1 630 76 BIOLOGICAL AND MECHANICAL FACTORS AND EPIGENETIC REGULATION INVOLVED IN TENDON HEALING. TENDONS ARE AN IMPORTANT PART OF THE MUSCULOSKELETAL SYSTEM. CONNECTING MUSCLES TO BONES, TENDONS CONVERT FORCE INTO MOVEMENT. TENDON INJURY CAN BE ACUTE OR CHRONIC. NOTICEABLY, TENDON HEALING REQUIRES A LONG TIME SPAN AND INCLUDES INFLAMMATION, PROLIFERATION, AND REMODELING PROCESSES. THE MISMATCH BETWEEN ENDOGENOUS AND EXOGENOUS HEALING MAY LEAD TO ADHESION CAUSING FURTHER NEGATIVE EFFECTS. MANAGEMENT OF TENDON INJURIES AND COMPLICATIONS SUCH AS SUBSEQUENT ADHESION FORMATION ARE STILL CHALLENGES FOR CLINICIANS. DUE TO NUMEROUS FACTORS, TENDON HEALING IS A COMPLEX PROCESS. THIS REVIEW INTRODUCES THE ROLE OF VARIOUS BIOLOGICAL AND MECHANICAL FACTORS AND EPIGENETIC REGULATION PROCESSES INVOLVED IN TENDON HEALING. 2023 2 2381 24 EPIGENETIC REGULATION OF WOUND HEALING AND FIBROSIS. PURPOSE OF REVIEW: WOUND HEALING IS A NORMAL PHYSIOLOGICAL RESPONSE TO TISSUE INJURY WHICH CAN OCCUR IN ANY ORGAN. MECHANISMS THAT ORCHESTRATE WOUND HEALING IN DIFFERENT ORGANS ARE SURPRISINGLY GENERIC, INVOLVING GENERATION OF FIBROBLASTS AND MYOFIBROBLASTS BY DIFFERENTIATION PROCESSES THAT REQUIRE EXTENSIVE ALTERATIONS IN GENE EXPRESSION. THIS PROCESS AND INDEED PHENOTYPE OF CELLS ARE ORCHESTRATED BY THE COMBINED INFLUENCES OF MOLECULAR COMPONENTS OF EPIGENOME INCLUDING DNA METHYLATION, VAST ARRAY OF POSTTRANSLATIONAL MODIFICATIONS OF THE HISTONE PROTEIN CONSTITUENTS OF CHROMATIN AND REGULATORY NONCODING RNAS OF WHICH MICRORNAS (MIRS) ARE THE MOST EXTENSIVELY STUDIED. RECENT FINDINGS: NUMEROUS STUDIES FROM THE LAST 12 MONTHS SHOW ALL THE THREE EPIGENETIC MECHANISMS TO BE REGULATING GENERATION AND APOPTOSIS OF MYOFIBROBLASTS IN ORGANS AFFECTED BY PERTURBED WOUND HEALING. FURTHERMORE, THESE MECHANISMS ARE INVOLVED IN FIBROTIC DISEASE ITSELF, WITH SOME MIRS AND EPIGENETIC DRUGS BEING TESTED FOR THEIR THERAPEUTIC POTENTIAL. SUMMARY: FIELDS OF WOUND HEALING AND FIBROSIS WILL BE ENRICHED OVER THE NEXT DECADE BY PLETHORA OF NEW INFORMATION REGARDING EPIGENETIC CONTROL MECHANISMS WHICH WILL HOPEFULLY PROVIDE NEW ADVANCES IN DIAGNOSTICS AND PROGNOSTICS. WITH THE DESIGN OF EVER MORE SPECIFIC EPIGENETIC DRUGS, WE MAY IMPROVE OUR ABILITY TO THERAPEUTICALLY OPTIMIZE WOUND HEALING AND PREVENT FIBROSIS IN CHRONIC DISEASE AND AGEING. 2013 3 2694 28 EVOLVING SPECTRUM OF DIABETIC WOUND: MECHANISTIC INSIGHTS AND THERAPEUTIC TARGETS. DIABETES MELLITUS IS A CHRONIC METABOLIC DISORDER RESULTING IN AN INCREASED BLOOD GLUCOSE LEVEL AND PROLONGED HYPERGLYCEMIA, CAUSES LONG TERM HEALTH CONSE-QUENCES. CHRONIC WOUND IS FREQUENTLY OCCURRING IN DIABETES PATIENTS DUE TO COMPROMISED WOUND HEALING CAPABILITY. MANAGEMENT OF WOUNDS IN DIABETIC PATIENTS REMAINS A CLINICAL CHALLENGE DESPITE MANY ADVANCEMENTS IN THE FIELD OF SCIENCE AND TECHNOLOGY. INCREASING EVIDENCE INDICATES THAT ALTERATION OF THE BIOCHEMICAL MILIEU RESULTING FROM ALTERATION IN INFLAMMATORY CYTOKINES AND MATRIX METALLOPROTEINASE, DECREASE IN FIBROBLAST AND KERATINOCYTE FUNCTIONING, NEUROPATHY, ALTERED LEUKOCYTE FUNCTIONING, INFECTION, ETC., PLAYS A SIGNIFICANT ROLE IN IMPAIRED WOUND HEALING IN DIABETIC PEOPLE. APART FROM THE CURRENT PHARMACOTHERAPY, DIFFERENT OTHER APPROACHES LIKE THE USE OF CONVENTIONAL DRUGS, ANTIDIABETIC MEDICATION, ANTIBIOTICS, DEBRIDEMENT, OFFLOADING, PLATELET-RICH PLASMA, GROWTH