1 5922 117 TARGETING DNA METHYLATION AND DEMETHYLATION IN DIABETIC FOOT ULCERS. BACKGROUND: POOR WOUND HEALING IS A SIGNIFICANT COMPLICATION OF DIABETES, WHICH IS COMMONLY CAUSED BY NEUROPATHY, TRAUMA, DEFORMITIES, PLANTAR HYPERTENSION AND PERIPHERAL ARTERIAL DISEASE. DIABETIC FOOT ULCERS (DFU) ARE DIFFICULT TO HEAL, WHICH MAKES PATIENTS SUSCEPTIBLE TO INFECTIONS AND CAN ULTIMATELY CONDUCE TO LIMB AMPUTATION OR EVEN DEATH IN SEVERE CASES. AN INCREASING NUMBER OF STUDIES HAVE FOUND THAT EPIGENETIC ALTERATIONS ARE STRONGLY ASSOCIATED WITH POOR WOUND HEALING IN DIABETES. AIM OF REVIEW: THIS WORK PROVIDES SIGNIFICANT INSIGHTS INTO THE DEVELOPMENT OF THERAPEUTICS FOR IMPROVING CHRONIC DIABETIC WOUND HEALING, PARTICULARLY BY TARGETING AND REGULATING DNA METHYLATION AND DEMETHYLATION IN DFU. KEY SCIENTIFIC CONCEPTS OF REVIEW: DNA METHYLATION AND DEMETHYLATION PLAY AN IMPORTANT PART IN DIABETIC WOUND HEALING, VIA REGULATING CORRESPONDING SIGNALING PATHWAYS IN DIFFERENT BREEDS OF CELLS, INCLUDING MACROPHAGES, VASCULAR ENDOTHELIAL CELLS AND KERATINOCYTES. IN THIS REVIEW, WE DESCRIBE THE FOUR MAIN PHASES OF WOUND HEALING AND THEIR ABNORMALITY IN DIABETIC PATIENTS. FURTHERMORE, WE PROVIDED AN IN-DEPTH SUMMARY AND DISCUSSION ON HOW DNA METHYLATION AND DEMETHYLATION REGULATE DIABETIC WOUND HEALING IN DIFFERENT TYPES OF CELLS; AND GAVE A BRIEF SUMMARY ON RECENT ADVANCES IN APPLYING CELLULAR REPROGRAMMING TECHNIQUES FOR IMPROVING DIABETIC WOUND HEALING. 2023 2 2953 33 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 3 2248 32 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 4 1713 32 DYSFUNCTIONAL WOUND HEALING IN DIABETIC FOOT ULCERS: NEW CROSSROADS. PURPOSE OF REVIEW: DIABETIC FOOT ULCERATIONS (DFU) AFFECT 25% OF PATIENTS WITH DIABETES MELLITUS DURING THEIR LIFETIME AND CONSTITUTE A MAJOR HEALTH PROBLEM AS THEY ARE OFTEN RECALCITRANT TO HEALING DUE TO A CONSTELLATION OF BOTH INTRINSIC AND EXTRINSIC FACTORS. THE PURPOSE OF THIS REVIEW IS TO (1) DETAIL THE CURRENT MECHANISTIC UNDERSTANDING OF DFU FORMATION AND (2) HIGHLIGHT FUTURE THERAPEUTIC TARGETS. RECENT FINDINGS: FROM A MOLECULAR PERSPECTIVE, DFUS EXHIBIT A CHRONIC INFLAMMATORY PREDISPOSITION. IN ADDITION, INCREASED LOCAL HYPOXIC CONDITIONS AND IMPAIRED CELLULAR RESPONSES TO HYPOXIA ARE PATHOGENIC FACTORS THAT CONTRIBUTE TO DELAYED WOUND HEALING. FINALLY, RECENT EVIDENCE SUGGESTS A ROLE FOR EPIGENETIC ALTERATIONS, INCLUDING MICRORNAS, IN DELAYED DFU HEALING DUE TO THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. IN THIS REGARD, NOTABLE PROGRESS HAS BEEN MADE IN THE MOLECULAR AND GENETIC UNDERSTANDING OF DFU FORMATION. HOWEVER, FURTHER STUDIES ARE NEEDED TO TRANSLATE PRECLINICAL INVESTIGATIONS INTO CLINICAL THERAPIES. 