GENE REGULATION GOVERNED BY NON-MENDELIAN PROCESSES, PRIMARILY THROUGH BIOCHEMICAL MODIFICATIONS TO CHROMATIN THAT OCCUR DURING CELL DIFFERENTIATION AND DEVELOPMENT. ABNORMAL LEVELS OF DNA AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. DRUGS THAT TARGET THE PROTEINS CONTROLLING THESE CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS WITH SINGLE TARGET PHARMACOLOGIES THAT ARE SUSCEPTIBLE TO BIOCHEMICAL PATHWAY DEGENERACY. AREAS COVERED: THIS ARTICLE REVIEWS RESEARCH CHARACTERIZING DYSREGULATION OF EPIGENETIC PROCESSES IN CANCER, IMMUNO-INFLAMMATORY, PSYCHIATRIC, NEUROLOGICAL, METABOLIC AND VIROLOGY DISEASE AREAS, AND SUMMARIZES RECENT DEVELOPMENTS IN IDENTIFYING SMALL MOLECULE MODULATORS THAT ARE BEING USED TO INFORM TARGET DISCOVERY AND INITIATE DRUG DISCOVERY PROJECTS. EXPERT OPINION: THERE ARE NUMEROUS POTENTIAL OPPORTUNITIES FOR EPIGENETIC MODULATORS IN TREATING A WIDE RANGE OF CHRONIC DISEASES; HOWEVER, THE FIELD IS COMPLEX, INVOLVING > 300 PROTEINS, AND MUCH WORK IS STILL REQUIRED TO PROVIDE TOOLS TO UNRAVEL THE FUNCTIONS OF INDIVIDUAL PROTEINS, PARTICULARLY IN VIVO. THIS GROUNDWORK IS ESSENTIAL TO ALLOW THE DRUG DISCOVERY COMMUNITY TO FOCUS ON THOSE EPIGENETIC PROTEINS MOST LIKELY TO BE SUITABLE TARGETS FOR SAFE, EFFICACIOUS NEW THERAPIES. 2011 10 5857 29 SUBSTRATE-SPECIFIC BINDING OF 8-OXOGUANINE DNA GLYCOSYLASE 1 (OGG1) REPROGRAMS MUCOSAL ADAPTATIONS TO CHRONIC AIRWAY INJURY. RECENT ADVANCES HAVE UNCOVERED THE NON-RANDOM DISTRIBUTION OF 7, 8-DIHYDRO-8-OXOGUANINE (8-OXOGUA) INDUCED BY REACTIVE OXYGEN SPECIES, WHICH IS BELIEVED TO HAVE EPIGENETIC EFFECTS. ITS COGNATE REPAIR PROTEIN, 8-OXOGUANINE DNA GLYCOSYLASE 1 (OGG1), READS OXIDATIVE SUBSTRATES AND PARTICIPATES IN TRANSCRIPTIONAL INITIATION. WHEN REDOX SIGNALING IS ACTIVATED IN SMALL AIRWAY EPITHELIAL CELLS, THE DNA REPAIR FUNCTION OF OGG1 IS REPURPOSED TO TRANSMIT ACUTE INFLAMMATORY SIGNALS ACCOMPANIED BY CELL STATE TRANSITIONS AND MODIFICATION OF THE EXTRACELLULAR MATRIX. EPITHELIAL-MESENCHYMAL AND EPITHELIAL-IMMUNE INTERACTIONS ACT COOPERATIVELY TO ESTABLISH A LOCAL NICHE THAT INSTRUCTS THE MUCOSAL IMMUNE LANDSCAPE. IF THE TRANSITIONAL CELL STATE GOVERNED BY OGG1 REMAINS RESPONSIVE TO INFLAMMATORY MEDIATORS INSTEAD OF DIFFERENTIATION, THE COLLATERAL DAMAGE PROVIDES POSITIVE FEEDBACK TO INFLAMMATION, ASCRIBING INFLAMMATORY REMODELING TO ONE OF THE DRIVERS IN CHRONIC PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE SUBSTRATE-SPECIFIC READ THROUGH OGG1 HAS EVOLVED IN REGULATING THE INNATE IMMUNE RESPONSE, CONTROLLING ADAPTATIONS OF THE AIRWAY TO ENVIRONMENTAL AND INFLAMMATORY INJURY, WITH A FOCUS ON THE READER FUNCTION OF OGG1 IN INITIATION AND PROGRESSION OF EPITHELIAL TO MESENCHYMAL TRANSITIONS IN CHRONIC PULMONARY DISEASE. 