FACTOR, OXYGEN THERAPY, NEGATIVE PRESSURE WOUND THERAPY, LOW-LEVEL LASER, EXTRACORPOREAL SHOCK WAVE BIOENGINEERED SUBSTITUTE CAN BE CONSIDERED IN THE MANAGEMENT OF DIABETIC WOUNDS. DRUGS/THERAPEUTIC STRATEGY THAT INDUCE ANGIOGENESIS AND COLLAGEN SYNTHESIS, INHIBITION OF MMPS, REDUCTION OF OXIDATIVE STRESS, CONTROLLING HYPERGLYCEMIA, INCREASE GROWTH FACTORS, REGULATE INFLAMMATORY CYTOKINES, CAUSE NO INDUCTION, INDUCE FIBROBLAST AND KERATINOCYTE PROLIFERATION, CONTROL MICROBIAL INFECTIONS ARE CONSIDERED IMPORTANT IN CONTROLLING DIABETIC WOUND. FURTHER, MEDICINAL PLANTS AND/OR PHYTOCONSTITUENTS ALSO OFFER A VIABLE ALTERNATIVE IN THE TREATMENT OF DIABETIC WOUND. THE FOCUS OF THE PRESENT REVIEW IS TO HIGHLIGHT THE MOLECULAR AND CELLULAR MECHANISMS, AND DISCUSS THE DRUG TARGETS AND TREATMENT STRATEGIES INVOLVED IN THE DIABETIC WOUND. 2022 4 2248 23 EPIGENETIC MODULATION OF MACROPHAGE POLARIZATION- PERSPECTIVES IN DIABETIC WOUNDS. DIABETES IS A CHRONIC METABOLIC DISORDER THAT POSES A GLOBAL BURDEN TO HEALTHCARE. INCREASING INCIDENCE OF DIABETES-RELATED COMPLICATIONS IN THE AFFECTED POPULATION INCLUDES A DELAY IN WOUND HEALING THAT OFTEN RESULTS IN NON-TRAUMATIC LIMB AMPUTATIONS. OWING TO THE INTRICACIES OF THE HEALING PROCESS AND CROSSTALK BETWEEN THE MULTITUDE OF PARTICIPATING CELLS, THE IDENTIFICATION OF HYPERGLYCAEMIA-INDUCED CHANGES AT BOTH CELLULAR AND MOLECULAR LEVELS POSES A CHALLENGE. MACROPHAGES ARE ONE OF THE KEY PARTICIPANTS IN WOUND HEALING AND CONTINUE TO EXERT FUNCTIONAL CHANGES AT THE WOUND SITE SINCE THE TIME OF INJURY. IN THE PRESENT REVIEW, WE DISCUSS THE ROLE OF THESE CELLS AND THEIR ABERRANT FUNCTIONS IN DIABETIC WOUNDS. WE HAVE EXTENSIVELY STUDIED THE PROCESS OF MACROPHAGE POLARIZATION (MP) AND ITS MODULATION THROUGH EPIGENETIC MODIFICATIONS. DATA FROM BOTH PRE-CLINICAL AND CLINICAL STUDIES ON DIABETES HAVE CO-RELATED HYPERGLYCAEMIA INDUCED CHANGES IN GENE EXPRESSION TO AN INCREASED INCIDENCE OF DIABETIC COMPLICATIONS. HYPERGLYCAEMIA AND OXIDATIVE STRESS, CREATE AN ENVIRONMENT PRONE TO CHANGES IN THE EPIGENETIC CODE, THAT IS MANIFESTED AS AN ALTERED INFLAMMATORY GENE EXPRESSION. HERE, WE HAVE ATTEMPTED TO UNDERSTAND THE DIFFERENT EPIGENETIC MODULATIONS THAT POSSIBLY CONTRIBUTE TOWARDS DYSREGULATED MP, RESULTING IN DELAYED WOUND HEALING. 2018 5 4679 27 NEW MOLECULAR TARGETS FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DEGENERATIVE JOINT DISORDER CHARACTERIZED BY DESTRUCTION OF THE ARTICULAR CARTILAGE, SUBCHONDRAL BONE ALTERATIONS AND SYNOVITIS. CURRENT TREATMENTS ARE FOCUSED ON SYMPTOMATIC RELIEF BUT THEY LACK EFFICACY TO CONTROL THE PROGRESSION OF THIS DISEASE WHICH IS A LEADING CAUSE OF DISABILITY. THEREFORE, THE DEVELOPMENT OF EFFECTIVE DISEASE-MODIFYING DRUGS IS URGENTLY NEEDED. DIFFERENT INITIATIVES ARE IN PROGRESS TO DEFINE THE MOLECULAR MECHANISMS INVOLVED IN THE INITIATION AND PROGRESSION OF OA. THESE STUDIES SUPPORT THE THERAPEUTIC POTENTIAL OF PATHWAYS RELEVANT IN JOINT METABOLISM SUCH AS WNT/BETA-CATENIN, DISCOIDIN DOMAIN RECEPTOR 2 OR PROTEINASE-ACTIVATED RECEPTOR 2. THE DYSREGULATION IN CARTILAGE CATABOLISM AND SUBCHONDRAL BONE REMODELING COULD BE IMPROVED BY SELECTIVE INHIBITORS OF MATRIX METALLOPROTEINASES, AGGRECANASES AND OTHER PROTEASES. ANOTHER APPROACH WOULD FAVOR THE ACTIVITY OF ANABOLIC PROCESSES BY USING GROWTH FACTORS OR REGULATORY MOLECULES. RECENT STUDIES HAVE ALSO REVEALED THE ROLE OF OXIDATIVE STRESS AND SYNOVITIS IN THE PROGRESSION OF THIS DISEASE, SUPPORTING THE DEVELOPMENT OF A NUMBER OF INHIBITORY STRATEGIES. NOVEL TARGETS IN OA ARE REPRESENTED BY GENES INVOLVED IN OA PATHOPHYSIOLOGY DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA APPROACHES. FURTHER INSIGHTS INTO THE MOLECULAR MECHANISMS INVOLVED IN OA INITIATION AND PROGRESSION MAY LEAD TO THE DEVELOPMENT OF NEW THERAPIES ABLE TO CONTROL JOINT DESTRUCTION AND REPAIR. 