2018 5 2381 36 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 6 2171 32 EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF DIABETIC FOOT ULCERS. THE INCIDENCE OF DIABETES MELLITUS, A CHRONIC METABOLIC DISEASE ASSOCIATED WITH BOTH PREDISPOSING GENETIC AND ENVIRONMENTAL FACTORS, IS INCREASING GLOBALLY. AS A RESULT, IT IS EXPECTED THAT THERE WILL ALSO BE AN INCREASING INCIDENCE OF DIABETIC COMPLICATIONS WHICH ARISE AS A RESULT OF POOR GLYCEMIC CONTROL. COMPLICATIONS INCLUDE CARDIOVASCULAR DISEASES, NEPHROPATHY, RETINOPATHY AND DIABETIC FOOT ULCERS. THE FINDINGS OF SEVERAL MAJOR CLINICAL TRIALS HAVE IDENTIFIED THAT DIABETIC COMPLICATIONS MAY ARISE EVEN AFTER MANY YEARS OF PROPER GLYCEMIC CONTROL. THIS HAS LED TO THE CONCEPT OF PERSISTENT EPIGENETIC CHANGES. VARIOUS EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED AS IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF DIABETES AND DIABETIC COMPLICATIONS. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE PATHOBIOLOGY OF TYPE 2 DIABETES WITH AN EMPHASIS ON COMPLICATIONS, PARTICULARLY DIABETIC FOOT ULCERS. AN OVERVIEW OF EPIGENETIC MECHANISMS IS PROVIDED AND THE FOCUS IS ON THE EMERGING EVIDENCE FOR ABERRANT EPIGENETIC MECHANISMS IN DIABETIC FOOT ULCERS. 2012 7 2307 28 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 8 6284 37 THE POTENTIAL OF HUMAN INDUCED PLURIPOTENT STEM CELLS FOR MODELLING DIABETIC WOUND HEALING IN VITRO. IMPAIRED WOUND HEALING AND ULCERATION CAUSED BY DIABETES MELLITUS, IS A SIGNIFICANT HEALTHCARE BURDEN, MARKEDLY IMPAIRS QUALITY OF LIFE FOR PATIENTS, AND IS THE MAJOR CAUSE OF AMPUTATION WORLDWIDE. CURRENT EXPERIMENTAL APPROACHES USED TO INVESTIGATE THE COMPLEX WOUND HEALING PROCESS OFTEN INVOLVE CULTURES OF FIBROBLASTS AND/OR KERATINOCYTES IN VITRO, WHICH CAN BE LIMITED IN TERMS OF COMPLEXITY AND CAPACITY, OR UTILISATION OF RODENT MODELS IN WHICH THE MECHANISMS OF WOUND REPAIR DIFFER SUBSTANTIVELY FROM THAT IN HUMANS. HOWEVER, ADVANCES IN TISSUE ENGINEERING, AND THE DISCOVERY OF STRATEGIES TO REPROGRAMME ADULT SOMATIC CELLS TO PLURIPOTENCY, HAS LED TO THE POSSIBILITY OF DEVELOPING MODELS OF HUMAN SKIN ON A LARGE SCALE. GENERATION OF INDUCED PLURIPOTENT STEM CELLS (IPSCS) FROM TISSUES DONATED BY DIABETIC PATIENTS ALLOWS THE (EPI)GENETIC BACKGROUND OF THIS DISEASE TO BE STUDIED, AND THE ABILITY TO DIFFERENTIATE IPSCS TO MULTIPLE CELL TYPES FOUND WITHIN SKIN MAY FACILITATE THE DEVELOPMENT OF MORE COMPLEX SKIN MODELS; THESE ADVANCES OFFER KEY OPPORTUNITIES FOR IMPROVING MODELLING OF WOUND HEALING IN DIABETES, AND THE DEVELOPMENT OF EFFECTIVE THERAPEUTICS FOR TREATMENT OF CHRONIC WOUNDS. 