2023 11 5494 18 REVIEW OF THE MOLECULAR MECHANISMS IN WOUND HEALING: NEW THERAPEUTIC TARGETS? THE RESTORATION OF THE SKIN BARRIER IN ACUTE AND CHRONIC WOUNDS IS CONTROLLED BY SEVERAL MOLECULAR MECHANISMS THAT SYNERGISTICALLY REGULATE CELL KINETICS, ENZYMATIC FUNCTIONS, AND NEUROVASCULAR ACTIVATION. THESE PATHWAYS INCLUDE GENETIC AND EPIGENETIC ACTIVATION, WHICH MODULATE PHYSIOLOGICAL WOUND HEALING. OUR REVIEW DESCRIBES THE GENETIC BACKGROUND OF SKIN REPAIR, NAMELY TRANSCRIPTION-INDEPENDENT DIFFUSIBLE DAMAGE SIGNALS, INDIVIDUAL VARIABILITY, EPIGENETIC MECHANISM, CONTROLLED QUALITATIVE TRAITS, POST-TRANSLATIONAL MECHANISMS, ANTIOXIDANTS, NUTRIENTS, DNA MODIFICATIONS, BACTERIA ACTIVATION, MITOCHONDRIAL ACTIVITY, AND OXIDATIVE STRESS. THE DNA BACKGROUND MODULATING SKIN RESTORATION COULD BE USED TO PLAN NEW DIAGNOSTICS AND THERAPEUTICS. 2017 12 6400 27 THE ROLES OF CLASS I HISTONE DEACETYLASES (HDACS) IN MEMORY, LEARNING, AND EXECUTIVE COGNITIVE FUNCTIONS: A REVIEW. COORDINATED CHANGES IN GENE EXPRESSION ARE CRITICAL FOR SYNAPTIC PLASTICITY SUPPORTING LEARNING, MEMORY, AND OPTIMAL COGNITIVE TASK PERFORMANCE. THESE GENE EXPRESSION CHANGES ARE NOT ONLY MEDIATED BY SIGNALING PATHWAYS THAT ACTIVATE TRANSCRIPTION FACTORS, BUT ALSO BY CHROMATIN MODIFICATIONS THAT INFLUENCE THE ACCESSIBILITY OF THE TRANSCRIPTIONAL MACHINERY TO SPECIFIC GENOMIC REGIONS. DURING THE PAST DECADE, EVIDENCE ACCUMULATED THAT ALTERATIONS IN CHROMATIN-BASED EPIGENETIC REGULATION OF GENE EXPRESSION ARE LINKED TO COGNITIVE DYSFUNCTIONS IN THE AGEING OR NEURODEGENERATING BRAIN AS WELL AS TO COGNITIVE DYSFUNCTIONS RESULTING FROM CHRONIC STRESS EXPOSURE. THIS REVIEW SUMMARIZES THE RESULTS OF STUDIES THAT UNRAVELED A ROLE OF HISTONE MODIFYING ENZYMES AND HISTONE MODIFICATIONS IN NORMAL AND IMPAIRED LEARNING AND MEMORY, AND IN THE DISRUPTION OF EXECUTIVE COGNITIVE TASK PERFORMANCE. IT EMPHASIZES THE DIFFERENT ROLES OF SPECIFIC CLASS I HISTONE DEACETYLASES (HDACS) IN COGNITIVE PROCESSES GOVERNED BY THE HIPPOCAMPUS AND PREFRONTAL CORTEX AND DISCUSSES THE POTENTIAL THERAPEUTIC IMPLICATIONS OF TARGETING THEM TO HOLD THE PROGRESSION OF DISEASE-RELATED COGNITIVE DYSFUNCTIONS. 