2010 6 2309 22 EPIGENETIC REGULATION OF CHONDROCYTES AND SUBCHONDRAL BONE IN OSTEOARTHRITIS. THE AIM OF THIS REVIEW IS TO PROVIDE AN UPDATED REVIEW OF THE EPIGENETIC FACTORS INVOLVED IN THE ONSET AND DEVELOPMENT OF OSTEOARTHRITIS (OA). OA IS A PREVALENT DEGENERATIVE JOINT DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION, ECTOPIC BONE FORMATION WITHIN THE JOINT, AND PHYSICAL AND PROTEOLYTIC CARTILAGE DEGRADATION WHICH RESULT IN CHRONIC PAIN AND LOSS OF MOBILITY. AT PRESENT, NO DISEASE-MODIFYING THERAPEUTICS EXIST FOR THE PREVENTION OR TREATMENT OF THE DISEASE. RESEARCH HAS IDENTIFIED SEVERAL OA RISK FACTORS INCLUDING MECHANICAL STRESSORS, PHYSICAL ACTIVITY, OBESITY, TRAUMATIC JOINT INJURY, GENETIC PREDISPOSITION, AND AGE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN IDENTIFYING EPIGENETIC FACTORS INVOLVED IN THE PATHOGENESIS OF OA. IN THIS REVIEW, WE DETAIL SEVERAL OF THESE EPIGENETIC MODIFICATIONS WITH KNOWN FUNCTIONS IN THE ONSET AND PROGRESSION OF THE DISEASE. WE ALSO REVIEW CURRENT THERAPEUTICS TARGETING ABERRANT EPIGENETIC REGULATION AS POTENTIAL OPTIONS FOR PREVENTIVE OR THERAPEUTIC TREATMENT. 2022 7 2232 21 EPIGENETIC MODIFICATIONS OF MIRNAS IN OSTEOARTHRITIS: A SYSTEMATIC REVIEW ON THEIR METHYLATION LEVELS AND EFFECTS ON CHONDROCYTES, EXTRACELLULAR MATRIX AND JOINT INFLAMMATION. OSTEOARTHRITIS (OA) IS A JOINT DISORDER CHARACTERIZED BY PROGRESSIVE DEGENERATION OF CARTILAGE EXTRACELLULAR MATRIX (ECM), CHONDROCYTE HYPERTROPHY AND APOPTOSIS AND INFLAMMATION. THE CURRENT TREATMENTS MAINLY CONCERN PAIN CONTROL AND REDUCTION OF INFLAMMATION, BUT NO THERAPEUTIC STRATEGY HAS BEEN IDENTIFIED AS A DISEASE-MODIFYING TREATMENT. THEREFORE, IDENTIFYING SPECIFIC BIOMARKERS USEFUL TO PREVENT, TREAT OR DISTINGUISH THE STAGES OF OA DISEASE HAS BECOME AN IMMEDIATE NEED OF CLINICAL PRACTICE. THE ROLE OF MICRORNAS (MIRNAS) IN OA HAS BEEN INVESTIGATED IN THE LAST DECADE, AND INCREASING EVIDENCE HAS EMERGED THAT THE INFLUENCE OF THE ENVIRONMENT ON GENE EXPRESSION THROUGH EPIGENETIC PROCESSES CONTRIBUTES TO THE DEVELOPMENT, PROGRESSION AND AGGRESSIVENESS OF OA, IN PARTICULAR ACTING ON THE MICROENVIRONMENT MODULATIONS. THE EFFECTS OF EPIGENETIC REGULATION, PARTICULARLY DIFFERENT MIRNA METHYLATION DURING OA DISEASE, WERE HIGHLIGHTED IN THE PRESENT SYSTEMATIC REVIEW. THE EVIDENCE ARISING FROM THIS STUDY OF THE LITERATURE CONDUCTED IN THREE DATABASES (PUBMED, SCOPUS, WEB OF SCIENCE) SUGGESTED THAT MIRNA METHYLATION STATE ALREADY STRONGLY IMPACTS OA PROGRESSION, DRIVING CHONDROCYTES AND SYNOVIOCYTE PROLIFERATION, APOPTOSIS, INFLAMMATION AND ECM DEPOSITION. HOWEVER, THE POSSIBILITY OF UNDERSTANDING THE MECHANISM BY WHICH DIFFERENT EPIGENETIC MODIFICATIONS OF MIRNA OR PRE-MIRNA SEQUENCES DRIVE THE AGGRESSIVENESS OF OA COULD BE THE NEW FOCUS OF FUTURE INVESTIGATIONS. 