1 4635 149 NEUROINFLAMMATORY MECHANISMS IN PARKINSON'S DISEASE: POTENTIAL ENVIRONMENTAL TRIGGERS, PATHWAYS, AND TARGETS FOR EARLY THERAPEUTIC INTERVENTION. MOST ACUTE AND CHRONIC NEURODEGENERATIVE CONDITIONS ARE ACCOMPANIED BY NEUROINFLAMMATION; YET THE EXACT NATURE OF THE INFLAMMATORY PROCESSES AND WHETHER THEY MODIFY DISEASE PROGRESSION IS NOT WELL UNDERSTOOD. IN THIS REVIEW, WE DISCUSS THE KEY EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL EVIDENCE IMPLICATING INFLAMMATORY PROCESSES IN THE PROGRESSIVE DEGENERATION OF THE DOPAMINERGIC (DA) NIGROSTRIATAL PATHWAY AND THEIR POTENTIAL CONTRIBUTION TO THE PATHOPHYSIOLOGY OF PARKINSON'S DISEASE (PD). GIVEN THAT INTERPLAY BETWEEN GENETICS AND ENVIRONMENT ARE LIKELY TO CONTRIBUTE TO RISK FOR DEVELOPMENT OF IDIOPATHIC PD, RECENT DATA SHOWING INTERACTIONS BETWEEN PRODUCTS OF GENES LINKED TO HERITABLE PD THAT FUNCTION TO PROTECT DA NEURONS AGAINST OXIDATIVE OR PROTEOLYTIC STRESS AND INFLAMMATION PATHWAYS WILL BE DISCUSSED. CELLULAR MECHANISMS ACTIVATED OR ENHANCED BY INFLAMMATORY PROCESSES THAT MAY CONTRIBUTE TO MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, OR APOPTOSIS OF DOPAMINERGIC (DA) NEURONS WILL BE REVIEWED, WITH SPECIAL EMPHASIS ON TUMOR NECROSIS FACTOR (TNF) AND INTERLEUKIN-1-BETA (IL-1BETA) SIGNALING PATHWAYS. EPIGENETIC FACTORS WHICH HAVE THE POTENTIAL TO TRIGGER NEUROINFLAMMATION, INCLUDING ENVIRONMENTAL EXPOSURES AND AGE-ASSOCIATED CHRONIC INFLAMMATORY CONDITIONS, WILL BE DISCUSSED AS POSSIBLE 'SECOND-HIT' TRIGGERS THAT MAY AFFECT DISEASE ONSET OR PROGRESSION OF IDIOPATHIC PD. IF INFLAMMATORY PROCESSES HAVE AN ACTIVE ROLE IN NIGROSTRIATAL PATHWAY DEGENERATION, THEN EVIDENCE SHOULD EXIST TO INDICATE THAT SUCH PROCESSES BEGIN IN THE EARLY STAGES OF DISEASE AND THAT THEY CONTRIBUTE TO NEURONAL DYSFUNCTION AND/OR HASTEN NEURODEGENERATION OF THE NIGROSTRIATAL PATHWAY. THERAPEUTICALLY, IF ANTI-INFLAMMATORY INTERVENTIONS CAN BE SHOWN TO RESCUE NIGRAL DA NEURONS FROM DEGENERATION AND LOWER PD RISK, THEN TIMELY USE OF ANTI-INFLAMMATORY THERAPIES SHOULD BE INVESTIGATED FURTHER IN WELL-DESIGNED CLINICAL TRIALS FOR THEIR ABILITY TO PREVENT OR DELAY THE PROGRESSIVE LOSS OF NIGRAL DA NEURONS IN GENETICALLY SUSCEPTIBLE POPULATIONS. 2007 2 2350 51 EPIGENETIC REGULATION OF NEUROINFLAMMATION IN PARKINSON'S DISEASE. NEUROINFLAMMATION IS ONE OF THE MOST SIGNIFICANT FACTORS INVOLVED IN THE INITIATION AND PROGRESSION OF PARKINSON'S DISEASE. PD IS A NEURODEGENERATIVE DISORDER WITH A MOTOR DISABILITY LINKED WITH VARIOUS COMPLEX AND DIVERSIFIED RISK FACTORS. THESE FACTORS TRIGGER MYRIADS OF CELLULAR AND MOLECULAR PROCESSES, SUCH AS MISFOLDING DEFECTIVE PROTEINS, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND NEUROTOXIC SUBSTANCES