2017 13 2812 27 FIBROBLAST MEMORY IN DEVELOPMENT, HOMEOSTASIS AND DISEASE. FIBROBLASTS ARE THE MAJOR CELL POPULATION IN THE CONNECTIVE TISSUE OF MOST ORGANS, WHERE THEY ARE ESSENTIAL FOR THEIR STRUCTURAL INTEGRITY. THEY ARE BEST KNOWN FOR THEIR ROLE IN REMODELLING THE EXTRACELLULAR MATRIX, HOWEVER MORE RECENTLY THEY HAVE BEEN RECOGNISED AS A FUNCTIONALLY HIGHLY DIVERSE CELL POPULATION THAT CONSTANTLY RESPONDS AND ADAPTS TO THEIR ENVIRONMENT. BIOLOGICAL MEMORY IS THE PROCESS OF A SUSTAINED ALTERED CELLULAR STATE AND FUNCTIONS IN RESPONSE TO A TRANSIENT OR PERSISTENT ENVIRONMENTAL STIMULUS. WHILE IT IS WELL ESTABLISHED THAT FIBROBLASTS RETAIN A MEMORY OF THEIR ANATOMICAL LOCATION, HOW OTHER ENVIRONMENTAL STIMULI INFLUENCE FIBROBLAST BEHAVIOUR AND FUNCTION IS LESS CLEAR. THE ABILITY OF FIBROBLASTS TO RESPOND AND MEMORISE DIFFERENT ENVIRONMENTAL STIMULI IS ESSENTIAL FOR TISSUE DEVELOPMENT AND HOMEOSTASIS AND MAY BECOME DYSREGULATED IN CHRONIC DISEASE CONDITIONS SUCH AS FIBROSIS AND CANCER. HERE WE SUMMARISE THE FOUR EMERGING KEY AREAS OF FIBROBLAST ADAPTATION: POSITIONAL, MECHANICAL, INFLAMMATORY, AND METABOLIC MEMORY AND HIGHLIGHT THE UNDERLYING MECHANISMS AND THEIR IMPLICATIONS IN TISSUE HOMEOSTASIS AND DISEASE. 2021 14 2344 28 EPIGENETIC REGULATION OF MACROPHAGES: FROM HOMEOSTASIS MAINTENANCE TO HOST DEFENSE. MACROPHAGES ARE CRUCIAL MEMBERS OF THE INNATE IMMUNE RESPONSE AND IMPORTANT REGULATORS. THE DIFFERENTIATION AND ACTIVATION OF MACROPHAGES REQUIRE THE TIMELY REGULATION OF GENE EXPRESSION, WHICH DEPENDS ON THE INTERACTION OF A VARIETY OF FACTORS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC MODIFICATIONS. EPIGENETIC CHANGES ALSO GIVE MACROPHAGES THE ABILITY TO SWITCH RAPIDLY BETWEEN CELLULAR PROGRAMS, INDICATING THE ABILITY OF EPIGENETIC MECHANISMS TO AFFECT PHENOTYPE PLASTICITY. IN THIS REVIEW, WE FOCUS ON KEY EPIGENETIC EVENTS ASSOCIATED WITH MACROPHAGE FATE, HIGHLIGHTING EVENTS RELATED TO THE MAINTENANCE OF TISSUE HOMEOSTASIS, RESPONSES TO DIFFERENT STIMULI AND THE FORMATION OF INNATE IMMUNE MEMORY. FURTHER UNDERSTANDING OF THE EPIGENETIC REGULATION OF MACROPHAGES WILL BE HELPFUL FOR MAINTAINING TISSUE INTEGRITY, PREVENTING CHRONIC INFLAMMATORY DISEASES AND DEVELOPING THERAPIES TO ENHANCE HOST DEFENSE. 