2023 8 4738 23 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 9 3640 29 INCREASED EXTRACELLULAR MATRIX PROTEIN PRODUCTION IN CHRONIC DIABETIC COMPLICATIONS: IMPLICATIONS OF NON-CODING RNAS. MANAGEMENT OF CHRONIC DIABETIC COMPLICATIONS REMAINS A MAJOR MEDICAL CHALLENGE WORLDWIDE. ONE OF THE CHARACTERISTIC FEATURES OF ALL CHRONIC DIABETIC COMPLICATIONS IS AUGMENTED PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS. SUCH ECM PROTEINS ARE DEPOSITED IN ALL TISSUES AFFECTED BY CHRONIC COMPLICATIONS, ULTIMATELY CAUSING ORGAN DAMAGE AND DYSFUNCTION. A CONTRIBUTING FACTOR TO THIS PATHOGENETIC PROCESS IS GLUCOSE-INDUCED ENDOTHELIAL DAMAGE, WHICH INVOLVES PHENOTYPIC TRANSFORMATION OF ENDOTHELIAL CELLS (ECS). THIS PHENOTYPIC TRANSITION OF ECS, FROM A QUIESCENT STATE TO AN ACTIVATED DYSFUNCTIONAL STATE, CAN BE MEDIATED THROUGH ALTERATIONS IN THE SYNTHESIS OF CELLULAR PROTEINS. IN THIS REVIEW, WE DISCUSSED THE ROLES OF NON-CODING RNAS, SPECIFICALLY MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS), IN SUCH PROCESSES. WE FURTHER OUTLINED OTHER EPIGENETIC MECHANISMS REGULATING THE BIOGENESIS AND/OR FUNCTION OF NON-CODING RNAS. OVERALL, WE BELIEVE THAT BETTER UNDERSTANDING OF SUCH MOLECULAR PROCESSES MAY LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC STRATEGIES IN THE FUTURE. 2019 10 2307 23 EPIGENETIC REGULATION OF CELLULAR FUNCTIONS IN WOUND HEALING. STRINGENT SPATIOTEMPORAL REGULATION OF THE WOUND HEALING PROCESS INVOLVING MULTIPLE CELL TYPES IS ASSOCIATED WITH EPIGENETIC MECHANISMS OF GENE REGULATION, SUCH AS DNA METHYLATION, HISTONE MODIFICATION AND CHROMATIN REMODELLING, AS WELL AS NON-CODING RNAS. HERE, WE DISCUSS THE EPIGENETIC CHANGES THAT OCCUR DURING WOUND HEALING AND THE RAPIDLY EXPANDING UNDERSTANDING OF HOW THESE MECHANISMS AFFECT HEALING RESOLUTION IN BOTH ACUTE AND CHRONIC WOUND MILIEU. WE PROVIDE A FOCUSSED OVERVIEW OF CURRENT RESEARCH INTO EPIGENETIC REGULATORS THAT CONTRIBUTE TO WOUND HEALING BY SPECIFIC CELL TYPE. WE HIGHLIGHT THE ROLE OF EPIGENETIC REGULATORS IN THE MOLECULAR PATHOPHYSIOLOGY OF CHRONIC WOUND CONDITIONS. THE UNDERSTANDING OF HOW EPIGENETIC REGULATORS CAN AFFECT CELLULAR FUNCTIONS DURING NORMAL AND IMPAIRED WOUND HEALING COULD LEAD TO NOVEL THERAPEUTIC APPROACHES, AND WE OUTLINE QUESTIONS THAT CAN PROVIDE GUIDANCE FOR FUTURE RESEARCH ON EPIGENETIC-BASED INTERVENTIONS TO PROMOTE HEALING. DISSECTING THE DYNAMIC INTERPLAY BETWEEN CELLULAR SUBTYPES INVOLVED IN WOUND HEALING AND EPIGENETIC PARAMETERS DURING BARRIER REPAIR WILL DEEPEN OUR UNDERSTANDING OF HOW TO IMPROVE HEALING OUTCOMES IN PATIENTS AFFECTED BY CHRONIC NON-HEALING WOUNDS. 2021 11 2953 23 GENETIC AND EPIGENETIC EVENTS IN DIABETIC WOUND HEALING. THE PREVALENCE OF THE CHRONIC METABOLIC DISORDER, DIABETES MELLITUS, IS EXPECTED TO INCREASE IN THE COMING YEARS AND WORLDWIDE PANDEMIC LEVELS ARE PREDICTED. INEVITABLY, THIS WILL BE ACCOMPANIED BY AN INCREASE IN THE PREVALENCE OF DIABETIC COMPLICATIONS, INCLUDING DIABETIC FOOT ULCERS. AT PRESENT, TREATMENT OPTIONS FOR DIABETIC FOOT ULCERS ARE IN MANY CASES INSUFFICIENT, AND PROGRESSION OF THE CONDITION RESULTS IN THE REQUIREMENT FOR LIMB AMPUTATION IN A PROPORTION OF PATIENTS. TO IMPROVE THERAPY, AN INCREASE IN OUR UNDERSTANDING OF THE PATHOBIOLOGY OF DIABETIC COMPLICATIONS SUCH AS IMPAIRED WOUND HEALING IS NECESSARY. IN THIS REVIEW, RECENT ADVANCES IN MOLECULAR ASPECTS OF NORMAL AND IMPAIRED DIABETIC WOUND HEALING ARE DISCUSSED. FURTHERMORE, INVESTIGATIONS OF THE ROLE OF EPIGENETIC PROCESSES IN THE PATHOGENESIS OF IMPAIRED DIABETIC WOUND HEALING ARE NOW EMERGING. INDEED, EPIGENETIC CHANGES HAVE ALREADY BEEN IDENTIFIED AS KEY FACTORS IN DIABETES AND RELATED COMPLICATIONS AND THESE ARE OVERVIEWED IN THIS REVIEW. 