1 2163 108 EPIGENETIC MECHANISMS IN DIABETIC VASCULAR COMPLICATIONS. THERE HAS BEEN A RAPID INCREASE IN THE INCIDENCE OF DIABETES AS WELL THE ASSOCIATED VASCULAR COMPLICATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN IMPLICATED IN THESE PATHOLOGIES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. ACTIONS OF MAJOR PATHOLOGICAL MEDIATORS OF DIABETES AND ITS COMPLICATIONS SUCH AS HYPERGLYCAEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS CAN LEAD TO DYSREGULATED EPIGENETIC MECHANISMS THAT AFFECT CHROMATIN STRUCTURE AND GENE EXPRESSION. FURTHERMORE, PERSISTENCE OF THIS ALTERED STATE OF THE EPIGENOME MAY BE THE UNDERLYING MECHANISM CONTRIBUTING TO A 'METABOLIC MEMORY' THAT RESULTS IN CHRONIC INFLAMMATION AND VASCULAR DYSFUNCTION IN DIABETES EVEN AFTER ACHIEVING GLYCAEMIC CONTROL. FURTHER EXAMINATION OF EPIGENETIC MECHANISMS BY ALSO TAKING ADVANTAGE OF RECENTLY DEVELOPED NEXT-GENERATION SEQUENCING TECHNOLOGIES CAN PROVIDE NOVEL INSIGHTS INTO THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS AND LEAD TO THE DISCOVERY OF MUCH NEEDED NEW DRUG TARGETS FOR THESE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF EPIGENETICS IN DIABETES AND ITS VASCULAR COMPLICATIONS, AND RECENT TECHNOLOGICAL ADVANCES THAT HAVE SIGNIFICANTLY ACCELERATED THE FIELD. 2011 2 2190 63 EPIGENETIC MECHANISMS. THE INCIDENCE OF DIABETES AND RELATED COMPLICATIONS LIKE NEPHROPATHY IS GROWING RAPIDLY AND HAS BECOME A MAJOR HEALTH CARE ISSUE. CHANGES IN THE ENVIRONMENT AND NUTRITIONAL HABITS HAVE BEEN IMPLICATED AS MAJOR PLAYERS. FURTHERMORE, IT IS BECOMING INCREASINGLY CLEAR THAT EPIGENETIC FACTORS MAY MODULATE THE CONNECTIONS BETWEEN GENES AND THE ENVIRONMENT. WHILE DIABETES IN ITSELF IS TREATABLE TO A LARGE EXTENT, IT IS STILL ASSOCIATED WITH SIGNIFICANTLY INCREASED RISK FOR COMPLICATIONS INCLUDING CHRONIC KIDNEY AND CARDIOVASCULAR DISEASES. CURRENT TREATMENTS HAVE ADDED PREVENTATIVE APPROACHES SO AS TO AVOID FUTURE DIABETIC COMPLICATIONS. UNFORTUNATELY, DIABETIC PATIENTS ARE OFTEN PLAGUED WITH THE CONTINUED DEVELOPMENT OF VARIOUS COMPLICATIONS EVEN AFTER ACHIEVING GLUCOSE CONTROL. THIS HAS BEEN SUGGESTED TO BE ATTRIBUTABLE TO A MYSTERIOUS PHENOMENON TERMED 'METABOLIC MEMORY' OF THE PRIOR GLYCEMIC STATE. RECENT STUDIES HAVE SUGGESTED THAT EPIGENETIC CHANGES TO CHROMATIN CAN AFFECT GENE EXPRESSION IN RESPONSE TO VARIOUS STIMULI, AND CHANGES IN KEY BIOCHEMICAL PATHWAYS AND EPIGENETIC HISTONE AND DNA METHYLATION PATTERNS IN CHROMATIN HAVE BEEN OBSERVED IN A DIABETIC MILIEU. THESE ACCUMULATING DATA SUGGEST THAT METABOLIC OR HYPERGLYCEMIC MEMORY MAY BE DUE TO EPIGENETIC CHANGES IN SPECIFIC TARGET TISSUES ALTERING GENE EXPRESSION WITHOUT CHANGING THE GENETIC CODE ITSELF. WHILE THE GENETICS OF DIABETES HAS LONG BEEN THE FOCUS OF SCIENTIFIC RESEARCH, MUCH LESS IS KNOWN ABOUT THE ROLE OF EPIGENETICS AND THE RELATED MOLECULAR PATHWAYS THAT MIGHT AFFECT THE DEVELOPMENT OF DIABETES AND THE ASSOCIATED COMPLICATIONS. FURTHER STUDIES OF EPIGENETIC MECHANISMS ARE THEREFORE TIMELY AND COULD PROVIDE VALUABLE NEW INSIGHTS INTO THE PATHOLOGY OF DIABETIC COMPLICATIONS AND ALSO UNCOVER MUCH NEEDED NEW THERAPEUTIC TARGETS. 2011 3 2613 59 EPIGENETICS: DECIPHERING ITS ROLE IN DIABETES AND ITS CHRONIC COMPLICATIONS. 1. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS MIGHT REGULATE THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT, AND AFFECT HUMAN DISEASES, SUCH AS DIABETES AND ITS COMPLICATIONS. 2. CLINICAL TRIALS HAVE UNDERSCORED THE LONG LASTING BENEFICIAL EFFECTS OF STRICT GLYCAEMIC CONTROL FOR REDUCING THE PROGRESSION OF DIABETIC COMPLICATIONS. THEY HAVE ALSO SHOWN THAT DIABETIC COMPLICATIONS, SUCH AS DIABETIC NEPHROPATHY, A CHRONIC KIDNEY DISORDER, CAN CONTINUE EVEN AFTER BLOOD GLUCOSE NORMALIZATION, SUGGESTING A METABOLIC MEMORY OF THE PRIOR GLYCAEMIC STATE. 3. DYSREGULATION OF EPIGENETIC POST-TRANSCRIPTIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, INCLUDING HISTONE LYSINE METHYLATION, HAS BEEN IMPLICATED IN ABERRANT GENE REGULATION ASSOCIATED WITH THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS. GENOME-WIDE STUDIES HAVE SHOWN CELL-TYPE SPECIFIC CHANGES IN HISTONE METHYLATION PATTERNS UNDER DIABETIC CONDITIONS. IN ADDITION, STUDIES IN VASCULAR CELLS HAVE SHOWN LONG LASTING CHANGES IN EPIGENETIC MODIFICATIONS AT KEY INFLAMMATORY GENE PROMOTERS AFTER PRIOR EXPOSURE TO DIABETIC CONDITIONS, SUGGESTING A POSSIBLE MECHANISM FOR METABOLIC MEMORY. 4. RECENT STUDIES HAVE SHOWN ROLES FOR HISTONE METHYLATION, DNA METHYLATION, AS WELL AS MICRORNA IN DIABETIC NEPHROPATHY. WHETHER THESE EPIGENETIC FACTORS PLAY A ROLE IN METABOLIC MEMORY OF DIABETIC KIDNEY DISEASE IS LESS WELL UNDERSTOOD. 5. THE INCIDENCE OF DIABETES IS GROWING RAPIDLY, AS ALSO THE COST OF TREATING THE RESULTING COMPLICATIONS. A BETTER UNDERSTANDING OF METABOLIC MEMORY AND THE POTENTIAL INVOLVEMENT OF EPIGENETIC MECHANISMS IN THIS PHENOMENON COULD ENABLE THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS FOR THE TREATMENT AND/OR PREVENTION OF SUSTAINED DIABETIC COMPLICATIONS. 2011 4 2154 43 EPIGENETIC MECHANISMS AND KIDNEY DISEASES. IN RECENT YEARS, MOLECULAR RESEARCH HAS BROUGHT TO LIGHT A SERIES OF MECHANISMS INVOLVED IN THE REGULATION OF GENE FUNCTION WITHOUT ALTERING THE DNA SEQUENCE. THESE MECHANISMS ARE DESCRIBED WITH THE TERM "EPIGENETICS" AND INCLUDE MODIFICATIONS IN THE STRUCTURE OF THE HUMAN GENOME, LEADING TO HERITABLE AND POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION. THERE IS NOW INCREASING EVIDENCE SUGGESTING THAT SEVERAL CHARACTERISTIC FEATURES OF CHRONIC KIDNEY DISEASE SUCH AS HYPERHOMOCYSTEINEMIA, SUBCLINICAL INFLAMMATION, INCREASED OXIDATIVE STRESS AND OTHERS MAY AFFECT THE HUMAN EPIGENOME. IN ADDITION, ANIMAL STUDIES HAVE SUGGESTED A POSSIBLE LINK BETWEEN NUTRITION AND ENVIRONMENTAL EXPOSURE DURING THE PERICONCEPTIONAL PERIOD AND EPIGENETIC CHANGES IN THE EXPRESSION OF MAJOR GENES IMPLICATED IN KIDNEY ORGANOGENESIS; THESE CHANGES RESULT IN A DIMINISHED NUMBER OF NEPHRONS IN THE DEVELOPING KIDNEY, WHICH PREDISPOSES TO AN INCREASED RISK FOR HYPERTENSION AND CHRONIC KIDNEY DISEASE IN FUTURE LIFE. THE UNDERSTANDING OF THE ROLE OF EPIGENETIC PHENOMENA IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE OPENS NEW AVENUES FOR FUTURE THERAPEUTIC STRATEGIES, THROUGH THE DEVELOPMENT OF PHARMACEUTICAL AGENTS THAT TARGET DIRECTLY WITH THE CHANGES IN THE HUMAN EPIGENOME. SUCH EPIGENETIC DRUGS ARE ALREADY IN CLINICAL USE FOR THE TREATMENT OF CANCER AS WELL AS UNDER INVESTIGATION FOR THE USE IN OTHER DISEASES. THIS REVIEW WILL SUMMARIZE THE EXISTING DATA ON THE LINK BETWEEN EPIGENETIC MECHANISMS AND CHRONIC UREMIC MILIEU, AS WELL AS THE PROMISING RESULTS OF ONGOING