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 1886 31 ENDOGENOUS BIOLOGICAL DRIVERS IN DIABETIC LOWER LIMB WOUNDS RECURRENCE: HYPOTHETICAL REFLECTIONS. AN IMPAIRED HEALING RESPONSE UNDERLIES DIABETIC FOOT WOUND CHRONICITY, FREQUENTLY TRANSLATING TO AMPUTATION, DISABILITY, AND MORTALITY. DIABETICS SUFFER FROM UNDERAPPRECIATED EPISODES OF POST-EPITHELIZATION ULCER RECURRENCE. RECURRENCE EPIDEMIOLOGICAL DATA ARE ALARMINGLY HIGH, SO THE ULCER IS CONSIDERED IN "REMISSION" AND NOT HEALED FROM THE TIME IT REMAINS EPITHELIALIZED. RECURRENCE MAY RESULT FROM THE COMBINED EFFECTS OF BEHAVIORAL AND ENDOGENOUS BIOLOGICAL FACTORS. ALTHOUGH THE DAMAGING ROLE OF BEHAVIORAL, CLINICAL PREDISPOSING FACTORS IS UNDEBATABLE, IT STILL REMAINS ELUSIVE IN THE IDENTIFICATION OF ENDOGENOUS BIOLOGICAL CULPRITS THAT MAY PRIME THE RESIDUAL SCAR TISSUE FOR RECURRENCE. FURTHERMORE, THE EVENT OF ULCER RECURRENCE STILL WAITS FOR THE IDENTIFICATION OF A MOLECULAR PREDICTOR. WE PROPOSE THAT ULCER RECURRENCE IS DEEPLY IMPINGED BY CHRONIC HYPERGLYCEMIA AND ITS DOWNSTREAM BIOLOGICAL EFFECTORS, WHICH ORIGINATE EPIGENETIC DRIVERS THAT ENFORCE ABNORMAL PATHOLOGIC PHENOTYPES TO DERMAL FIBROBLASTS AND KERATINOCYTES AS MEMORY CELLS. HYPERGLYCEMIA-DERIVED CYTOTOXIC REACTANTS ACCUMULATE AND MODIFY DERMAL PROTEINS, REDUCE SCAR TISSUE MECHANICAL TOLERANCE, AND DISRUPT FIBROBLAST-SECRETORY ACTIVITY. ACCORDINGLY, THE COMBINATION OF EPIGENETIC AND LOCAL AND SYSTEMIC CYTOTOXIC SIGNALERS INDUCE THE ONSET OF "AT-RISK PHENOTYPES" SUCH AS PREMATURE SKIN CELL AGING, DYSMETABOLISM, INFLAMMATORY, PRO-DEGRADATIVE, AND OXIDATIVE PROGRAMS THAT MAY ULTIMATELY CONVERGE TO SCAR CELL DEMISE. POST-EPITHELIALIZATION RECURRENCE RATE DATA ARE MISSING IN CLINICAL STUDIES OF REPUTED ULCER HEALING THERAPIES DURING FOLLOW-UP PERIODS. INTRA-ULCER INFILTRATION OF EPIDERMAL GROWTH FACTOR EXHIBITS THE MOST CONSISTENT REMISSION DATA WITH THE LOWEST RECURRENCES DURING 12-MONTH FOLLOW-UP. RECURRENCE DATA SHOULD BE REGARDED AS A VALUABLE CLINICAL ENDPOINT DURING THE INVESTIGATIONAL PERIOD FOR EACH EMERGENT HEALING CANDIDATE. 