2020 15 2298 24 EPIGENETIC REGULATION OF ADIPOGENESIS. PURPOSE OF REVIEW: EPIGENETIC REGULATION PLAYS AN ESSENTIAL ROLE IN CELL DIFFERENTIATION, BY ALLOWING THE ESTABLISHMENT AND MAINTENANCE OF THE GENE-EXPRESSION PATTERN OF THE MATURE CELL TYPE. BECAUSE OF ITS IMPORTANCE IN CHRONIC DISEASES, ADIPOGENESIS IS ONE OF THE BEST-STUDIED DIFFERENTIATION PROCESSES. THE HORMONAL AND TRANSCRIPTIONAL CASCADES GOVERNING THE DIFFERENTIATION OF THE ADIPOCYTES ARE WELL KNOWN, BUT THE ROLE OF EPIGENETIC MECHANISMS IS ONLY STARTING TO EMERGE. IN THIS REVIEW, WE INTEND TO SUMMARIZE THE RECENTLY DESCRIBED EPIGENETIC EVENTS THAT PARTICIPATE IN ADIPOGENESIS AND THEIR CONNECTIONS WITH THE MAIN FACTORS THAT CONSTITUTE THE CLASSICAL TRANSCRIPTIONAL CASCADE. RECENT FINDINGS: THE ADVENT OF HIGH-THROUGHPUT TECHNOLOGIES HAS MADE POSSIBLE THE EXHAUSTIVE ANALYSIS OF THE EPIGENETIC PHENOMENONS TAKING PLACE DURING ADIPOGENESIS. THE COOPERATIVE RECRUITMENT OF CCAAT/ENHANCER-BINDING PROTEIN (C/EBPBETA) AND OTHER EARLY PROADIPOGENIC TRANSCRIPTION FACTORS TO TRANSCRIPTION FACTOR HOTSPOTS SHORTLY AFTER INDUCTION OF ADIPOGENESIS IS REQUIRED TO ESTABLISH A TRANSIENT EPIGENOMIC STATE THAT THEN INFORMS THE RECRUITMENT OF THE LATER ADIPOGENIC TRANSCRIPTION FACTORS PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPARGAMMA) AND C/EBPALPHA TO THEIR TARGET GENES. SUMMARY: EPIGENETIC MARKS AND CHROMATIN-MODIFYING PROTEINS CONTRIBUTE TO ADIPOGENESIS AND, THROUGH REGULATION OF THE PHENOTYPIC MAINTENANCE OF THE MATURE ADIPOCYTES, TO THE CONTROL OF METABOLISM. 2012 16 5545 24 ROLE OF EPIGENETIC MECHANISMS IN CHRONIC PAIN. PAIN IS AN UNPLEASANT BUT ESSENTIAL-TO-LIFE SENSATION, USUALLY RESULTING FROM TISSUE DAMAGE. WHEN PAIN PERSISTS LONG AFTER THE INJURY HAS RESOLVED, IT BECOMES PATHOLOGICAL. THE PRECISE MOLECULAR AND CELLULAR MECHANISMS CAUSING THE TRANSITION FROM ACUTE TO CHRONIC PAIN ARE NOT FULLY UNDERSTOOD. A KEY ASPECT OF PAIN CHRONICITY IS THAT SEVERAL PLASTICITY EVENTS HAPPEN ALONG THE NEURAL PATHWAYS INVOLVED IN PAIN. THESE LONG-LASTING ADAPTIVE CHANGES ARE ENABLED BY ALTERATION IN THE EXPRESSION OF RELEVANT GENES. AMONG THE DIFFERENT MODULATORS OF GENE TRANSCRIPTION IN ADAPTIVE PROCESSES IN THE NERVOUS SYSTEM, EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE. IN THIS REVIEW, I WILL FIRST OUTLINE THE MAIN CLASSES OF EPIGENETIC MEDIATORS AND THEN DISCUSS THEIR IMPLICATIONS IN CHRONIC PAIN. 2022 17 3854 29 IS PTSD AN EVOLUTIONARY SURVIVAL ADAPTATION