1 2491 95 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 2 2163 32 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 3 2190 41 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 4 2613 43 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 5 6377 34 THE ROLE OF NON-CODING RNAS IN DIABETIC NEPHROPATHY: POTENTIAL APPLICATIONS AS BIOMARKERS FOR DISEASE DEVELOPMENT AND PROGRESSION. DIABETIC NEPHROPATHY, A PROGRESSIVE KIDNEY DISEASE THAT DEVELOPS SECONDARY TO DIABETES, IS THE MAJOR CAUSE OF CHRONIC KIDNEY DISEASE IN DEVELOPED COUNTRIES, AND CONTRIBUTES SIGNIFICANTLY TO INCREASED MORBIDITY AND MORTALITY AMONG INDIVIDUALS WITH DIABETES. ALTHOUGH THE CAUSES OF DIABETIC NEPHROPATHY ARE NOT FULLY UNDERSTOOD, RECENT STUDIES DEMONSTRATE A ROLE FOR EPIGENETIC FACTORS IN THE DEVELOPMENT OF THE DISEASE. FOR EXAMPLE, NON-CODING RNA (NCRNA) MOLECULES, INCLUDING MICRORNAS (MIRNAS), HAVE BEEN SHOWN TO BE FUNCTIONALLY IMPORTANT IN MODULATING RENAL RESPONSE TO HYPERGLYCEMIA AND PROGRESSION OF DIABETIC NEPHROPATHY. CHARACTERIZATION OF MIRNA EXPRESSION IN DIABETIC NEPHROPATHY FROM STUDIES OF ANIMAL MODELS OF DIABETES, AND IN VITRO INVESTIGATIONS USING DIFFERENT TYPES OF KIDNEY CELLS ALSO SUPPORT THIS ROLE. THE GOAL OF THIS REVIEW, THEREFORE, IS TO SUMMARIZE THE CURRENT STATE OF KNOWLEDGE OF SPECIFIC NCRNAS INVOLVED IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, WITH A FOCUS ON THE POTENTIAL ROLE OF MIRNAS TO SERVE AS SENSITIVE, NON-INVASIVE BIOMARKERS OF KIDNEY DISEASE AND PROGRESSION. NON-CODING RNAS ARE CURRENTLY RECOGNIZED AS POTENTIALLY IMPORTANT REGULATORS OF GENES INVOLVED IN PROCESSES RELATED TO THE DEVELOPMENT OF DIABETIC NEPHROPATHY, AND AS SUCH, REPRESENT VIABLE TARGETS FOR BOTH CLINICAL DIAGNOSTIC STRATEGIES AND THERAPEUTIC INTERVENTION. 2013 6 6204 30 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 7 2154 36 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 8 6067 37 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 9 1871 35 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 1505 28 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 11 607 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 12 6341 38 THE ROLE OF EPIGENETIC MODIFICATIONS IN LATE COMPLICATIONS IN TYPE 1 DIABETES. TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE IN WHICH THE DESTRUCTION OF PANCREATIC BETA CELLS LEADS TO HYPERGLYCEMIA. THE PREVENTION OF HYPERGLYCEMIA IS VERY IMPORTANT TO AVOID OR AT LEAST POSTPONE THE DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS, ALSO KNOWN AS LATE COMPLICATIONS. THESE INCLUDE DIABETIC RETINOPATHY, CHRONIC RENAL FAILURE, DIABETIC NEUROPATHY, AND CARDIOVASCULAR DISEASES. THE IMPACT OF LONG-TERM HYPERGLYCEMIA HAS BEEN SHOWN TO PERSIST LONG AFTER THE NORMALIZATION OF BLOOD GLUCOSE LEVELS, A PHENOMENON KNOWN AS METABOLIC MEMORY. IT IS BELIEVED THAT EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, PLAY AN IMPORTANT ROLE IN METABOLIC MEMORY. THE AIM OF THIS REVIEW IS TO ADDRESS THE IMPACT OF LONG-TERM HYPERGLYCEMIA ON EPIGENETIC MARKS IN LATE COMPLICATIONS OF TYPE 1 DIABETES. 