2023 3 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 4 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 5 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 6 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 7 2385 35 EPIGENETIC REGULATORS OF THE REVASCULARIZATION RESPONSE TO CHRONIC ARTERIAL OCCLUSION. PERIPHERAL ARTERIAL DISEASE (PAD) IS THE LEADING CAUSE OF LOWER LIMB AMPUTATION AND ESTIMATED TO AFFECT OVER 202 MILLION PEOPLE WORLDWIDE. PAD IS CAUSED BY ATHEROSCLEROTIC LESIONS THAT OCCLUDE LARGE ARTERIES IN THE LOWER LIMBS, LEADING TO INSUFFICIENT BLOOD PERFUSION OF DISTAL TISSUES. GIVEN THE SEVERITY OF THIS CLINICAL PROBLEM, THERE HAS BEEN LONG-STANDING INTEREST IN BOTH UNDERSTANDING HOW CHRONIC ARTERIAL OCCLUSIONS AFFECT MUSCLE TISSUE AND VASCULATURE AND IDENTIFYING THERAPEUTIC APPROACHES CAPABLE OF RESTORING TISSUE COMPOSITION AND VASCULAR FUNCTION TO A HEALTHY STATE. TO DATE, THE MOST WIDELY UTILIZED ANIMAL MODEL FOR PERFORMING SUCH STUDIES HAS BEEN THE ISCHAEMIC MOUSE HINDLIMB. DESPITE NOT BEING A MODEL OF PAD PER SE, THE ISCHAEMIC HINDLIMB MODEL DOES RECAPITULATE SEVERAL KEY ASPECTS OF PAD. FURTHER, IT HAS SERVED AS A VALUABLE PLATFORM UPON WHICH WE HAVE BUILT MUCH OF OUR UNDERSTANDING OF HOW CHRONIC ARTERIAL OCCLUSIONS AFFECT MUSCLE TISSUE COMPOSITION, MUSCLE REGENERATION AND ANGIOGENESIS, AND COLLATERAL ARTERIOGENESIS. RECENTLY, THERE HAS BEEN A GLOBAL SURGE IN RESEARCH AIMED AT UNDERSTANDING HOW GENE EXPRESSION IS REGULATED BY EPIGENETIC FACTORS (I.E. NON-CODING RNAS, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND DNA METHYLATION). THUS, PERHAPS NOT UNEXPECTEDLY, MANY RECENT STUDIES HAVE IDENTIFIED ESSENTIAL ROLES FOR EPIGENETIC FACTORS IN REGULATING KEY RESPONSES TO CHRONIC ARTERIAL OCCLUSION(S). IN THIS REVIEW, WE SUMMARIZE THE MECHANISMS OF ACTION OF THESE EPIGENETIC REGULATORS AND HIGHLIGHT SEVERAL RECENT STUDIES INVESTIGATING THE ROLE OF SAID REGULATORS IN THE CONTEXT OF HINDLIMB ISCHAEMIA. IN ADDITION, WE FOCUS ON HOW THESE RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF EPIGENETICS IN REGULATING RESPONSES TO CHRONIC ARTERIAL OCCLUSION(S) CAN INFORM FUTURE THERAPEUTIC APPLICATIONS TO PROMOTE REVASCULARIZATION AND PERFUSION RECOVERY IN THE SETTING OF PAD. 2019 8 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 9 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 10 6282 34 THE POTENTIAL IMPACT OF SOCIAL GENOMICS ON WOUND HEALING. SIGNIFICANCE: HUMAN SKIN WOUNDS CARRY AN IMMENSE EPIDEMIOLOGIC AND FINANCIAL BURDEN, AND THEIR IMPACT WILL CONTINUE TO GROW WITH AN AGING POPULATION AND RISING INCIDENCE OF COMORBID CONDITIONS KNOWN TO AFFECT WOUND HEALING. TO COMPREHENSIVELY ADDRESS THIS GROWING CLINICAL ISSUE, PHYSICIANS SHOULD ALSO BE AWARE OF HOW CONDITIONS OF THE HUMAN SOCIAL ENVIRONMENT MAY AFFECT WOUND