RESEARCH IN THE FIELD OF EPIGENETIC DRUGS THAT COULD REPRESENT ADDITIONAL OPTIONS IN OUR THERAPEUTIC ARMAMENTARIUM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE. 2011 5 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 6 2491 32 EPIGENETICS AND CARDIOVASCULAR DISEASE IN DIABETES. TYPE 2 DIABETES HAS BECOME A MAJOR HEALTH ISSUE WORLDWIDE. CHRONIC HYPERGLYCEMIA INDUCES A LOW-GRADE INFLAMMATION THAT, ON TOP OF OTHER MECHANISMS, LEADS TO ENDOTHELIAL DYSFUNCTION. MOUNTING EVIDENCE SUGGESTS THAT DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, AND LONG NON-CODING RNAS PLAY AN IMPORTANT ROLE IN THE INITIATION, MAINTENANCE, AND PROGRESSION OF BOTH MACRO- AND MICRO-VASCULAR COMPLICATIONS OF DIABETES. LONG-TERM EXPOSURE TO HYPERGLYCEMIA INDUCES EPIGENETIC CHANGES THAT COULD BECOME IRREVERSIBLE, A PHENOMENON KNOWN AS THE 'METABOLIC MEMORY.' WHETHER EPIGENETIC-BASED THERAPIES COULD BE USED TO SLOW OR LIMIT THE PROGRESSION OF CARDIOVASCULAR DISEASE REMAINS UNCLEAR. WHILE NON-CODING RNAS ARE CURRENTLY INVESTIGATED AS POTENTIAL BIOMARKERS THAT PREDICT DIABETIC CARDIOVASCULAR DISEASE INCIDENCE AND PROGRESSION, THEIR THERAPEUTIC ROLE IS ONLY HYPOTHETICAL. IN THIS REVIEW, WE HIGHLIGHT THE LATEST FINDINGS IN EXPERIMENTAL AND CLINICAL STUDIES RELEVANT TO EPIGENETICS AND CARDIOVASCULAR DISEASE IN DIABETES. 2015 7 5376 57 RECENT DEVELOPMENTS IN EPIGENETICS OF ACUTE AND CHRONIC KIDNEY DISEASES. THE GROWING EPIDEMIC OF OBESITY AND DIABETES, THE AGING POPULATION AS WELL AS PREVALENCE OF DRUG ABUSE HAS LED TO SIGNIFICANT INCREASES IN THE RATES OF THE CLOSELY ASSOCIATED ACUTE AND CHRONIC KIDNEY DISEASES, INCLUDING DIABETIC NEPHROPATHY. FURTHERMORE, EVIDENCE SHOWS THAT PARENTAL BEHAVIOR AND DIET CAN AFFECT THE PHENOTYPE OF SUBSEQUENT GENERATIONS VIA EPIGENETIC TRANSMISSION MECHANISMS. THESE DATA SUGGEST A STRONG INFLUENCE OF THE ENVIRONMENT ON DISEASE SUSCEPTIBILITY AND THAT, APART FROM GENETIC SUSCEPTIBILITY, EPIGENETIC MECHANISMS NEED TO BE EVALUATED TO GAIN CRITICAL NEW INFORMATION ABOUT KIDNEY DISEASES. EPIGENETICS IS THE STUDY OF PROCESSES THAT CONTROL GENE EXPRESSION AND PHENOTYPE WITHOUT ALTERATIONS IN THE UNDERLYING DNA SEQUENCE. EPIGENETIC MODIFICATIONS, INCLUDING CYTOSINE DNA METHYLATION AND COVALENT POST-TRANSLATIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, ARE PART OF THE EPIGENOME, THE INTERFACE BETWEEN THE STABLE GENOME AND THE VARIABLE ENVIRONMENT. THIS DYNAMIC EPIGENETIC LAYER RESPONDS TO EXTERNAL ENVIRONMENTAL CUES TO INFLUENCE THE EXPRESSION OF GENES ASSOCIATED WITH DISEASE STATES. THE FIELD OF EPIGENETICS HAS SEEN REMARKABLE GROWTH IN THE PAST FEW YEARS WITH SIGNIFICANT ADVANCES IN BASIC BIOLOGY, CONTRIBUTIONS TO HUMAN DISEASE, AS WELL AS EPIGENOMICS TECHNOLOGIES. FURTHER UNDERSTANDING OF HOW THE RENAL CELL EPIGENOME IS ALTERED BY METABOLIC AND OTHER STIMULI CAN YIELD NOVEL NEW INSIGHTS INTO THE PATHOGENESIS OF KIDNEY DISEASES. IN THIS REVIEW, WE HAVE DISCUSSED THE CURRENT KNOWLEDGE ON THE ROLE OF EPIGENETIC MECHANISMS (PRIMARILY DNAME AND HISTONE MODIFICATIONS) IN ACUTE AND CHRONIC KIDNEY DISEASES, AND THEIR TRANSLATIONAL POTENTIAL TO IDENTIFY MUCH NEEDED NEW THERAPIES. 