THAT INDUCE SELECTIVE NEURODEGENERATION OF DOPAMINE NEURONS. THIS NEURONAL DAMAGE ACTIVATES THE NEURONAL IMMUNE SYSTEM, INCLUDING GLIAL CELLS AND INFLAMMATORY CYTOKINES, TO TRIGGER NEUROINFLAMMATION. THE TRANSITION OF ACUTE TO CHRONIC NEUROINFLAMMATION ENHANCES THE SUSCEPTIBILITY OF INFLAMMATION-INDUCED DOPAMINERGIC NEURON DAMAGE, FORMING A VICIOUS CYCLE AND PROMPTING AN INDIVIDUAL TO PD DEVELOPMENT. EPIGENETIC MECHANISMS RECENTLY HAVE BEEN AT THE FOREFRONT OF THE REGULATION OF NEUROINFLAMMATORY FACTORS IN PD, PROPOSING A NEW DAWN FOR BREAKING THIS VICIOUS CYCLE. THIS REVIEW EXAMINED THE CORE EPIGENETIC MECHANISMS INVOLVED IN THE ACTIVATION AND PHENOTYPIC TRANSFORMATION OF GLIAL CELLS MEDIATED NEUROINFLAMMATION IN PD. WE FOUND THAT EPIGENETIC MECHANISMS DO NOT WORK INDEPENDENTLY, DESPITE BEING COORDINATED WITH EACH OTHER TO ACTIVATE NEUROINFLAMMATORY PATHWAYS. IN THIS REGARD, WE ATTEMPTED TO FIND THE SYNERGIC CORRELATION AND CONTRIBUTION OF THESE EPIGENETIC MODIFICATIONS WITH VARIOUS NEUROINFLAMMATORY PATHWAYS TO BROADEN THE CANVAS OF UNDERLYING PATHOLOGICAL MECHANISMS INVOLVED IN PD DEVELOPMENT. MOREOVER, THIS STUDY HIGHLIGHTED THE DUAL CHARACTERISTICS (NEUROPROTECTIVE/NEUROTOXIC) OF THESE EPIGENETIC MARKS, WHICH MAY COUNTERACT PD PATHOGENESIS AND MAKE THEM POTENTIAL CANDIDATES FOR DEVISING FUTURE PD DIAGNOSIS AND TREATMENT. 2021 3 3123 41 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 4 1199 35 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 5 1414 47 DIETARY PHYTOCHEMICALS IN NEUROIMMUNOAGING: A NEW THERAPEUTIC POSSIBILITY FOR HUMANS? ALTHOUGH SEVERAL EFFORTS HAVE BEEN MADE IN THE SEARCH FOR GENETIC AND EPIGENETIC PATTERNS LINKED TO DISEASES, A COMPREHENSIVE EXPLANATION OF THE MECHANISMS UNDERLYING PATHOLOGICAL PHENOTYPIC PLASTICITY IS STILL FAR FROM BEING CLARIFIED. OXIDATIVE STRESS AND INFLAMMATION ARE TWO OF THE MAJOR TRIGGERS OF THE EPIGENETIC ALTERATIONS OCCURRING IN CHRONIC PATHOLOGIES, SUCH AS NEURODEGENERATIVE DISEASES. IN FACT, OVER THE LAST DECADE, REMARKABLE PROGRESS HAS BEEN MADE TO REALIZE THAT CHRONIC, LOW-GRADE INFLAMMATION IS ONE OF THE MAJOR RISK FACTOR UNDERLYING BRAIN AGING. ACCUMULATED DATA STRONGLY SUGGEST THAT PHYTOCHEMICALS FROM FRUITS, VEGETABLES, HERBS, AND SPICES MAY EXERT RELEVANT IMMUNOMODULATORY AND/OR ANTI-INFLAMMATORY ACTIVITIES IN THE CONTEXT OF BRAIN AGING. STARTING BY THE EVIDENCE THAT A COMMON DENOMINATOR OF AGING AND CHRONIC DEGENERATIVE DISEASES IS REPRESENTED BY INFLAMMATION, AND THAT SEVERAL DIETARY PHYTOCHEMICALS ARE ABLE TO POTENTIALLY INTERFERE WITH AND REGULATE THE NORMAL FUNCTION OF CELLS, IN PARTICULAR NEURONAL COMPONENTS, AIM OF THIS REVIEW IS TO SUMMARIZE RECENT STUDIES ON NEUROINFLAMMAGING PROCESSES AND PROOFS INDICATING THAT SPECIFIC PHYTOCHEMICALS MAY ACT AS POSITIVE MODULATORS OF NEUROINFLAMMATORY EVENTS. IN ADDITION, CRITICAL PATHWAYS INVOLVED IN MEDIATING PHYTOCHEMICALS EFFECTS ON NEUROINFLAMMAGING WERE DISCUSSED, EXPLORING THE REAL IMPACT OF THESE COMPOUNDS IN PRESERVING BRAIN HEALTH BEFORE THE ONSET OF SYMPTOMS LEADING TO INFLAMMATORY NEURODEGENERATION AND COGNITIVE DECLINE. 