2018 9 6131 29 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 10 2694 31 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 11 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 12 2613 34 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 13 1505 39 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 14 2532 32 EPIGENETICS IN ATHEROSCLEROSIS AND INFLAMMATION. ATHEROSCLEROSIS IS A MULTIFACTORIAL DISEASE WITH A SEVERE BURDEN ON WESTERN SOCIETY. RECENT INSIGHTS INTO THE PATHOGENESIS OF ATHEROSCLEROSIS UNDERSCORE THE IMPORTANCE OF CHRONIC INFLAMMATION IN BOTH THE INITIATION AND PROGRESSION OF VASCULAR REMODELLING. EXPRESSION OF IMMUNOREGULATORY MOLECULES BY VASCULAR WALL COMPONENTS WITHIN THE ATHEROSCLEROTIC LESIONS IS ACCORDINGLY THOUGHT TO CONTRIBUTE TO THE ONGOING INFLAMMATORY PROCESS. BESIDES GENE REGULATORY PROTEINS (TRANSCRIPTION FACTORS), EPIGENETIC MECHANISMS ALSO PLAY AN ESSENTIAL AND FUNDAMENTAL ROLE IN THE TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION. THESE EPIGENETIC MECHANISMS CHANGE THE ACCESSIBILITY OF CHROMATIN BY DNA METHYLATION AND HISTONE MODIFICATIONS. EPIGENETIC MODULATORS ARE THUS CRITICALLY INVOLVED IN THE REGULATION OF VASCULAR, IMMUNE AND TISSUE-SPECIFIC GENE EXPRESSION WITHIN THE ATHEROSCLEROTIC LESION. IMPORTANTLY, EPIGENETIC PROCESSES ARE REVERSIBLE AND MAY PROVIDE AN EXCELLENT THERAPEUTIC TARGET. THE CONCEPT OF EPIGENETIC REGULATION IS GRADUALLY BEING RECOGNIZED AS AN IMPORTANT FACTOR IN THE PATHOGENESIS OF ATHEROSCLEROSIS. RECENT RESEARCH PROVIDES AN ESSENTIAL LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME. IN THIS REVIEW WE THEREFORE DISCUSS THE BASIS OF EPIGENETIC REGULATION - AND THE CONTRIBUTION THEREOF IN THE REGULATION OF INFLAMMATORY PROCESSES IN GENERAL AND DURING ATHEROSCLEROSIS IN PARTICULAR. MOREOVER WE HIGHLIGHT POTENTIAL THERAPEUTIC INTERVENTIONS BASED ON EPIGENETIC MECHANISMS. 