2015 8 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 9 1871 38 EMERGING ROLE OF EPIGENETICS IN EXPLAINING RELATIONSHIP OF PERIODONTITIS AND CARDIOVASCULAR DISEASES. CARDIOVASCULAR DISEASES SUCH AS ISCHEMIC HEART DISEASES OR STROKE ARE AMONG THE LEADING CAUSE OF DEATHS GLOBALLY, AND EVIDENCE SUGGESTS THAT THESE DISEASES ARE MODULATED BY A MULTIFACTORIAL AND COMPLEX INTERPLAY OF GENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. GENETIC PREDISPOSITION AND CHRONIC EXPOSURE TO MODIFIABLE RISK FACTORS HAVE BEEN EXPLORED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF CVD. ENVIRONMENTAL FACTORS CONTRIBUTE TO AN INDIVIDUAL'S PROPENSITY TO DEVELOP MAJOR CARDIOVASCULAR RISK FACTORS THROUGH EPIGENETIC MODIFICATIONS OF DNA AND HISTONES VIA MIRNA REGULATION OF PROTEIN TRANSLATION THAT ARE TYPES OF EPIGENETIC MECHANISMS AND PARTICIPATE IN DISEASE DEVELOPMENT. PERIODONTAL DISEASE (PD) IS ONE OF THE MOST COMMON ORAL DISEASES IN HUMANS THAT IS CHARACTERIZED BY LOW-GRADE INFLAMMATION AND HAS BEEN SHOWN TO INCREASE THE RISK OF CVDS. RISK FACTORS INVOLVED IN PD AND CVD ARE DETERMINED BOTH GENETICALLY AND BEHAVIORALLY. PERIODONTAL DISEASES SUCH AS CHRONIC INFLAMMATION PROMOTE DNA METHYLATION. EPIGENETIC MODIFICATIONS INVOLVED IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS PLAY AN ESSENTIAL ROLE IN PLAQUE DEVELOPMENT AND VULNERABILITY. EPIGENETICS HAS OPENED A NEW WORLD TO UNDERSTAND AND MANAGE HUMAN DISEASES, INCLUDING CVDS AND PERIODONTAL DISEASES. GENETIC MEDICINE HAS STARTED A NEW ERA OF EPIGENETICS TO OVERCOME HUMAN DISEASES WITH VARIOUS NEW METHODOLOGY. EPIGENETIC PROFILING MAY AID IN BETTER DIAGNOSIS AND STRATIFICATION OF PATIENTS SHOWING POTENTIAL PREDISPOSED STATES FOR DISEASE. A BETTER UNDERSTANDING OF THE EXACT REGULATORY MECHANISMS OF EPIGENETIC PATHWAYS DRIVING INFLAMMATION IS SLOWLY EMERGING AND WILL AID IN DEVELOPING NOVEL TOOLS FOR THE TREATMENT OF DISEASE. 2021 10 2028 42 EPIGENETIC CHANGES IN DIABETES. DIABETES IS A MULTIFACTORIAL DISEASE WITH NUMEROUS PATHWAYS INFLUENCING ITS PROGRESSION AND RECENT OBSERVATIONS SUGGEST THAT THE COMPLEXITY OF THE DISEASE CANNOT BE ENTIRELY ACCOUNTED FOR BY GENETIC PREDISPOSITION. A COMPELLING ARGUMENT FOR AN EPIGENETIC COMPONENT IS RAPIDLY EMERGING. EPIGENETIC PROCESSES AT THE CHROMATIN TEMPLATE SIGNIFICANTLY SENSITIZE TRANSCRIPTIONAL AND PHENOTYPIC OUTCOMES TO ENVIRONMENTAL SIGNALING INFORMATION INCLUDING METABOLIC STATE, NUTRITIONAL REQUIREMENTS AND HISTORY. EPIGENETIC MECHANISMS IMPACT GENE EXPRESSION THAT COULD PREDISPOSE INDIVIDUALS TO THE DIABETIC PHENOTYPE DURING INTRAUTERINE AND EARLY POSTNATAL DEVELOPMENT, AS WELL AS THROUGHOUT ADULT LIFE. FURTHERMORE, EPIGENETIC CHANGES COULD ACCOUNT FOR THE ACCELERATED RATES OF CHRONIC AND PERSISTENT MICROVASCULAR AND MACROVASCULAR COMPLICATIONS ASSOCIATED WITH DIABETES. EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES IDENTIFIED POOR GLYCEMIC CONTROL AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF DIABETIC COMPLICATIONS AND HIGHLIGHT THE REQUIREMENT FOR EARLY INTERVENTION. EARLY EXPOSURE TO HYPERGLYCEMIA CAN DRIVE THE DEVELOPMENT OF COMPLICATIONS THAT MANIFEST LATE IN THE PROGRESSION OF THE DISEASE AND PERSIST DESPITE IMPROVED GLYCEMIC CONTROL, INDICATING A MEMORY OF THE METABOLIC INSULT. UNDERSTANDING THE MOLECULAR EVENTS THAT UNDERLIE THESE TRANSCRIPTIONAL CHANGES WILL SIGNIFICANTLY CONTRIBUTE TO NOVEL THERAPEUTIC INTERVENTIONS TO PREVENT, REVERSE OR RETARD THE DELETERIOUS EFFECTS OF THE DIABETIC MILIEU. 