INITIATED BY UNRESTRAINED CYTOKINE SIGNALING AND MAINTAINED BY EPIGENETIC CHANGE? INTRODUCTION: TREATMENT OUTCOMES FOR PTSD WITH CURRENT PSYCHOLOGICAL THERAPIES ARE POOR, WITH VERY FEW PATIENTS ACHIEVING SUSTAINED SYMPTOM REMISSION. A NUMBER OF AUTHORS HAVE IDENTIFIED PHYSIOLOGICAL AND IMMUNE DISTURBANCES IN POST TRAUMATIC STRESS DISORDER (PTSD) PATIENTS, BUT THERE IS NO UNIFYING HYPOTHESIS THAT EXPLAINS THE MYRIAD FEATURES OF THE DISORDER. MATERIALS AND METHODS: THE MEDICAL LITERATURE WAS REVIEWED OVER A 6-YEAR PERIOD PRIMARILY USING THE MEDICAL DATABASE PUBMED. RESULTS: THE LITERATURE CONTAINS NUMEROUS PAPERS THAT HAVE IDENTIFIED A RANGE OF PHYSIOLOGICAL AND IMMUNE DYSFUNCTION IN ASSOCIATION WITH PTSD. THIS PAPER PROPOSES THAT UNRESTRAINED CYTOKINE SIGNALING INDUCES EPIGENETIC CHANGES THAT PROMOTE AN EVOLUTIONARY SURVIVAL ADAPTATION, WHICH MAINTAINS A DEFENSIVE PTSD PHENOTYPE. THE BRAIN CAN ASSOCIATE IMMUNE SIGNALING WITH PAST THREAT AND INITIATE A DEFENSIVE BEHAVIORAL RESPONSE. THE SYMPATHETIC NERVOUS SYSTEM IS PRO-INFLAMMATORY, WHILE THE PARASYMPATHETIC NERVOUS SYSTEM IS ANTI-INFLAMMATORY. PROLONGED CHOLINERGIC WITHDRAWAL WILL PROMOTE A CHRONIC INFLAMMATORY STATE. THE INNATE IMMUNE CYTOKINE IL-1BETA HAS PLEIOTROPIC PROPERTIES AND CAN REGULATE AUTONOMIC, GLUCOCORTICOID, AND GLUTAMATE RECEPTOR FUNCTIONS, SLEEP, MEMORY, AND EPIGENETIC ENZYMES. CHANGES IN EPIGENETIC ENZYME ACTIVITY CAN POTENTIALLY ALTER PHENOTYPE AND INDUCE AN ADAPTATION. LEVELS OF IL-1BETA CORRELATE WITH SEVERITY AND DURATION OF PTSD AND PTSD CAN BE PREVENTED BY BOLUS ADMINISTRATION OF HYDROCORTISONE IN ACUTE SEPSIS, CONSISTENT WITH UNRESTRAINED INFLAMMATION BEING A RISK FACTOR FOR PTSD. THE NERVOUS AND IMMUNE SYSTEMS ENGAGE IN CROSSTALK, GOVERNED BY COMMON RECEPTORS. THE BENEFITS OF CURRENTLY USED PSYCHIATRIC MEDICATION MAY ARISE FROM IMMUNE, AS WELL AS SYNAPTIC, MODULATION. THE PSYCHEDELIC DRUGS (3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA), PSILOCYBIN, AND KETAMINE) HAVE POTENT IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATORY EFFECTS ON THE ADAPTIVE IMMUNE SYSTEM, WHICH MAY CONTRIBUTE TO THEIR REPORTED BENEFIT IN PTSD. THERE MAY BE DISTINCT PTSD PHENOTYPES INDUCED BY INNATE AND ADAPTIVE CYTOKINE SIGNALING. CONCLUSION: IN ORDER FOR AN ORGANISM TO SURVIVE, IT MUST ADAPT TO ITS ENVIRONMENT. CYTOKINES SIGNAL DANGER TO THE BRAIN AND CAN INDUCE EPIGENETIC CHANGES THAT RESULT IN A PERSISTENT DEFENSIVE PHENOTYPE. PTSD MAY BE THE PRICE INDIVIDUALS PAY FOR THE GENOMIC FLEXIBILITY THAT PROMOTES ADAPTATION AND SURVIVAL. 