2010 15 1604 33 DNA METHYLATION SUSTAINS "INFLAMED" MEMORY OF PERIPHERAL IMMUNE CELLS AGGRAVATING KIDNEY INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE. THE INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) HAS RAPIDLY INCREASED IN THE PAST DECADES. A PROGRESSIVE LOSS OF KIDNEY FUNCTION CHARACTERIZES A PART OF CKD EVEN WITH INTENSIVE SUPPORTIVE TREATMENT. IRRESPECTIVE OF ITS ETIOLOGY, CKD PROGRESSION IS GENERALLY ACCOMPANIED WITH THE DEVELOPMENT OF CHRONIC KIDNEY INFLAMMATION THAT IS PATHOLOGICALLY FEATURED BY THE LOW-GRADE BUT CHRONIC ACTIVATION OF RECRUITED IMMUNE CELLS. CUMULATIVE EVIDENCE SUPPORT THAT ABERRANT DNA METHYLATION PATTERN OF DIVERSE PERIPHERAL IMMUNE CELLS, INCLUDING T CELLS AND MONOCYTES, IS CLOSELY ASSOCIATED WITH CKD DEVELOPMENT IN MANY CHRONIC DISEASE SETTINGS. THE CHANGE OF DNA METHYLATION PROFILE CAN SUSTAIN FOR A LONG TIME AND AFFECT THE FUTURE GENES EXPRESSION IN THE CIRCULATING IMMUNE CELLS EVEN AFTER THEY MIGRATE FROM THE CIRCULATION INTO THE INVOLVED KIDNEY. IT IS OF CLINICAL INTEREST TO REVEAL THE UNDERLYING MECHANISM OF HOW ALTERED DNA METHYLATION REGULATES THE INTENSITY AND THE TIME LENGTH OF THE INFLAMMATORY RESPONSE IN THE RECRUITED EFFECTOR CELLS. WE AND OTHERS RECENTLY DEMONSTRATED THAT ALTERED DNA METHYLATION OCCURS IN PERIPHERAL IMMUNE CELLS AND PROFOUNDLY CONTRIBUTES TO CKD DEVELOPMENT IN SYSTEMIC CHRONIC DISEASES, SUCH AS DIABETES AND HYPERTENSION. THIS REVIEW WILL SUMMARIZE THE CURRENT FINDINGS ABOUT THE INFLUENCE OF ABERRANT DNA METHYLATION ON CIRCULATING IMMUNE CELLS AND HOW IT POTENTIALLY DETERMINES THE OUTCOME OF CKD. 2021 16 2976 49 GENETIC AND MOLECULAR BASIS OF DIABETIC FOOT ULCERS: CLINICAL REVIEW. DIABETIC FOOT ULCERS (DFUS) ARE MAJOR COMPLICATIONS ASSOCIATED WITH DIABETES AND OFTEN CORRELATE WITH PERIPHERAL NEUROPATHY, TRAUMA AND PERIPHERAL VASCULAR DISEASE. IT IS NECESSARY TO UNDERSTAND THE MOLECULAR AND GENETIC BASIS OF DIABETIC FOOT ULCERS IN ORDER TO TAILOR PATIENT CENTRED CARE TOWARDS PARTICULAR PATIENT GROUPS. THIS REVIEW AIMED TO EVALUATE WHETHER CURRENT LITERATURE WAS INDICATIVE OF AN UNDERLYING MOLECULAR AND GENETIC BASIS FOR DFUS AND TO DISCUSS CLINICAL APPLICATIONS. FROM A MOLECULAR PERSPECTIVE, WOUND HEALING IS A PROCESS THAT TRANSPIRES FOLLOWING BREACH OF THE SKIN BARRIER AND IS USUALLY MEDIATED BY GROWTH FACTORS AND CYTOKINES RELEASED BY SPECIALISED CELLS ACTIVATED BY THE IMMUNE RESPONSE, INCLUDING FIBROBLASTS, ENDOTHELIAL CELLS, PHAGOCYTES, PLATELETS AND KERATINOCYTES. GROWTH FACTORS AND CYTOKINES ARE FUNDAMENTAL IN THE ORGANISATION OF THE MOLECULAR PROCESSES INVOLVED IN MAKING CUTANEOUS WOUND HEALING POSSIBLE. THERE IS A SIGNIFICANT ROLE FOR SINGLE NUCLEOTIDE POLYMORPHISM (SNPS) IN THE FLUCTUATION OF THESE GROWTH