HEALING. HERE WE PROVIDE A REVIEW OF THE EMERGING FIELD OF SOCIAL GENOMICS AND ITS POTENTIAL IMPACT ON THE WOUND HEALING. RECENT ADVANCES: MULTIPLE STUDIES USING HUMAN AND ANIMAL MODELS HAVE CORRELATED SOCIAL INFLUENCES AND THEIR CONTRIBUTING EFFECTS TO ACUTE AND CHRONIC STRESS WITH DELAYS IN WOUND HEALING. FURTHERMORE, OBSERVATIONS BETWEEN NONGENETIC FACTORS SUCH AS NUTRITION, SOCIOECONOMIC, AND EDUCATIONAL STATUS HAVE ALSO SHOWN TO HAVE A DIRECT OR INDIRECT IMPACT ON CLINICAL OUTCOMES OF WOUND HEALING. CRITICAL ISSUES: NUTRITION, FINANCIAL BURDEN, SOCIOECONOMIC AND EDUCATION STATUS, AND ACUTE AND CHRONIC STRESS ARE VARIABLES THAT HAVE EITHER DIRECT (EPIGENETIC) OR INDIRECT IMPACT ON WOUND HEALING AND PATIENTS' QUALITY OF LIFE. WOUND CARE IS COSTLY AND REMAINS A CHALLENGE PLACING ECONOMIC BURDEN ON PATIENTS. FURTHERMORE, POOR CLINICAL OUTCOMES AND COMPLICATIONS INCLUDING LOSS OF MOBILITY AND DISABILITY MAY LEAD TO JOB LOSS, FURTHER CONTRIBUTING TO SOCIOECONOMIC RELATED STRESS. THUS, THE ECONOMIC BURDEN AND INADEQUATE WOUND HEALING ARE INTERTWINED, MAKING EACH OTHER WORSE. FUTURE DIRECTIONS: ALTHOUGH SOME EVIDENCE REGARDING THE SPECIFIC CHANGES IN GENETIC PATHWAYS IMPARTED BY CONDITIONS OF THE SOCIAL ENVIRONMENT EXISTS, FURTHER STUDIES ARE WARRANTED TO IDENTIFY POTENTIAL MECHANISMS, INTERVENTIONS, AND PREVENTION APPROACHES. 2020 11 2941 32 GENETIC AND EPIGENETIC ALTERATIONS IN TOLL LIKE RECEPTOR 2 AND WOUND HEALING IMPAIRMENT IN TYPE 2 DIABETES PATIENTS. AIM: PERSISTENT HYPERGLYCEMIC MICROENVIRONMENT IN TYPE 2 DIABETES MELLITUS (T2DM) LEADS TO THE DEVELOPMENT OF SECONDARY COMPLICATIONS LIKE WOUND HEALING IMPAIRMENT. PROPER CO-ORDINATION OF INNATE IMMUNE SYSTEM PLAYS AN INTEGRAL ROLE IN WOUND HEALING. TOLL LIKE RECEPTORS (TLRS) ARE PROMINENT CONTRIBUTORS FOR THE INDUCTION OF THE INNATE IMMUNE AND INFLAMMATION RESPONSE. TLR2 IS AN IMPORTANT EXTRACELLULAR MEMBER IN MAMMALIAN TLR FAMILY AND HAS BEEN SHOWN TO BE A POTENT PLAYER IN THE WOUND HEALING MECHANISM. METHODS: EXPRESSIONAL STATUS OF TLR2 WAS SEEN IN WOUNDS OF T2DM CASES WITH RESPECT TO THE SEVERITY OF WOUNDS IN 110 HUMAN LOWER EXTREMITY WOUNDS. THE METHYLATION STATUS OF TLR2 PROMOTER WAS ALSO EXAMINED. RESULTS: ALTHOUGH TLR2 TRANSCRIPTS WERE DOWNREGULATED IN T2DM WOUNDS COMPARED TO CONTROL, THEIR LEVELS TEND TO INCREASE WITH THE SEVERITY OF T2DM WOUNDS. THE METHYLATION STATUS OF TLR2 GENE PROMOTER WAS NOT SIGNIFICANTLY DIFFERENT AMONG DIFFERENT GRADES OF