2013 11 6204 40 THE INFLUENCE OF EPIGENETICS AND INFLAMMATION ON CARDIOMETABOLIC RISKS. CARDIOMETABOLIC DISEASES INCLUDE METABOLIC SYNDROME, OBESITY, TYPE 2 DIABETES MELLITUS, AND HYPERTENSION. EPIGENETIC MODIFICATIONS PARTICIPATE IN CARDIOMETABOLIC DISEASES THROUGH SEVERAL PATHWAYS, INCLUDING INFLAMMATION, VASCULAR DYSFUNCTION, AND INSULIN RESISTANCE. EPIGENETIC MODIFICATIONS, WHICH ENCOMPASS ALTERATIONS TO GENE EXPRESSION WITHOUT MUTATING THE DNA SEQUENCE, HAVE GAINED MUCH ATTENTION IN RECENT YEARS, SINCE THEY HAVE BEEN CORRELATED WITH CARDIOMETABOLIC DISEASES AND MAY BE TARGETED FOR THERAPEUTIC INTERVENTIONS. EPIGENETIC MODIFICATIONS ARE GREATLY INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS DIET, PHYSICAL ACTIVITY, CIGARETTE SMOKING, AND POLLUTION. SOME MODIFICATIONS ARE HERITABLE, INDICATING THAT THE BIOLOGICAL EXPRESSION OF EPIGENETIC ALTERATIONS MAY BE OBSERVED ACROSS GENERATIONS. MOREOVER, MANY PATIENTS WITH CARDIOMETABOLIC DISEASES PRESENT WITH CHRONIC INFLAMMATION, WHICH CAN BE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS. THE INFLAMMATORY ENVIRONMENT WORSENS THE PROGNOSIS OF CARDIOMETABOLIC DISEASES AND FURTHER INDUCES EPIGENETIC MODIFICATIONS, PREDISPOSING PATIENTS TO THE DEVELOPMENT OF OTHER METABOLISM-ASSOCIATED DISEASES AND COMPLICATIONS. A DEEPER UNDERSTANDING OF INFLAMMATORY PROCESSES AND EPIGENETIC MODIFICATIONS IN CARDIOMETABOLIC DISEASES IS NECESSARY TO IMPROVE OUR DIAGNOSTIC CAPABILITIES, PERSONALIZED MEDICINE APPROACHES, AND THE DEVELOPMENT OF TARGETED THERAPEUTIC INTERVENTIONS. FURTHER UNDERSTANDING MAY ALSO ASSIST IN PREDICTING DISEASE OUTCOMES, ESPECIALLY IN CHILDREN AND YOUNG ADULTS. THIS REVIEW DESCRIBES EPIGENETIC MODIFICATIONS AND INFLAMMATORY PROCESSES UNDERLYING CARDIOMETABOLIC DISEASES, AND FURTHER DISCUSSES ADVANCES IN THE RESEARCH FIELD WITH A FOCUS ON SPECIFIC POINTS FOR INTERVENTIONAL THERAPY. 2023 12 1505 35 DNA METHYLATION AND HISTONE MODIFICATION IN HYPERTENSION. SYSTEMIC HYPERTENSION, WHICH EVENTUALLY RESULTS IN HEART FAILURE, RENAL FAILURE OR STROKE, IS A COMMON CHRONIC HUMAN DISORDER THAT PARTICULARLY AFFECTS ELDERS. ALTHOUGH MANY SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF HYPERTENSION HAVE BEEN REPORTED OVER THE PAST DECADES, WHICH HAS LED TO THE IMPLEMENTATION OF A WIDE VARIETY OF ANTI-HYPERTENSIVE THERAPIES, ONE HALF OF ALL HYPERTENSIVE PATIENTS STILL DO NOT HAVE THEIR BLOOD PRESSURE CONTROLLED. THE FRONTIER IN UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING HYPERTENSION HAS NOW ADVANCED TO THE LEVEL OF EPIGENOMICS. PARTICULARLY, INCREASING EVIDENCE IS EMERGING THAT DNA METHYLATION AND HISTONE MODIFICATIONS PLAY AN IMPORTANT ROLE IN GENE REGULATION AND ARE INVOLVED IN ALTERATION OF THE PHENOTYPE AND FUNCTION OF VASCULAR CELLS IN RESPONSE TO ENVIRONMENTAL STRESSES. THIS REVIEW SEEKS TO HIGHLIGHT THE RECENT ADVANCES IN OUR KNOWLEDGE OF THE EPIGENETIC REGULATIONS AND MECHANISMS OF HYPERTENSION, FOCUSING ON THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATION IN THE VASCULAR WALL. A BETTER UNDERSTANDING OF THE EPIGENOMIC REGULATION IN THE HYPERTENSIVE VESSEL MAY LEAD TO THE IDENTIFICATION OF NOVEL TARGET MOLECULES THAT, IN TURN, MAY LEAD TO NOVEL DRUG DISCOVERIES FOR THE TREATMENT OF HYPERTENSION. 