2011 12 6131 26 THE EPIGENETIC REGULATION OF WOUND HEALING. SIGNIFICANCE: EPIGENETIC REGULATORY MECHANISMS ARE ESSENTIAL FOR EPIDERMAL HOMEOSTASIS AND CONTRIBUTE TO THE PATHOGENESIS OF MANY SKIN DISEASES, INCLUDING SKIN CANCER AND PSORIASIS. HOWEVER, WHILE THE EPIGENETIC REGULATION OF EPIDERMAL HOMEOSTASIS IS NOW BECOMING ACTIVE AREA OF RESEARCH, THE EPIGENETIC MECHANISMS CONTROLLING THE WOUND HEALING RESPONSE REMAIN RELATIVELY UNTOUCHED. RECENT ADVANCES: SUBSTANTIAL PROGRESS ACHIEVED WITHIN THE LAST TWO DECADES IN UNDERSTANDING EPIGENETIC MECHANISMS CONTROLLING GENE EXPRESSION ALLOWED DEFINING SEVERAL LEVELS, INCLUDING COVALENT DNA AND HISTONE MODIFICATIONS, ATP-DEPENDENT AND HIGHER-ORDER CHROMATIN CHROMATIN REMODELING, AS WELL AS NONCODING RNA- AND MICRORNA-DEPENDENT REGULATION. RESEARCH PERTAINED OVER THE LAST FEW YEARS SUGGESTS THAT EPIGENETIC REGULATORY MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF SKIN REGENERATION AND CONTROL AN EXECUTION OF REPARATIVE GENE EXPRESSION PROGRAMS IN BOTH SKIN EPITHELIUM AND MESENCHYME. CRITICAL ISSUES: EPIGENETIC REGULATORS APPEAR TO BE INHERENTLY INVOLVED IN THE PROCESSES OF SKIN REPAIR, AND ARE ABLE TO DYNAMICALLY REGULATE KERATINOCYTE PROLIFERATION, DIFFERENTIATION, AND MIGRATION, TOGETHER WITH INFLUENCING DERMAL REGENERATION AND NEOANGIOGENESIS. THIS IS ACHIEVED THROUGH A SERIES OF COMPLEX REGULATORY MECHANISMS THAT ARE ABLE TO BOTH STIMULATE AND REPRESS GENE ACTIVATION TO TRANSIENTLY ALTER CELLULAR PHENOTYPE AND BEHAVIOR, AND INTERACT WITH GROWTH FACTOR ACTIVITY. FUTURE DIRECTIONS: UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC REGULATION IS A PRIORITY AS IT REPRESENTS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC SKIN CONDITIONS. FUTURE RESEARCH IS, THEREFORE, IMPERATIVE TO HELP DISTINGUISH EPIGENETIC MODULATING DRUGS THAT CAN BE USED TO IMPROVE WOUND HEALING. 2014 13 5109 31 POLYPHENOL-RELATED EPIGENETIC MODIFICATIONS IN OSTEOARTHRITIS: CURRENT THERAPEUTIC PERSPECTIVES. THE HYALINE CARTILAGE IS AN AVASCULAR, ANEURAL AND ALYMPHATIC TISSUE WITH A LIMITED ABILITY TO REPAIR ITSELF. WHEN THE CARTILAGE IS EXPOSED TO SOME KIND OF INJURY, IT USUALLY TRIGGERS OSTEOARTHRITIS (OA), A PREVALENT AND DEGENERATIVE JOINT DISEASE CLOSELY RELATED TO AGING. OA IS BOTH COMPLEX AND MULTIFACTORIAL, AND IS THE MOST COMMON FORM OF ARTHRITIS, BEING POSITIONED AS A MAJOR CAUSE OF PAIN AND DYSFUNCTION IN THE WORLD. IN ADDITION, HIGH OA PREVALENCE CAN GREATLY AFFECT WORK CAPACITY, MAKING THIS DISEASE A SIGNIFICANT SOCIAL PROBLEM, THEREFORE, ITS PREVENTION AND TREATMENT BECOMES A PRIORITY. AT THIS TIME, THERE ARE NUMEROUS THERAPEUTIC STRATEGIES AVAILABLE TO IMPROVE HYALINE CARTILAGE REPAIR BY USING CHONDROCYTES OR MESENCHYMAL CELLS, BUT NEITHER IS EFFECTIVE ENOUGH TO GENERATE FUNCTIONAL AND DURABLE TISSUE REPARATION OVER TIME. IN OA, CHONDROCYTES HAVE AN ABERRANT GENE EXPRESSION AND PHENOTYPE, RESULTING IN A LOSS OF BALANCE BETWEEN ANABOLIC AND CATABOLIC PROCESSES. ENVIRONMENTAL INFLUENCES SUCH AS RADIATION, INFECTION, SMOKING, NUTRIENTS, TOXINS AND STRESS CAN AFFECT GENE EXPRESSION