2022 13 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 14 2333 30 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 15 2195 30 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 16 5376 34 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 17 2208 40 EPIGENETIC MODIFICATIONS AND NON-CODING RNA IN DIABETES-MELLITUS-INDUCED CORONARY ARTERY DISEASE: PATHOPHYSIOLOGICAL LINK AND NEW THERAPEUTIC FRONTIERS. DIABETES MELLITUS (DM) IS A GLUCOSE METABOLISM DISORDER CHARACTERIZED BY CHRONIC HYPERGLYCEMIA RESULTING FROM A DEFICIT OF INSULIN PRODUCTION AND/OR ACTION. DM AFFECTS MORE THAN 1 IN 10 ADULTS, AND IT IS ASSOCIATED WITH AN INCREASED RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. CARDIOVASCULAR DISEASE (CVD) ACCOUNTS FOR TWO THIRDS OF THE OVERALL DEATHS IN DIABETIC PATIENTS, WITH CORONARY ARTERY DISEASE (CAD) AND ISCHEMIC CARDIOMYOPATHY AS THE MAIN CONTRIBUTORS. HYPERGLYCEMIC DAMAGE ON VASCULAR ENDOTHELIAL CELLS LEADING TO ENDOTHELIAL DYSFUNCTION REPRESENTS THE MAIN INITIATING FACTOR IN THE PATHOGENESIS OF DIABETIC VASCULAR COMPLICATIONS; HOWEVER, THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS ARE STILL NOT ENTIRELY UNDERSTOOD. THIS REVIEW ADDRESSES THE CURRENT KNOWLEDGE ON THE PATHOPHYSIOLOGICAL LINKS BETWEEN DM AND CAD WITH A FOCUS ON THE ROLE OF EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND NONCODING RNA CONTROL. INCREASED KNOWLEDGE OF EPIGENETIC MECHANISMS HAS CONTRIBUTED TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL TREATMENTS ("EPIDRUGS") WITH EPIGENETIC TARGETS, ALTHOUGH THESE APPROACHES PRESENT SEVERAL CHALLENGES. SPECIFIC EPIGENETIC BIOMARKERS MAY ALSO BE USED TO PREDICT OR DETECT THE DEVELOPMENT AND PROGRESSION OF DIABETES COMPLICATIONS. FURTHER STUDIES ON DIABETES AND CAD EPIGENETICS ARE NEEDED IN ORDER TO IDENTIFY POSSIBLE NEW THERAPEUTIC TARGETS AND ADVANCE PERSONALIZED MEDICINE WITH THE PREDICTION OF INDIVIDUAL DRUG RESPONSES AND MINIMIZATION OF ADVERSE EFFECTS. 2022 18 5364 30 RECENT ADVANCES IN EPIGENETICS OF AGE-RELATED KIDNEY DISEASES. RENAL AGING HAS ATTRACTED INCREASING ATTENTION IN TODAY'S AGING SOCIETY, AS ELDERLY PEOPLE WITH ADVANCED AGE ARE MORE SUSCEPTIBLE TO VARIOUS KIDNEY DISORDERS SUCH AS ACUTE KIDNEY INJURY (AKI) AND CHRONIC KIDNEY DISEASE (CKD). THERE IS NO CLEAR-CUT UNIVERSAL MECHANISM FOR IDENTIFYING AGE-RELATED KIDNEY DISEASES, AND THEREFORE, THEY POSE A CONSIDERABLE MEDICAL AND PUBLIC HEALTH CHALLENGE. EPIGENETICS REFERS TO THE STUDY OF HERITABLE MODIFICATIONS IN THE REGULATION OF GENE EXPRESSION THAT DO NOT REQUIRE CHANGES IN THE UNDERLYING GENOMIC DNA SEQUENCE. A VARIETY OF EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASES (HDAC) INHIBITORS AND DNA METHYLTRANSFERASE (DNMT) INHIBITORS HAVE BEEN PROPOSED AS POTENTIAL BIOMARKERS AND THERAPEUTIC TARGETS IN NUMEROUS FIELDS INCLUDING CARDIOVASCULAR DISEASES, IMMUNE SYSTEM DISEASE, NERVOUS SYSTEM DISEASES, AND NEOPLASMS. ACCUMULATING EVIDENCE IN RECENT YEARS INDICATES THAT EPIGENETIC MODIFICATIONS HAVE BEEN IMPLICATED IN RENAL AGING. HOWEVER, NO PREVIOUS SYSTEMATIC REVIEW HAS BEEN PERFORMED TO SYSTEMATICALLY GENERALIZE THE RELATIONSHIP BETWEEN EPIGENETICS AND AGE-RELATED KIDNEY DISEASES. IN THIS REVIEW, WE AIM TO SUMMARIZE THE RECENT ADVANCES IN EPIGENETIC MECHANISMS OF