WOUNDS IN T2DM SUBJECTS. THE CPG SITES INVESTIGATED WERE TOTALLY OR PARTIALLY METHYLATED IN MAJORITY OF DFU CASES. CONCLUSION: TLR2 DOWN REGULATION IN WOUNDS OF T2DM PATIENTS COMPARED TO NON DIABETIC PATIENTS MAY LEAD TO DEVELOPMENT OF NON HEALING CHRONIC ULCERS IN THEM. 2015 12 1943 31 EPIDERMAL GROWTH FACTOR IN HEALING DIABETIC FOOT ULCERS: FROM GENE EXPRESSION TO TISSUE HEALING AND SYSTEMIC BIOMARKER CIRCULATION. LOWER-EXTREMITY DIABETIC ULCERS ARE RESPONSIBLE FOR 80% OF ANNUAL WORLDWIDE NONTRAUMATIC AMPUTATIONS. EPIDERMAL GROWTH FACTOR (EGF) REDUCTION IS ONE OF THE MOLECULAR PILLARS OF DIABETIC ULCER CHRONICITY, THUS EGF ADMINISTRATION MAY BE CONSIDERED A TYPE OF REPLACEMENT THERAPY. TOPICAL EGF AD-MINISTRATION TO IMPROVE AND SPEED WOUND HEALING BEGAN IN 1989 ON BURN PATIENTS AS PART OF AN ACUTE-HEALING THERAPY. FURTHER CLINICAL STUDIES BASED ON TOPICALLY ADMINISTERING EGF TO DIFFERENT CHRONIC WOUNDS RESULTED IN DISAPPOINTING OUT-COMES. AN ANALYSIS OF THE LITERATURE ON UNSUCCESSFUL CLINICAL TRIALS IDENTIFI ED A LACK OF KNOWLEDGE CONCERNING: (I) MOLECULAR AND CELLULAR FOUNDATIONS OF WOUND CHRONICITY AND (II) THE PHAR-MACODYNAMIC REQUISITES GOVERNING EGF INTERACTION WITH ITS RECEPTOR TO PROMOTE CELL RESPONSE. YET, EGF INTRA- AND PERILE-SIONAL INFI LTRATION WERE SHOWN TO CIRCUMVENT THE PHARMACODY-NAMIC LIMITATIONS OF TOPICAL APPLICATION. SINCE THE FI RST STUDIES, THE FOLLOWING DECADES OF BASIC AND CLINICAL RESEARCH ON EGF THERAPY FOR PROBLEM WOUNDS HAVE SHED LIGHT ON POTENTIAL USES OF GROWTH FACTORS IN REGENERATIVE MEDICINE. EGF'S MOLECULAR AND BIOCHEMICAL EFFECTS AT BOTH LOCAL AND SYSTEMIC LEVELS ARE DIVERSE: (1) DOWNREGULATION OF GENES ENCODING INFL AMMATION MEDIATORS AND INCREASED EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION, ANGIOGENESIS AND MATRIX SECRETION; (2) EGF IN-TERVENTION POSITIVELY IMPACTS BOTH MESENCHYMAL AND EPITHELIAL CELLS, REDUCING INFL AMMATION AND STIMULATING THE RECRUITMENT OF PRECURSOR CIRCULATING CELLS THAT PROMOTE THE FORMATION OF NEW BLOOD VESSELS; (3) AT THE SUBCELLULAR LEVEL, UPREGULATION OF THE EGF RECEPTOR WITH SUBSEQUENT INTRACELLULAR TRAFFI CKING, INCLUD-ING MITOCHONDRIAL ALLOCATION ALONG WITH RESTORED MORPHOLOGY OF MULTIPLE ORGANELLES; AND (4) LOCAL EGF INFI LTRATION RESULTING IN A SYSTEMIC, ORGANISMAL REPERCUSSION, THUS CONTRIBUTING TO ATTENUATION OF CIRCULATING INFL AMMATORY AND CATABOLIC REAC-TANTS, RESTORED REDUCTION-OXIDATION BALANCE, AND DECREASED TOXIC