2016 6 2586 37 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 7 6136 44 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 8 4783 39 NUTRIGENOMICS IN PARKINSON'S DISEASE: DIVERSITY OF MODULATORY ACTIONS OF POLYPHENOLS ON EPIGENETIC EFFECTS INDUCED BY TOXINS. ALTHOUGH THE PATHOGENESIS OF PARKINSON'S DISEASE (PD) IS NOT COMPLETELY UNDERSTOOD, THERE IS A CONSENSUS THAT IT CAN BE CAUSED BY MULTIFACTORIAL MECHANISMS INVOLVING GENETIC SUSCEPTIBILITY, EPIGENETIC MODIFICATIONS INDUCED BY TOXINS AND MITOCHONDRIAL DYSFUNCTION. IN THE PAST 20 YEARS, GREAT EFFORTS HAVE BEEN MADE IN ORDER TO CLARIFY MOLECULAR MECHANISMS THAT ARE RISK FACTORS FOR THIS DISEASE, AS WELL AS TO IDENTIFY BIOACTIVE AGENTS FOR PREVENTION AND SLOWING DOWN OF ITS PROGRESSION. NUTRACEUTICAL PRODUCTS HAVE RECEIVED SUBSTANTIAL INTEREST DUE TO THEIR NUTRITIONAL, SAFE AND THERAPEUTIC EFFECTS ON SEVERAL CHRONIC DISEASES. THE AIM OF THIS REVIEW WAS TO GATHER THE MAIN EVIDENCE OF THE EPIGENETIC MECHANISMS INVOLVED IN THE NEUROPROTECTIVE EFFECTS OF PHENOLIC COMPOUNDS CURRENTLY UNDER INVESTIGATION FOR THE TREATMENT OF TOXIN-INDUCED PD. THESE STUDIES CONFIRM THAT THE NEUROPROTECTIVE ACTIONS OF POLYPHENOLS INVOLVE COMPLEX EPIGENETIC MODULATIONS, DEMONSTRATING THAT THE INTAKE OF THESE NATURAL COMPOUNDS CAN BE A PROMISING, LOW-COST, PHARMACOGENOMIC STRATEGY AGAINST THE DEVELOPMENT OF PD. 2023 9 3404 36 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 10 2611 34 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 11 2010 41 EPIGENETIC BASIS OF LEAD-INDUCED NEUROLOGICAL DISORDERS. ENVIRONMENTAL LEAD (PB) EXPOSURE IS CLOSELY ASSOCIATED WITH PATHOGENESIS OF A RANGE OF NEUROLOGICAL DISORDERS, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD), ETC. EPIGENETIC MACHINERY MODULATES NEURAL DEVELOPMENT AND ACTIVITIES, WHILE FAULTY EPIGENETIC REGULATION CONTRIBUTES TO THE DIVERSE FORMS OF CNS (CENTRAL NERVOUS SYSTEM) ABNORMALITIES AND DISEASES. AS A POTENT EPIGENETIC MODIFIER, LEAD IS THOUGHT TO CAUSE NEUROLOGICAL DISORDERS THROUGH MODULATING EPIGENETIC MECHANISMS. SPECIFICALLY, INCREASING EVIDENCE LINKED ABERRANT DNA METHYLATIONS, HISTONE MODIFICATIONS AS WELL AS NCRNAS (NON-CODING RNAS) WITH AD CASES, AMONG WHICH CIRCRNA (CIRCULAR RNA) STANDS OUT AS A NEW AND PROMISING FIELD FOR ASSOCIATION STUDIES. IN 23-YEAR-OLD PRIMATES WITH DEVELOPMENTAL LEAD TREATMENT, ZAWIA GROUP DISCOVERED