AGE-RELATED KIDNEY DISEASES AS WELL AS DISCUSS THE APPLICATION OF EPIGENETIC MODIFIERS AS POTENTIAL BIOMARKERS AND THERAPEUTIC TARGETS IN THE FIELD OF AGE-RELATED KIDNEY DISEASES. IN SUMMARY, THE MAIN TYPES OF EPIGENETIC PROCESSES INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA (NCRNA) MODULATION HAVE ALL BEEN IMPLICATED IN THE PROGRESSION OF AGE-RELATED KIDNEY DISEASES, AND THERAPEUTIC TARGETING OF THESE PROCESSES WILL YIELD NOVEL THERAPEUTIC STRATEGIES FOR THE PREVENTION AND/OR TREATMENT OF AGE-RELATED KIDNEY DISEASES. 2022 19 3834 30 INVOLVEMENTS OF LONG NONCODING RNAS IN OBESITY-ASSOCIATED INFLAMMATORY DISEASES. OBESITY IS ASSOCIATED WITH CHRONIC LOW-GRADE INFLAMMATION THAT AFFECTS THE PHENOTYPE OF MULTIPLE TISSUES AND THEREFORE IS IMPLICATED IN THE DEVELOPMENT AND PROGRESSION OF SEVERAL AGE-RELATED CHRONIC INFLAMMATORY DISORDERS. IMPORTANTLY, A NEW FAMILY OF NONCODING RNAS, TERMED LONG NONCODING RNAS (LNCRNAS), HAVE BEEN IDENTIFIED AS KEY REGULATORS OF INFLAMMATORY SIGNALLING PATHWAYS THAT CAN MEDIATE BOTH PRETRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL GENE REGULATION. FURTHERMORE, SEVERAL LNCRNAS HAVE BEEN IDENTIFIED, WHICH ARE DIFFERENTIALLY EXPRESSED IN MULTIPLE TISSUE TYPES IN INDIVIDUALS WHO ARE OBESE OR IN PRECLINICAL MODELS OF OBESITY. IN THIS REVIEW, WE EXAMINE THE EVIDENCE FOR THE ROLE OF SEVERAL OF THE MOST WELL-STUDIED LNCRNAS IN THE REGULATION OF INFLAMMATORY PATHWAYS ASSOCIATED WITH OBESITY. WE HIGHLIGHT THE EVIDENCE FOR THEIR DIFFERENTIAL EXPRESSION IN THE OBESE STATE AND IN AGE-RELATED CONDITIONS INCLUDING INSULIN RESISTANCE, TYPE 2 DIABETES (T2D), SARCOPENIA, OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS, WHERE OBESITY PLAYS A SIGNIFICANT ROLE. DETERMINING THE EXPRESSION AND FUNCTIONAL ROLE OF LNCRNAS IN MEDIATING OBESITY-ASSOCIATED CHRONIC INFLAMMATION WILL ADVANCE OUR UNDERSTANDING OF THE EPIGENETIC REGULATORY PATHWAYS THAT UNDERLIE AGE-RELATED INFLAMMATORY DISEASES AND MAY ALSO ULTIMATELY IDENTIFY NEW TARGETS FOR THERAPEUTIC INTERVENTION. 2021 20 2168 31 EPIGENETIC MECHANISMS IN MONOCYTES/MACROPHAGES REGULATE INFLAMMATION IN CARDIOMETABOLIC AND VASCULAR DISEASE. CARDIOMETABOLIC AND VASCULAR DISEASE, WITH THEIR ASSOCIATED SECONDARY COMPLICATIONS, ARE THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN WESTERN SOCIETY. CHRONIC INFLAMMATION IS A COMMON THEME THAT UNDERLIES INITIATION AND PROGRESSION OF CARDIOVASCULAR DISEASE. IN THIS REGARD, MONOCYTES/MACROPHAGES ARE KEY PLAYERS IN THE DEVELOPMENT OF A CHRONIC INFLAMMATORY STATE. OVER THE PAST DECADE, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND POSTTRANSLATIONAL HISTONE PROCESSING, HAVE EMERGED AS IMPORTANT REGULATORS OF IMMUNE CELL PHENOTYPES. ACCUMULATING STUDIES REVEAL THE IMPORTANCE OF EPIGENETIC ENZYMES IN THE DYNAMIC REGULATION OF KEY SIGNALING PATHWAYS THAT ALTER MONOCYTE/MACROPHAGE PHENOTYPES IN RESPONSE TO ENVIRONMENTAL STIMULI. IN THIS REVIEW, WE HIGHLIGHT THE CURRENT PARADIGMS OF MONOCYTE/MACROPHAGE POLARIZATION AND THE EMERGING ROLE OF EPIGENETIC MODIFICATION IN THE REGULATION OF MONOCYTE/MACROPHAGE PHENOTYPE IN OBESITY, DIABETES MELLITUS, ATHEROSCLEROSIS, AND ABDOMINAL AORTIC ANEURYSMS. 2019