GLYCATION PRODUCTS AND SOLUBLE APOPTOGENIC EFFECTORS. IT IS LIKELY THAT EGF TREATMENT MAY REARRANGE CRITICAL EPIGENETIC DRIVERS OF DIABETIC METABOLIC MEMORY. KEYWORDS EPIDERMAL GROWTH FACTOR, DIABETES, DIABETES COMPLICATIONS, WOUND HEALING, DIABETIC FOOT, AMPUTATION, ULCER, CUBA. 2020 13 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 14 5726 28 SKIN WELL-BEING IN DIABETES: ROLE OF MACROPHAGES. MACROPHAGES ARE KEY PLAYERS IN WOUND HEALING- ALONG WITH MEDIATING THE ACUTE INFLAMMATORY RESPONSE, MACROPHAGES ACTIVATE CUTANEOUS EPITHELIAL CELLS AND PROMOTE TISSUE REPAIR. DIABETES COMPLICATIONS, INCLUDING DIABETIC CHRONIC WOUNDS, ARE ACCOMPANIED BY PERSISTENT INFLAMMATION AND MACROPHAGE MALFUNCTION. SEVERAL STUDIES INDICATE THAT HYPERGLYCEMIA INDUCES VARIOUS ALTERATIONS THAT AFFECT MACROPHAGE FUNCTION IN WOUND HEALING INCLUDING EPIGENETIC CHANGES, IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY MODULATORS, AND INSENSITIVITY TO PROLIFERATIVE STIMULI. IN THIS REVIEW, WE BRIEFLY SUMMARIZE RECENT STUDIES REGARDING THOSE ALTERATIONS AND THEIR IMPLICATIONS ON SKIN WELL-BEING IN DIABETES. 2020 15 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 16 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 17 3630 28 INCLUSION OF SOCIAL AND STRUCTURAL DETERMINANTS OF HEALTH TO ADVANCE UNDERSTANDING OF THEIR INFLUENCE ON THE BIOLOGY OF CHRONIC DISEASE. SOCIAL DETERMINANTS OF HEALTH (SDOH) CONSIDER SOCIAL, POLITICAL, AND ECONOMIC FACTORS THAT CONTRIBUTE TO HEALTH DISPARITIES IN PATIENTS AND POPULATIONS. THE MOST COMMON HEALTH-RELATED SDOH EXPOSURES ARE FOOD AND HOUSING INSECURITY, FINANCIAL INSTABILITY, TRANSPORTATION NEEDS, LOW LEVELS OF EDUCATION, AND PSYCHOSOCIAL STRESS. THESE DOMAINS DESCRIBE RISKS THAT CAN IMPACT HEALTH OUTCOMES MORE THAN HEALTH CARE. EPIDEMIOLOGIC AND TRANSLATIONAL RESEARCH DEMONSTRATES THAT SDOH FACTORS REPRESENT EXPOSURES THAT PREDICT HARM AND IMPACT THE HEALTH OF INDIVIDUALS. INTERNATIONAL AND NATIONAL GUIDELINES URGE HEALTH PROFESSIONALS TO ADDRESS SDOH IN CLINICAL PRACTICE AND PUBLIC HEALTH. THE FURTHER IMPLEMENTATION OF THESE RECOMMENDATIONS INTO BASIC AND TRANSLATIONAL RESEARCH, HOWEVER, IS LAGGING. HEREIN, WE CONSIDER A PRECISION HEALTH FRAMEWORK TO DESCRIBE HOW SDOH CONTRIBUTES TO THE EXPOSOME AND EXACERBATES PHYSIOLOGIC PATHWAYS THAT LEAD TO CHRONIC DISEASE. SDOH FACTORS ARE ASSOCIATED WITH VARIOUS FORMS OF STRESSORS THAT IMPACT PHYSIOLOGICAL PROCESSES THROUGH EPIGENETIC, INFLAMMATORY, AND