FACTORS AND CYTOKINES IN DFUS. FURTHERMORE, RECENT EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION FROM LONG STANDING HYPERGLYCEMIA AND NON-CODING RNAS IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. GENETIC FACTORS AND ETHNICITY CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF DIABETIC NEUROPATHY LEADING TO DFUS. CLINICALLY, INTERVENTIONS WHICH HAVE IMPROVED OUTCOMES FOR PEOPLE WITH DFUS OR THOSE AT RISK OF DFUS INCLUDE SOME SYSTEMIC THERAPEUTIC DRUG INTERVENTIONS WHICH IMPROVE MICROVASCULAR BLOOD FLOW, SURGICAL INTERVENTIONS, HUMAN GROWTH FACTORS, AND HYPERBARIC OXYGEN THERAPY, NEGATIVE PRESSURE WOUND THERAPY, SKIN REPLACEMENT OR SHOCKWAVE THERAPY AND THE USE OF TOPICAL TREATMENTS. FUTURE TREATMENT MODALITIES INCLUDING STEM CELL AND GENE THERAPIES ARE PROMISING IN THE THERAPEUTIC APPROACH TO PREVENT THE PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. 2016 17 6181 31 THE IMMUNE FUNCTIONS OF KERATINOCYTES IN SKIN WOUND HEALING. AS THE MOST DOMINANT CELL TYPE IN THE SKIN, KERATINOCYTES PLAY CRITICAL ROLES IN WOUND REPAIR NOT ONLY AS STRUCTURAL CELLS BUT ALSO EXERTING IMPORTANT IMMUNE FUNCTIONS. THIS REVIEW FOCUSES ON THE COMMUNICATIONS BETWEEN KERATINOCYTES AND IMMUNE CELLS IN WOUND HEALING, WHICH ARE MEDIATED BY VARIOUS CYTOKINES, CHEMOKINES, AND EXTRACELLULAR VESICLES. KERATINOCYTES CAN ALSO DIRECTLY INTERACT WITH T CELLS VIA ANTIGEN PRESENTATION. MOREOVER, KERATINOCYTES PRODUCE ANTIMICROBIAL PEPTIDES THAT CAN DIRECTLY KILL THE INVADING PATHOGENS AND CONTRIBUTE TO WOUND REPAIR IN MANY ASPECTS. WE ALSO REVIEWED THE EPIGENETIC MECHANISMS KNOWN TO REGULATE KERATINOCYTE IMMUNE FUNCTIONS, INCLUDING HISTONE MODIFICATIONS, NON-PROTEIN-CODING RNAS (E.G., MICRORNAS, AND LONG NONCODING RNAS), AND CHROMATIN DYNAMICS. LASTLY, WE SUMMARIZED THE CURRENT EVIDENCE ON THE DYSREGULATED IMMUNE FUNCTIONS OF KERATINOCYTES IN CHRONIC NONHEALING WOUNDS. BASED ON THEIR CRUCIAL IMMUNE FUNCTIONS IN SKIN WOUND HEALING, WE PROPOSE THAT KERATINOCYTES SIGNIFICANTLY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC WOUND INFLAMMATION. WE HOPE THIS REVIEW WILL TRIGGER AN INTEREST IN INVESTIGATING THE IMMUNE ROLES OF KERATINOCYTES IN CHRONIC WOUND PATHOLOGY, WHICH MAY OPEN UP NEW AVENUES FOR DEVELOPING INNOVATIVE WOUND TREATMENTS. 