A VARIETY OF EPIGENETIC CHANGES RELATING TO AD PATHOGENESIS. THIS IS A DIRECT EVIDENCE IMPLICATING EPIGENETIC BASIS IN LEAD-INDUCED AD ANIMALS WITH AN ENTIRE LIFESPAN. ADDITIONALLY, SOME EPIGENETIC MOLECULES ASSOCIATED WITH AD ETIOLOGY WERE ALSO KNOWN TO RESPOND TO CHRONIC LEAD EXPOSURE IN COMPARABLE DISEASE MODELS, INDICATING POTENTIALLY INTERLACED MECHANISMS WITH RESPECT TO THE STUDIED NEUROTOXIC AND PATHOLOGICAL EVENTS. OF NOTE, EPIGENETIC MOLECULES ACTED VIA GLOBALLY OR SELECTIVELY INFLUENCING THE EXPRESSION OF DISEASE-RELATED GENES. COMPARED TO AD, THE ASSOCIATION OF LEAD EXPOSURE WITH OTHER NEUROLOGICAL DISORDERS WERE PRIMARILY SUPPORTED BY EPIDEMIOLOGICAL SURVEY, WITH FEWER REPORTS CONNECTING EPIGENETIC REGULATORS WITH LEAD-INDUCED PATHOGENESIS. SOME PHARMACEUTICALS, SUCH AS HDAC (HISTONE DEACETYLASE) INHIBITORS AND DNA METHYLATION INHIBITORS, WERE DEVELOPED TO DEAL WITH CNS DISEASE BY TARGETING EPIGENETIC COMPONENTS. STILL, UNDERSTANDINGS ARE INSUFFICIENT REGARDING THE CAUSE-CONSEQUENCE RELATIONS OF EPIGENETIC FACTORS AND NEUROLOGICAL ILLNESS. THEREFORE, CLEAR EVIDENCE SHOULD BE PROVIDED IN FUTURE INVESTIGATIONS TO ADDRESS DETAILED ROLES OF NOVEL EPIGENETIC FACTORS IN LEAD-INDUCED NEUROLOGICAL DISORDERS, AND EFFORTS OF DEVELOPING SPECIFIC EPIGENETIC THERAPEUTICS SHOULD BE APPRAISED. 2020 12 2333 33 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 13 3540 34 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 14 6034 48 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 15 6846 28 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 16 2049 27 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014 17 789 46 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 5670 45 SHARED (EPI)GENOMIC BACKGROUND CONNECTING NEURODEGENERATIVE DISEASES AND TYPE 2 DIABETES. THE PROGRESSIVE AGING OF POPULATIONS HAS RESULTED IN AN INCREASED PREVALENCE OF CHRONIC PATHOLOGIES, ESPECIALLY OF METABOLIC, NEURODEGENERATIVE AND MOVEMENT DISORDERS. IN PARTICULAR, TYPE 2 DIABETES (T2D), ALZHEIMER'S DISEASE (AD) AND PARKINSON'S DISEASE (PD) ARE AMONG THE MOST PREVALENT AGE-RELATED, MULTIFACTORIAL PATHOLOGIES THAT DESERVE PARTICULAR ATTENTION, GIVEN THEIR DRAMATIC IMPACT ON PATIENT QUALITY OF LIFE, THEIR ECONOMIC AND SOCIAL BURDEN AS WELL THE ETIOPATHOGENETIC MECHANISMS, WHICH MAY OVERLAP IN SOME CASES. INDEED, THE EXISTENCE OF COMMON TRIGGERING FACTORS REFLECTS THE CONTRIBUTION OF MUTUAL GENETIC, EPIGENETIC AND ENVIRONMENTAL FEATURES IN THE ETIOPATHOGENETIC MECHANISMS UNDERLYING T2D AND AD/PD. ON THIS SUBJECT, THIS REVIEW WILL SUMMARIZE THE SHARED (EPI)GENOMIC FEATURES THAT CHARACTERIZE THESE COMPLEX PATHOLOGIES. IN PARTICULAR, GENETIC VARIANTS AND GENE EXPRESSION PROFILES ASSOCIATED WITH T2D AND