2018 13 3748 47 INSIGHTS INTO THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING IN DIABETES MELLITUS. BACKGROUND: DIABETES MELLITUS IS A METABOLIC DISORDER THAT IS CHARACTERIZED BY IMPAIRED GLUCOSE TOLERANCE RESULTING FROM DEFECTS IN INSULIN SECRETION, INSULIN ACTION, OR BOTH. EPIGENETIC MODIFICATIONS, WHICH ARE DEFINED AS INHERITED CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN GENE SEQUENCE, ARE INVOLVED IN THE ETIOLOGY OF DIABETES. METHODS: IN THIS REVIEW, WE FOCUSED ON THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING AND THEIR CONTRIBUTION TO THE DEVELOPMENT OF BOTH TYPE 1 AND TYPE 2 DIABETES MELLITUS. RESULTS: CHANGES IN DNA METHYLATION IN PARTICULAR ARE HIGHLY ASSOCIATED WITH THE DEVELOPMENT OF DIABETES. PROTEIN FUNCTION IS DEPENDENT ON THEIR PROPER FOLDING IN THE ENDOPLASMIC RETICULUM. DEFECTIVE PROTEIN FOLDING AND CONSEQUENTLY THEIR FUNCTIONS HAVE ALSO BEEN REPORTED TO PLAY A ROLE. EARLY TREATMENT OF DIABETES HAS PROVEN TO BE OF GREAT BENEFIT, AS EVEN TRANSIENT HYPERGLYCEMIA MAY LEAD TO PATHOLOGICAL EFFECTS AND COMPLICATIONS LATER ON. THIS HAS BEEN EXPLAINED BY THE THEORY OF THE DEVELOPMENT OF A METABOLIC MEMORY IN DIABETES. THE BASIS FOR THIS METABOLIC MEMORY WAS ATTRIBUTED TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, NON-ENZYMATIC GLYCATION OF PROTEINS AND IMPORTANTLY, EPIGENETIC CHANGES. THIS HIGHLIGHTS THE IMPORTANCE OF LINKING NEW THERAPEUTICS TARGETING EPIGENETIC MECHANISMS WITH TRADITIONAL ANTIDIABETIC DRUGS. CONCLUSION: ALTHOUGH NEW DATA IS EVOLVING ON THE RELATION BETWEEN DNA METHYLATION, PROTEIN MISFOLDING, AND THE ETIOLOGY OF DIABETES, MORE STUDIES ARE REQUIRED FOR DEVELOPING NEW RELEVANT DIAGNOSTICS AND THERAPEUTICS. 2019 14 2562 27 EPIGENETICS IN THE PRIMARY AND SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE: INFLUENCE OF EXERCISE AND NUTRITION. INCREASING EVIDENCE LINKS CHANGES IN EPIGENETIC SYSTEMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA EXPRESSION, TO THE OCCURRENCE OF CARDIOVASCULAR DISEASE (CVD). THESE EPIGENETIC MODIFICATIONS CAN CHANGE GENETIC FUNCTION UNDER INFLUENCE OF EXOGENOUS STIMULI AND CAN BE TRANSFERRED TO NEXT GENERATIONS, PROVIDING A POTENTIAL MECHANISM FOR INHERITANCE OF BEHAVIOURAL INTERVENTION EFFECTS. THE BENEFITS OF EXERCISE AND NUTRITIONAL INTERVENTIONS IN THE PRIMARY AND SECONDARY PREVENTION OF CVD ARE WELL ESTABLISHED, BUT THE MECHANISMS ARE NOT COMPLETELY UNDERSTOOD. IN THIS REVIEW, WE DESCRIBE THE ACUTE AND CHRONIC EPIGENETIC EFFECTS OF PHYSICAL ACTIVITY AND DIETARY CHANGES. WE PROPOSE EXERCISE AND NUTRITION AS POTENTIAL TRIGGERS OF EPIGENETIC SIGNALS, PROMOTING THE RESHAPING OF TRANSCRIPTIONAL PROGRAMMES WITH EFFECTS ON CVD PHENOTYPES. FINALLY, WE HIGHLIGHT RECENT DEVELOPMENTS IN EPIGENETIC THERAPEUTICS WITH IMPLICATIONS FOR PRIMARY AND SECONDARY CVD PREVENTION. 2022 15 4273 37 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 16 2062 28 EPIGENETIC CONTROL OF HYPERTENSION BY DNA METHYLATION: A REAL POSSIBILITY. HYPERTENSION IS A COMMON CHRONIC DISEASE THAT PARTICULARLY AFFECTS THE ELDERLY AND CAN TRIGGER SEVERAL CARDIOVASCULAR CONDITIONS. ALTHOUGH THE TREATMENT OF HYPERTENSION HAS EVOLVED IN RECENT DECADES, MANY HYPERTENSIVE PATIENTS STILL DO NOT HAVE PROPERLY CONTROLLED BLOOD PRESSURE. ACCUMULATING EVIDENCE SUPPORTS THE HYPOTHESIS THAT DNA METHYLATION PLAYS AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION, ALTERING THE PHENOTYPE AND FUNCTION OF THE CARDIOVASCULAR SYSTEM. THE PRESENT REVIEW HIGHLIGHTS RECENT ADVANCES IN RESEARCH ON DNA METHYLATION IN THE DEVELOPMENT OF HYPERTENSION. SEVERAL PRECLINICAL AND CLINICAL EVIDENCE SHOW THAT METHYLATION OF DIFFERENT TARGETS APPEARS TO BE INVOLVED IN HYPERTENSION. STUDIES OF THE INVOLVEMENT OF DNA METHYLATION HAVE GREATLY IMPROVED OUR UNDERSTANDING OF HYPERTENSION, BUT ITS USE AS A VALID THERAPEUTIC TARGET IS STILL UNKNOWN. FURTHER STUDIES COULD HELP TO BRING TO LIGHT THE TRUTH ABOUT GENE THERAPY IN HYPERTENSION. 