2020 18 4336 29 MICRORNAS: THE UNDERLYING MEDIATORS OF PATHOGENETIC PROCESSES IN VASCULAR COMPLICATIONS OF DIABETES. DIABETES MELLITUS CAUSES CHRONIC COMPLICATIONS PRIMARILY AFFECTING THE VASCULATURE OF VARIOUS ORGANS, RISKING PATIENTS FOR RENAL FAILURE, VISION LOSS AND HEART FAILURE. A NEWLY DISCOVERED CLASS OF MOLECULES, MICRORNAS, MAY BE IMPORTANT IN THE GENESIS OF THESE PATHOLOGIC PROCESSES. MICRORNAS REGULATE GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL BY INHIBITING TARGET MESSENGER RNA TRANSLATION. IN DISEASE STATES, HOWEVER, THE EXPRESSION OF MICRORNAS OFTEN IS ALTERED, RESULTING IN FURTHER ALTERED EXPRESSION (MOSTLY OVEREXPRESSION) OF DOWNSTREAM TARGET GENES. INTERESTINGLY, RESTORING MICRORNA EXPRESSION TO NORMAL LEVELS CAN CORRECT DOWNSTREAM EFFECTS AND PREVENT DIABETES-ASSOCIATED CHANGES. INVESTIGATIONS INTO MICRORNA INVOLVED IN VARIOUS PATHOGENETIC PROCESSES MEDIATING DIABETIC NEPHROPATHY, RETINOPATHY AND CARDIOMYOPATHY ARE HIGHLIGHTED IN THIS REVIEW. FUTURE DIRECTIONS OF MICRORNA IN THERAPEUTICS AND DIAGNOSTICS ARE ALSO DISCUSSED. IT IS OUR INTENT TO HELP THE READER APPRECIATE THE DIVERSE INTERACTIONS MICRORNAS HAVE IN CELLULAR SIGNALLING AND HOW UNDERSTANDING EPIGENETIC ELEMENTS, SUCH AS MICRORNAS, POTENTIALLY CAN YIELD NEW THERAPEUTIC STRATEGIES. 2013 19 3156 29 GLYCEMIC MEMORIES AND THE EPIGENETIC COMPONENT OF DIABETIC NEPHROPATHY. A STRONG CASE FOR THE DEREGULATION OF EPIGENETIC CHROMATIN MODIFICATIONS IN THE DEVELOPMENT AND PROGRESSION OF VARIOUS CHRONIC COMPLICATIONS OF DIABETES HAS EMERGED FROM RECENT EXPERIMENTAL OBSERVATIONS. CLINICAL TRIALS OF TYPE 1 AND TYPE 2 DIABETES PATIENTS HIGHLIGHT THE IMPORTANCE OF EARLY AND INTENSIVE TREATMENT AND THE PROLONGED DAMAGE OF HYPERGLYCEMIA ON ORGANS SUCH AS THE KIDNEY. THE FUNCTIONAL RELATIONSHIP BETWEEN THE REGULATION OF CHROMATIN ARCHITECTURE AND PERSISTENT GENE EXPRESSION CHANGES CONFERRED BY PRIOR HYPERGLYCEMIA REPRESENTS AN IMPORTANT AVENUE OF INVESTIGATION FOR EXPLAINING DIABETIC NEPHROPATHY. WHILE SEVERAL STUDIES IMPLICATE EPIGENETIC CHANGES AT THE CHROMATIN TEMPLATE IN THE DEREGULATED GENE EXPRESSION ASSOCIATED WITH DIABETIC NEPHROPATHY, THE MOLECULAR DETERMINANTS OF METABOLIC MEMORY IN RENAL CELLS REMAIN POORLY UNDERSTOOD. THERE IS NOW STRONG EVIDENCE FROM EXPERIMENTAL ANIMALS AND CELL CULTURE OF PERSISTENT GLUCOSE-DRIVEN CHANGES IN VASCULAR ENDOTHELIAL GENE EXPRESSION THAT MAY ALSO HAVE RELEVANCE FOR THE MICROVASCULATURE OF THE KIDNEY. EXPLORATION OF EPIGENETIC MECHANISMS UNDERLYING THE HYPERGLYCEMIC CUE MEDIATING PERSISTENT TRANSCRIPTIONAL CHANGES IN RENAL CELLS HOLDS NOVEL THERAPEUTIC POTENTIAL FOR DIABETIC NEPHROPATHY. 2013 20 2333 27 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