REDOX REGULATION. MANY SDOH EXPOSURES MAY ADD TO OR POTENTIATE THE PATHOLOGIC EFFECTS OF ADDITIONAL ENVIRONMENTAL EXPOSURES. THIS OVERVIEW AIMS TO INFORM BASIC LIFE SCIENCE AND TRANSLATIONAL RESEARCHERS ABOUT SDOH EXPOSURES THAT CAN CONFOUND ASSOCIATIONS BETWEEN CLASSIC BIOMEDICAL DETERMINANTS OF DISEASE AND HEALTH OUTCOMES. TO ADVANCE THE STUDY OF TOXICOLOGY THROUGH EITHER QUALITATIVE OR QUANTITATIVE ASSESSMENT OF EXPOSURES TO CHEMICAL AND BIOLOGICAL SUBSTANCES, A MORE COMPLETE ENVIRONMENTAL EVALUATION SHOULD INCLUDE SDOH EXPOSURES. WE DISCUSS COMMON APPROACHES TO MEASURE SDOH FACTORS AT INDIVIDUAL AND POPULATION LEVELS AND REVIEW THE ASSOCIATIONS BETWEEN SDOH RISK FACTORS AND PHYSIOLOGIC MECHANISMS THAT INFLUENCE CHRONIC DISEASE. WE PROVIDE CLINICAL AND POLICY-BASED MOTIVATION TO ENCOURAGE RESEARCHERS TO CONSIDER THE IMPACT OF SDOH EXPOSURES ON STUDY RESULTS AND DATA INTERPRETATION. WITH VALID MEASURES OF SDOH FACTORS INCORPORATED INTO STUDY DESIGN AND ANALYSES, FUTURE TOXICOLOGICAL RESEARCH MAY CONTRIBUTE TO AN EVIDENCE BASE THAT CAN BETTER INFORM PREVENTION AND TREATMENT OPTIONS, TO IMPROVE EQUITABLE CLINICAL CARE AND POPULATION HEALTH. (C) 2022 WILEY PERIODICALS LLC. 2022 18 465 32 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT. 2017 19 630 22 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 20 1896 28 ENDOTHELIAL-TO-MESENCHYMAL TRANSITION: AN UNDERAPPRECIATED MEDIATOR OF DIABETIC COMPLICATIONS. DIABETES AND ITS COMPLICATIONS REPRESENT A GREAT BURDEN ON THE GLOBAL HEALTHCARE SYSTEM. DIABETIC COMPLICATIONS ARE FUNDAMENTALLY DISEASES OF THE VASCULATURE, WITH ENDOTHELIAL CELLS BEING THE CENTERPIECE OF EARLY HYPERGLYCEMIA-INDUCED CHANGES. ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IS A TIGHTLY REGULATED PROCESS THAT RESULTS IN ENDOTHELIAL CELLS LOSING ENDOTHELIAL CHARACTERISTICS AND DEVELOPING MESENCHYMAL TRAITS. ALTHOUGH ENDOTHELIAL-TO-MESENCHYMAL TRANSITION HAS BEEN FOUND TO OCCUR WITHIN MOST OF THE MAJOR COMPLICATIONS OF DIABETES, IT HAS NOT BEEN A MAJOR FOCUS OF STUDY OR A COMMON TARGET IN THE TREATMENT OR PREVENTION OF DIABETIC COMPLICATIONS. IN THIS REVIEW WE SUMMARIZE THE IMPORTANCE OF ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN EACH MAJOR DIABETIC COMPLICATION, EXAMINE SPECIFIC MECHANISMS AT PLAY, AND HIGHLIGHT POTENTIAL MECHANISMS TO PREVENT ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN EACH OF THE MAJOR CHRONIC COMPLICATIONS OF DIABETES. 2023