PATTERNS, WHICH MAY CONSTITUTE RISK FACTORS FOR VARIOUS CHRONIC AND DEGENERATIVE DISEASES, SUCH AS OA. IN ADDITION, CONSIDERABLE EVIDENCE SHOWS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN OA CHONDROGENESIS AND PATHOGENESIS. NATURAL PLANT-DERIVED PRODUCTS SUCH AS POLYPHENOLS, WHICH ARE SECONDARY METABOLITES CONSIDERED TO HAVE POTENTIAL ACTIVITY TO BLOCK INFLAMMATION IN SEVERAL DEGENERATIVE DISEASES, CAN STIMULATE EPIGENETIC MODIFICATIONS, AND MAY PROVIDE NEW THERAPEUTIC TARGETS AND COST-EFFECTIVE TREATMENTS. THIS REVIEW AIMS TO PRESENT VARIOUS POLYPHENOLBASED THERAPIES CURRENTLY USED FOR THE TREATMENT OF SEVERAL PROGRESSIVE DISEASES, INCLUDING OA. 2016 14 4981 25 PATHOPHYSIOLOGY OF SYSTEMIC SCLEROSIS: CURRENT UNDERSTANDING AND NEW INSIGHTS. INTRODUCTION: SYSTEMIC SCLEROSIS (SSC) IS A COMPLEX AUTOIMMUNE CONNECTIVE TISSUE DISEASE CHARACTERIZED BY CHRONIC AND PROGRESSIVE TISSUE AND ORGAN FIBROSIS WITH BROAD PATIENT-TO-PATIENT VARIABILITY. SOME RISK FACTORS ARE KNOWN AND INCLUDE COMBINATION OF PERSISTENT RAYNAUD'S PHENOMENON, STEROID HORMONE IMBALANCE, SELECTED CHEMICALS, THERMAL, OR OTHER INJURIES. ENDOGENOUS AND/OR EXOGENOUS ENVIRONMENTAL TRIGGER/RISK FACTORS PROMOTE EPIGENETIC MECHANISMS IN GENETICALLY PRIMED SUBJECTS. DISEASE PATHOGENESIS PRESENTS EARLY MICROVASCULAR CHANGES WITH ENDOTHELIAL CELL DYSFUNCTION, FOLLOWED BY THE ACTIVATION OF MECHANISMS PROMOTING THEIR TRANSITION INTO MYOFIBROBLASTS. A COMPLEX AUTOIMMUNE RESPONSE, INVOLVING INNATE AND ADAPTIVE IMMUNITY WITH SPECIFIC/FUNCTIONAL AUTOANTIBODY PRODUCTION, CHARACTERIZES THE DISEASE. PROGRESSIVE FIBROSIS AND ISCHEMIA INVOLVE SKIN AND VISCERAL ORGANS RESULTING IN THEIR IRREVERSIBLE DAMAGE/FAILURE. PROGENITOR CIRCULATING CELLS (MONOCYTES, FIBROCYTES), TOGETHER WITH GROWTH FACTORS AND CYTOKINES PARTICIPATE IN DISEASE DIFFUSION AND EVOLUTION. EPIGENETIC, VASCULAR AND IMMUNOLOGIC MECHANISMS IMPLICATED IN SYSTEMIC FIBROSIS, REPRESENT MAJOR TARGETS FOR INCOMING DISEASE MODIFYING THERAPEUTIC APPROACHES. AREAS COVERED: THIS REVIEW DISCUSSES CURRENT UNDERSTANDING AND NEW INSIGHTS OF SSC PATHOGENESIS, THROUGH AN OVERVIEW OF THE MOST RELEVANT ADVANCEMENTS TO PRESENT ASPECTS AND MECHANISMS INVOLVED IN DISEASE PATHOGENESIS. EXPERT OPINION: CONSIDERING SSC INTRICACY/HETEROGENEITY, EARLY COMBINATION THERAPY WITH VASODILATORS, IMMUNOSUPPRESSIVE AND ANTIFIBROTIC DRUGS SHOULD SUCCESSFULLY DOWNREGULATE THE DISEASE PROGRESSION, ESPECIALLY IF STARTED FROM THE BEGINNING. 2019 15 3800 28 INTERPLAY OF INFLAMMATORY MEDIATORS WITH EPIGENETICS AND CARTILAGE MODIFICATIONS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA), A DEGENERATIVE DISEASE OF DIARTHRODIAL JOINTS, IS INFLUENCED BY MECHANICAL AND INFLAMMATORY FACTORS WITH AGING, OBESITY, CHRONIC INJURIES, AND SECONDARY DISEASES THOUGHT TO BE MAJOR FACTORS DRIVING THE PROCESS OF ARTICULAR CARTILAGE DEGENERATION. CHONDROCYTES, THE CELLULAR COMPONENT OF CARTILAGE, RESIDE IN AN AVASCULAR ENVIRONMENT AND NORMALLY HAVE LIMITED POTENTIAL TO REPLICATE. HOWEVER, EXTRINSIC FACTORS SUCH AS INJURY TO THE JOINT OR INTRINSIC ALTERATIONS TO THE CHONDROCYTES THEMSELVES CAN LEAD TO AN ALTERED PHENOTYPE AND DEVELOPMENT OF OA. SYNOVIAL INFLAMMATION IS ALSO A PIVOTAL ELEMENT OF THE OSTEOARTHRITIC, DEGENERATIVE PROCESS: INFLUX OF PRO-INFLAMMATORY CYTOKINES AND PRODUCTION OF MATRIX METALLOPROTEINASES ACCELERATE ADVANCED CELLULAR