2021 17 6067 40 THE DIABETES MELLITUS-ATHEROSCLEROSIS CONNECTION: THE ROLE OF LIPID AND GLUCOSE METABOLISM AND CHRONIC INFLAMMATION. DIABETES MELLITUS COMPRISES A GROUP OF CARBOHYDRATE METABOLISM DISORDERS THAT SHARE A COMMON MAIN FEATURE OF CHRONIC HYPERGLYCEMIA THAT RESULTS FROM DEFECTS OF INSULIN SECRETION, INSULIN ACTION, OR BOTH. INSULIN IS AN IMPORTANT ANABOLIC HORMONE, AND ITS DEFICIENCY LEADS TO VARIOUS METABOLIC ABNORMALITIES IN PROTEINS, LIPIDS, AND CARBOHYDRATES. ATHEROSCLEROSIS DEVELOPS AS A RESULT OF A MULTISTEP PROCESS ULTIMATELY LEADING TO CARDIOVASCULAR DISEASE ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. ALTERATION OF LIPID METABOLISM IS A RISK FACTOR AND CHARACTERISTIC FEATURE OF ATHEROSCLEROSIS. POSSIBLE LINKS BETWEEN THE TWO CHRONIC DISORDERS DEPENDING ON ALTERED METABOLIC PATHWAYS HAVE BEEN INVESTIGATED IN NUMEROUS STUDIES. IT WAS SHOWN THAT BOTH TYPES OF DIABETES MELLITUS CAN ACTUALLY INDUCE ATHEROSCLEROSIS DEVELOPMENT OR FURTHER ACCELERATE ITS PROGRESSION. ELEVATED GLUCOSE LEVEL, DYSLIPIDEMIA, AND OTHER METABOLIC ALTERATIONS THAT ACCOMPANY THE DISEASE DEVELOPMENT ARE TIGHTLY INVOLVED IN THE PATHOGENESIS OF ATHEROSCLEROSIS AT ALMOST EVERY STEP OF THE ATHEROGENIC PROCESS. CHRONIC INFLAMMATION IS CURRENTLY CONSIDERED AS ONE OF THE KEY FACTORS IN ATHEROSCLEROSIS DEVELOPMENT AND IS PRESENT STARTING FROM THE EARLIEST STAGES OF THE PATHOLOGY INITIATION. IT MAY ALSO BE REGARDED AS ONE OF THE POSSIBLE LINKS BETWEEN ATHEROSCLEROSIS AND DIABETES MELLITUS. HOWEVER, THE DATA AVAILABLE SO FAR DO NOT ALLOW FOR DEVELOPING EFFECTIVE ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES THAT WOULD STOP ATHEROSCLEROTIC LESION PROGRESSION OR INDUCE LESION REDUCTION. IN THIS REVIEW, WE SUMMARIZE THE MAIN ASPECTS OF DIABETES MELLITUS THAT POSSIBLY AFFECT THE ATHEROGENIC PROCESS AND ITS RELATIONSHIP WITH CHRONIC INFLAMMATION. WE ALSO DISCUSS THE ESTABLISHED PATHOPHYSIOLOGICAL FEATURES THAT LINK ATHEROSCLEROSIS AND DIABETES MELLITUS, SUCH AS OXIDATIVE STRESS, ALTERED PROTEIN KINASE SIGNALING, AND THE ROLE OF CERTAIN MIRNA AND EPIGENETIC MODIFICATIONS. 2020 18 5821 39 STRESS IN OBESITY AND ASSOCIATED METABOLIC AND CARDIOVASCULAR DISORDERS. OBESITY HAS SIGNIFICANT IMPLICATIONS FOR HEALTHCARE, SINCE IT IS A MAJOR RISK FACTOR FOR BOTH TYPE 2 DIABETES AND THE METABOLIC SYNDROME. THIS SYNDROME IS A COMMON AND COMPLEX DISORDER COMBINING OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND INSULIN RESISTANCE. IT IS ASSOCIATED WITH HIGH ATHEROSCLEROTIC CARDIOVASCULAR RISK, WHICH CAN ONLY PARTIALLY BE EXPLAINED BY ITS COMPONENTS. THEREFORE, TO EXPLAIN HOW OBESITY CONTRIBUTES TO THE DEVELOPMENT OF METABOLIC AND CARDIOVASCULAR DISORDERS, MORE AND BETTER INSIGHT IS REQUIRED INTO THE EFFECTS OF PERSONAL AND ENVIRONMENTAL STRESS ON DISEASE PROCESSES. IN THIS PAPER, WE SHOW THAT OBESITY IS A CHRONIC