2022 18 789 28 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 19 1712 33 DYSFUNCTIONAL VASCULAR ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS: EMERGING INSIGHTS INTO PATHOGENESIS AND TREATMENT. ATHEROSCLEROSIS, THE CHRONIC ACCUMULATION OF CHOLESTEROL-RICH PLAQUE WITHIN ARTERIES, IS ASSOCIATED WITH A BROAD SPECTRUM OF CARDIOVASCULAR DISEASES INCLUDING MYOCARDIAL INFARCTION, AORTIC ANEURYSM, PERIPHERAL VASCULAR DISEASE, AND STROKE. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE REMAINS A LEADING CAUSE OF MORTALITY IN HIGH-INCOME COUNTRIES AND RECENT YEARS HAVE WITNESSED A NOTABLE INCREASE IN PREVALENCE WITHIN LOW- AND MIDDLE-INCOME REGIONS OF THE WORLD. CONSIDERING THIS PROMINENT AND EVOLVING GLOBAL BURDEN, THERE IS A NEED TO IDENTIFY THE CELLULAR MECHANISMS THAT UNDERLIE THE PATHOGENESIS OF ATHEROSCLEROSIS TO DISCOVER NOVEL THERAPEUTIC TARGETS FOR PREVENTING OR MITIGATING ITS CLINICAL SEQUELAE. DESPITE DECADES OF RESEARCH, WE STILL DO NOT FULLY UNDERSTAND THE COMPLEX CELL-CELL INTERACTIONS THAT DRIVE ATHEROSCLEROSIS, BUT NEW INVESTIGATIVE APPROACHES ARE RAPIDLY SHEDDING LIGHT ON THESE ESSENTIAL MECHANISMS. THE VASCULAR ENDOTHELIUM RESIDES AT THE INTERFACE OF SYSTEMIC CIRCULATION AND THE UNDERLYING VESSEL WALL AND PLAYS AN ESSENTIAL ROLE IN GOVERNING PATHOPHYSIOLOGICAL PROCESSES DURING ATHEROGENESIS. IN THIS REVIEW, WE PRESENT EMERGING EVIDENCE THAT IMPLICATES THE ACTIVATED ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS BY DIRECTING SITE-SPECIFICITY OF PLAQUE FORMATION AND BY PROMOTING PLAQUE DEVELOPMENT THROUGH INTRACELLULAR PROCESSES, WHICH REGULATE ENDOTHELIAL CELL PROLIFERATION AND TURNOVER, METABOLISM, PERMEABILITY, AND PLASTICITY. MOREOVER, WE HIGHLIGHT NOVEL MECHANISMS OF INTERCELLULAR COMMUNICATION BY WHICH ENDOTHELIAL CELLS MODULATE THE ACTIVITY OF KEY VASCULAR CELL POPULATIONS INVOLVED IN ATHEROGENESIS, AND DISCUSS HOW ENDOTHELIAL CELLS CONTRIBUTE TO RESOLUTION BIOLOGY - A PROCESS THAT IS DYSREGULATED IN ADVANCED PLAQUES. FINALLY, WE DESCRIBE IMPORTANT FUTURE DIRECTIONS FOR PRECLINICAL ATHEROSCLEROSIS RESEARCH, INCLUDING EPIGENETIC AND TARGETED THERAPIES, TO LIMIT THE PROGRESSION OF ATHEROSCLEROSIS IN AT-RISK OR AFFECTED PATIENTS. 2021 20 6802 22 [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