PROCESSES SUCH AS SYNOVITIS AND CARTILAGE DAMAGE. AS WELL AS A GENETIC INPUT, RECENT DATA HAVE HIGHLIGHTED EPIGENETIC FACTORS AS CONTRIBUTING TO DISEASE. STUDIES CONDUCTED OVER THE LAST DECADE HAVE FOCUSED ON THREE KEY ASPECTS IN OA; INFLAMMATION AND THE IMMUNE RESPONSE, GENOME-WIDE ASSOCIATION STUDIES THAT HAVE IDENTIFIED IMPORTANT GENES UNDERGOING EPIGENETIC MODIFICATIONS, AND FINALLY HOW CHONDROCYTES TRANSFORM IN THEIR FUNCTION DURING DEVELOPMENT AND DISEASE. DATA HIGHLIGHTED HERE HAVE IDENTIFIED CRITICAL INFLAMMATORY GENES INVOLVED IN OA AND HOW THESE FACTORS IMPACT CHONDROCYTE HYPERTROPHY IN THE DISEASE. THIS REVIEW ALSO ADDRESSES KEY INFLAMMATORY FACTORS IN SYNOVIAL INFLAMMATION, EPIGENETICS, AND CHONDROCYTE FATE, AND HOW AGENTS THAT INHIBIT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS COULD AID IN DEVELOPMENT OF LONG-TERM TREATMENT STRATEGIES FOR THE DISEASE. 2018 16 2508 21 EPIGENETICS AND OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST COMMON FORM OF JOINT DISEASE AND THE LEADING CAUSE OF CHRONIC DISABILITY IN MIDDLE-AGED AND OLDER POPULATIONS. THE DEVELOPMENT OF DISEASE-MODIFYING THERAPY FOR OA CURRENTLY FACES MAJOR OBSTACLES LARGELY BECAUSE THE REGULATORY MECHANISMS FOR THE FUNCTION OF JOINT TISSUE CELLS REMAIN UNCLEAR. PREVIOUS STUDIES HAVE FOUND THAT THE ALTERATIONS IN GENE EXPRESSION OF SPECIFIC TRANSCRIPTION FACTORS (TFS), PRO- OR ANTI-INFLAMMATORY CYTOKINES, MATRIX PROTEINASES AND EXTRACELLULAR MATRIX (ECM) PROTEINS IN ARTICULAR CARTILAGE MAY BE INVOLVED IN THE DEVELOPMENT OF OA. HOWEVER, THE REGULATORY MECHANISMS FOR THE EXPRESSION OF THOSE GENES IN OA CHONDROCYTES ARE LARGELY UNKNOWN. THE RECENT ADVANCES IN EPIGENETIC STUDIES HAVE SHED LIGHTS ON THE IMPORTANCE OF EPIGENETIC REGULATION OF GENE EXPRESSION IN THE DEVELOPMENT OF OA. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS THE RECENT STUDIES ON THE REGULATORY ROLES OF VARIOUS EPIGENETIC MECHANISMS IN THE EXPRESSION OF GENES FOR SPECIFIC TFS, CYTOKINES, ECM PROTEINS AND MATRIX PROTEINASES, AS WELL THE SIGNIFICANCE OF THESE EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF OA. 2015 17 2333 23 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 18 2933 29 GENESIS OF THE MYOFIBROBLAST IN LUNG INJURY AND FIBROSIS. TISSUE INJURY INCITES A REPAIR RESPONSE WITH A KEY MESENCHYMAL COMPONENT THAT PROVIDES THE ESSENTIAL CONNECTIVE TISSUE FOR SUBSEQUENT REGENERATION OR PATHOLOGICAL FIBROSIS. THE FIBROBLAST IS THE MAJOR MESENCHYMAL CELL TYPE TO BE IMPLICATED IN THIS CONNECTIVE TISSUE RESPONSE, AND IT IS IN ITS ACTIVATED OR DIFFERENTIATED FORM THAT IT PARTICIPATES IN THE REPAIR PROCESS. THE MYOFIBROBLAST REPRESENTS SUCH AN ACTIVATED MESENCHYMAL CELL AND IS A KEY SOURCE OF EXTRACELLULAR MATRIX AND INFLAMMATORY/FIBROGENIC CYTOKINES AS WELL AS PARTICIPATING IN WOUND CONTRACTION. ALTHOUGH SUCCESSFUL HEALING RESULTS IN GRADUAL DISAPPEARANCE OF MYOFIBROBLASTS, THEIR PERSISTENCE IS ASSOCIATED WITH CHRONIC AND PROGRESSIVE FIBROSIS. THUS, ELUCIDATION OF THE MECHANISM INVOLVED IN THE GENESIS OF THE MYOFIBROBLAST SHOULD PROVIDE INSIGHT INTO BOTH PATHOGENESIS OF CHRONIC FIBROTIC DISEASES AND THERAPEUTIC STRATEGIES FOR THEIR MANAGEMENT AND CONTROL. ALTHOUGH THE FIBROBLAST IS A WELL-DOCUMENTED PROGENITOR CELL FOR THE MYOFIBROBLAST, RECENT STUDIES HAVE SUGGESTED ADDITIONAL PRECURSOR CELLS THAT HAVE THE POTENTIAL TO GIVE RISE TO