INFLAMMATORY DISEASE, WHICH HAS MANY MOLECULAR MECHANISMS IN COMMON WITH ATHEROSCLEROSIS. FURTHERMORE, WE FOCUS ON THE ROLE OF OXIDATIVE STRESS ASSOCIATED WITH OBESITY IN THE DEVELOPMENT OF THE METABOLIC SYNDROME. WE DISCUSS HOW SEVERAL STRESS CONDITIONS ARE RELATED TO INFLAMMATION AND OXIDATIVE STRESS IN ASSOCIATION WITH OBESITY AND ITS COMPLICATIONS. WE ALSO EMPHASIZE THE RELATION BETWEEN STRESS CONDITIONS AND THE DEREGULATION OF EPIGENETIC CONTROL MECHANISMS BY MEANS OF MICRORNAS AND SHOW HOW THIS IMPAIRMENT FURTHER CONTRIBUTES TO THE DEVELOPMENT OF OBESITY, CLOSING THE VICIOUS CIRCLE. FINALLY, WE DISCUSS THE LIMITATIONS OF CURRENT ANTI-INFLAMMATION AND ANTIOXIDANT THERAPY TO TREAT OBESITY. 2012 19 607 35 BEYOND GENETICS: EPIGENETIC CODE IN CHRONIC KIDNEY DISEASE. EPIGENETICS REFERS TO A HERITABLE CHANGE IN THE PATTERN OF GENE EXPRESSION THAT IS MEDIATED BY A MECHANISM SPECIFICALLY NOT DUE TO ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. WELL-KNOWN EPIGENETIC MECHANISMS ENCOMPASS DNA METHYLATION, CHROMATIN REMODELING (HISTONE MODIFICATIONS), AND RNA INTERFERENCE. FUNCTIONALLY, EPIGENETICS PROVIDES AN EXTRA LAYER OF TRANSCRIPTIONAL CONTROL AND PLAYS A CRUCIAL ROLE IN NORMAL PHYSIOLOGICAL DEVELOPMENT, AS WELL AS IN PATHOLOGICAL CONDITIONS. ABERRANT DNA METHYLATION IS IMPLICATED IN IMMUNE DYSFUNCTION, INFLAMMATION, AND INSULIN RESISTANCE. EPIGENETIC CHANGES MAY BE RESPONSIBLE FOR 'METABOLIC MEMORY' AND DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES. MICRORNAS ARE CRITICAL IN THE MAINTENANCE OF GLOMERULAR HOMEOSTASIS AND HENCE RNA INTERFERENCE MAY BE IMPORTANT IN THE PROGRESSION OF RENAL DISEASE. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS ORCHESTRATE THE EPITHELIAL-MESENCHYMAL TRANSITION AND EVENTUALLY FIBROSIS OF THE RENAL TISSUE. OXIDATIVE STRESS, INFLAMMATION, HYPERHOMOCYSTEINEMIA, AND UREMIC TOXINS COULD INDUCE EPIMUTATIONS IN CHRONIC KIDNEY DISEASE. EPIGENETIC ALTERATIONS ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. REVERSIBLE NATURE OF THE EPIGENETIC CHANGES GIVES A UNIQUE OPPORTUNITY TO HALT OR EVEN REVERSE THE DISEASE PROCESS THROUGH TARGETED THERAPEUTIC STRATEGIES. 2011 20 2570 29 EPIGENETICS OF CHRONIC INFLAMMATORY DISEASES. CHRONIC, NONCOMMUNICABLE, AND INFLAMMATION-ASSOCIATED DISEASES REMAIN THE LARGEST CAUSE OF MORBIDITY AND MORTALITY GLOBALLY AND WITHIN THE UNITED STATES. THIS IS MAINLY DUE TO OUR LIMITED UNDERSTANDING OF THE MOLECULAR MECHANISMS THAT UNDERLIE THESE COMPLEX PATHOLOGIES. THE AVAILABLE EVIDENCE INDICATES THAT STUDIES OF EPIGENETICS (TRADITIONALLY DEFINED AS THE HERITABLE CHANGES TO GENE EXPRESSION THAT ARE INDEPENDENT OF CHANGES TO DNA) ARE SIGNIFICANTLY ADVANCING OUR KNOWLEDGE OF THESE INFLAMMATORY CONDITIONS. THIS REVIEW WILL FOCUS ON EPIGENETIC STUDIES OF THREE DISEASES, THAT ARE AMONG THE MOST BURDENSOME GLOBALLY: CARDIOVASCULAR DISEASE, THE NUMBER ONE CAUSE OF DEATHS WORLDWIDE, TYPE 2 DIABETES AND, ALZHEIMER'S DISEASE. THE CURRENT STATUS OF EPIGENETIC RESEARCH, INCLUDING THE ABILITY TO PREDICT DISEASE RISK, AND KEY PATHOPHYSIOLOGICAL DEFECTS ARE DISCUSSED. THE SIGNIFICANCE OF DEFINING THE CONTRIBUTION OF EPIGENETIC DEFECTS TO NONRESOLVING INFLAMMATION AND AGING, EACH ASSOCIATED WITH THESE DISEASES, IS HIGHLIGHTED, AS THESE ARE LIKELY TO PROVIDE NEW INSIGHTS INTO INFLAMMATORY DISEASE PATHOGENESIS. 2019