AD/PD WILL BE DISCUSSED AS POSSIBLE CONTRIBUTORS TO DETERMINE THE SUSCEPTIBILITY AND PROGRESSION TO THESE DISORDERS. MOREOVER, POTENTIAL SHARED EPIGENETIC MODIFICATIONS AND FACTORS AMONG T2D, AD AND PD WILL ALSO BE ILLUSTRATED. OVERALL, THIS REVIEW SHOWS THAT FINDINGS FROM GENOMIC STUDIES STILL DESERVES FURTHER RESEARCH TO EVALUATE AND IDENTIFY GENETIC FACTORS THAT DIRECTLY CONTRIBUTE TO THE SHARED ETIOPATHOGENESIS. MOREOVER, A COMMON EPIGENETIC BACKGROUND STILL NEEDS TO BE INVESTIGATED AND CHARACTERIZED. THE EVIDENCES DISCUSSED IN THIS REVIEW UNDERLINE THE IMPORTANCE OF INTEGRATING LARGE-SCALE (EPI)GENOMIC DATA WITH ADDITIONAL MOLECULAR INFORMATION AND CLINICAL AND SOCIAL BACKGROUND IN ORDER TO FINELY DISSECT THE COMPLEX ETIOPATHOGENIC NETWORKS THAT BUILD UP THE "DISEASE INTERACTOME" CHARACTERIZING T2D, AD AND PD. 2020 19 5817 26 STRESS AND THE EPIGENETIC LANDSCAPE: A LINK TO THE PATHOBIOLOGY OF HUMAN DISEASES? ACCUMULATING EVIDENCE POINTS TO A MAJOR ROLE FOR CHRONIC STRESS OF CELL RENEWAL SYSTEMS IN THE PATHOGENESIS OF IMPORTANT HUMAN DISEASES, INCLUDING CANCER, ATHEROSCLEROSIS AND DIABETES. HERE WE DISCUSS EMERGING EVIDENCE THAT EPIGENETIC ABNORMALITIES MAY MAKE SUBSTANTIAL CONTRIBUTIONS TO THESE STRESS-INDUCED PATHOLOGIES. ALTHOUGH THE MECHANISMS REMAIN TO BE FULLY ELUCIDATED, WE SUGGEST THAT CHRONIC STRESS CAN ELICIT HERITABLE CHANGES IN THE CHROMATIN LANDSCAPE THAT 'LOCK' CELLS IN ABNORMAL STATES, WHICH THEN LEAD TO DISEASE. WE EMPHASIZE THE NEED TO INVESTIGATE EPIGENETIC STATES IN DISEASE AND LINKS TO STRESS AND TO CONSIDER HOW THE KNOWLEDGE GAINED THROUGH THESE STUDIES MAY FOSTER NEW MEANS OF DISEASE PREVENTION AND MANAGEMENT. 2010 20 2227 35 EPIGENETIC MODIFICATIONS OF CHRONIC HYPOXIA-MEDIATED NEURODEGENERATION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON NEURODEGENERATIVE DISORDER AFFECTING THE ELDERLY PEOPLE. AD IS CHARACTERIZED BY PROGRESSIVE AND GRADUAL DECLINE IN COGNITIVE FUNCTION AND MEMORY LOSS. WHILE FAMILIAL EARLY-ONSET AD IS USUALLY ASSOCIATED WITH GENE MUTATIONS, THE ETIOLOGY OF SPORADIC LATE-ONSET FORM OF AD IS LARGELY UNKNOWN. IT HAS BEEN REPORTED THAT ENVIRONMENTAL FACTORS AND EPIGENETIC ALTERATIONS SIGNIFICANTLY CONTRIBUTE TO THE PROCESS OF AD. OUR PREVIOUS STUDIES HAVE DOCUMENTED THAT CHRONIC HYPOXIA IS ONE OF THE ENVIRONMENTAL FACTORS THAT MAY TRIGGER THE AD DEVELOPMENT AND AGGRAVATE THE DISEASE PROGRESSION. IN THIS REVIEW, WE WILL SUMMARIZE THE PATHOLOGICAL EFFECTS OF CHRONIC HYPOXIA ON THE ONSET AND DEVELOPMENT OF AD AND PUT FORWARD THE POSSIBLE MOLECULE MECHANISMS UNDERLYING THE CHRONIC HYPOXIA MEDIATED AD PATHOGENESIS. FINALLY, WE PROPOSE THAT EPIGENETIC REGULATIONS MAY REPRESENT NEW OPPORTUNITY FOR THE THERAPEUTIC INTERVENTION OF THIS DISEASE. 2014