THE MYOFIBROBLAST. MANY OF THE STUDIES FOCUSED ON MECHANISMS AND FACTORS THAT REGULATE INDUCTION OF ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION, A KEY AND COMMONLY USED MARKER OF THE MYOFIBROBLAST. THESE REVEAL COMPLEX AND MULTIFACTORIAL MECHANISMS INVOLVING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND IMPLICATING DIVERSE CELL-SIGNALING PATHWAYS, INCLUDING THOSE ACTIVATED BY THE POTENT FIBROGENIC CYTOKINE TRANSFORMING GROWTH FACTOR BETA. DESPITE THESE EXTENSIVE STUDIES, MANY ASPECTS REMAIN POORLY UNDERSTOOD, WITH THE SUGGESTION THAT ADDITIONAL NOVEL MECHANISMS REMAIN TO BE DISCOVERED. FUTURE STUDIES WITH THE HELP OF NEWLY DEVELOPED TECHNICAL ADVANCEMENTS SHOULD EXPEDITE DISCOVERY IN THIS DIRECTION. 2012 19 5003 29 PERIODONTITIS IS AN INFLAMMATORY DISEASE OF OXIDATIVE STRESS: WE SHOULD TREAT IT THAT WAY. PERIODONTITIS IS A HIGHLY PREVALENT DISEASE. AS IT PROGRESSES, IT CAUSES SERIOUS MORBIDITY IN THE FORM OF PERIODONTAL ABSCESSES AND TOOTH LOSS AND, IN THE LATTER STAGES, PAIN. IT IS ALSO NOW KNOWN THAT PERIODONTITIS IS STRONGLY ASSOCIATED WITH SEVERAL NONORAL DISEASES. THUS, PATIENTS WITH PERIODONTITIS ARE AT GREATER RISK FOR THE DEVELOPMENT AND/OR EXACERBATION OF DIABETES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND CARDIOVASCULAR DISEASES, AMONG OTHER CONDITIONS. ALTHOUGH IT IS WITHOUT QUESTION THAT SPECIFIC GROUPS OF ORAL BACTERIA WHICH POPULATE DENTAL PLAQUE PLAY A CAUSATIVE ROLE IN THE DEVELOPMENT OF PERIODONTITIS, IT IS NOW THOUGHT THAT ONCE THIS DISEASE HAS BEEN TRIGGERED, OTHER FACTORS PLAY AN EQUAL, AND POSSIBLY MORE IMPORTANT, ROLE IN ITS PROGRESSION, PARTICULARLY IN SEVERE CASES OR IN CASES THAT PROVE DIFFICULT TO TREAT. IN THIS REGARD, WE ALLUDE TO THE HOST RESPONSE, SPECIFICALLY THE NOTION THAT THE HOST, ONCE INFECTED WITH ORAL PERIODONTAL PATHOGENIC BACTERIA, WILL MOUNT A DEFENSE RESPONSE MEDIATED LARGELY THROUGH THE INNATE IMMUNE SYSTEM. THE MOST ABUNDANT CELL TYPE OF THE INNATE IMMUNE SYSTEM - POLYMORPHONUCLEAR NEUTROPHILS - CAN, WHEN PROTECTING THE HOST FROM MICROBIAL INVASION, MOUNT A RESPONSE THAT INCLUDES UPREGULATION OF PROINFLAMMATORY CYTOKINES, MATRIX METALLOPROTEINASES, AND REACTIVE OXYGEN SPECIES, ALL OF WHICH THEN CONTRIBUTE TO THE TISSUE DAMAGE AND LOSS OF TEETH COMMONLY ASSOCIATED WITH PERIODONTITIS. OF THE MECHANISMS REFERRED TO HERE, WE SUGGEST THAT UPREGULATION OF REACTIVE OXYGEN SPECIES MIGHT PLAY ONE OF THE MOST IMPORTANT ROLES IN THE ESTABLISHMENT AND PROGRESSION OF PERIODONTITIS (AS WELL AS IN OTHER DISEASES OF INFLAMMATION) THROUGH THE DEVELOPMENT OF OXIDATIVE STRESS. IN THIS OVERVIEW, WE DISCUSS BOTH INNATE AND EPIGENETIC FACTORS (EG, DIABETES, SMOKING) THAT LEAD TO THE DEVELOPMENT OF OXIDATIVE STRESS. THIS OXIDATIVE STRESS THEN PROVIDES AN ENVIRONMENT CONDUCIVE TO THE DESTRUCTIVE PROCESSES OBSERVED IN PERIODONTITIS. THEREFORE, WE SHALL DESCRIBE SOME OF THE FUNDAMENTAL CHARACTERISTICS OF OXIDATIVE STRESS AND ITS EFFECTS ON THE PERIODONTIUM, DISCUSS THE DISEASES AND OTHER FACTORS THAT CAUSE OXIDATIVE STRESS, AND, FINALLY, REVIEW POTENTIALLY NOVEL THERAPEUTIC APPROACHES FOR THE MANAGEMENT (AND POSSIBLY EVEN THE REVERSAL) OF PERIODONTITIS, WHICH RELY ON THE USE OF THERAPIES, SUCH AS RESVERATROL AND OTHER ANTIOXIDANTS, THAT PROVIDE INCREASED ANTIOXIDANT ACTIVITY IN THE HOST. 2020 20 2163 26 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