1 1713 108 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 2 2953 35 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 5922 32 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 4 2976 48 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 5 2171 36 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 6 2248 34 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 2307 34 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 2163 42 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 9 2381 32 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 10 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 11 2190 47 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 12 2180 30 EPIGENETIC MECHANISMS OF PANCREATOBILIARY FIBROSIS. PURPOSE OF REVIEW: THE GOAL OF THIS MANUSCRIPT IS TO REVIEW THE CURRENT LITERATURE RELATED TO FIBROGENESIS IN THE PANCREATOBILIARY SYSTEM AND HOW THIS PROCESS CONTRIBUTES TO PANCREATIC AND BILIARY DISEASES. IN PARTICULAR, WE SEEK TO DEFINE THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC MECHANISMS THAT GOVERN AND REGULATE TISSUE FIBROSIS IN THESE ORGANS. A BETTER UNDERSTANDING OF THESE UNDERLYING MOLECULAR EVENTS WILL SET THE STAGE FOR FUTURE EPIGENETIC THERAPEUTICS. RECENT FINDINGS: WE HIGHLIGHT THE SIGNIFICANT ADVANCES THAT HAVE BEEN MADE IN DEFINING THE PATHOGENESIS OF PANCREATOBILIARY FIBROSIS AS IT RELATES TO CHRONIC PANCREATITIS, PANCREATIC CANCER, AND THE FIBRO-OBLITERATIVE CHOLANGIOPATHIES. WE ALSO REVIEW THE CELL TYPES INVOLVED AS WELL AS CONCEPTS RELATED TO EPITHELIAL-MESENCHYMAL CROSSTALK. FURTHERMORE, WE OUTLINE IMPORTANT SIGNALING PATHWAYS (E.G., TGFBETA) AND DIVERSE EPIGENETIC PROCESSES (I.E., DNA METHYLATION, NON-CODING RNAS, HISTONE MODIFICATIONS, AND 3D CHROMATIN REMODELING) THAT REGULATE FIBROGENIC GENE NETWORKS IN THESE CONDITIONS. WE REVIEW A GROWING BODY OF SCIENTIFIC EVIDENCE LINKING EPIGENETIC REGULATORY EVENTS TO FIBROTIC DISEASE STATES IN THE PANCREAS AND BILIARY SYSTEM. ADVANCES IN THIS UNDERSTUDIED AREA WILL BE CRITICAL TOWARD DEVELOPING EPIGENETIC PHARMACOLOGICAL APPROACHES THAT MAY LEAD TO MORE EFFECTIVE TREATMENTS FOR THESE DEVASTATING AND DIFFICULT TO TREAT DISORDERS. 2019 13 1871 36 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 14 2491 35 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 15 3404 30 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 16 2570 31 EPIGENETICS OF CHRONIC INFLAMMATORY DISEASES. CHRONIC, NONCOMMUNICABLE, AND INFLAMMATION-ASSOCIATED DISEASES REMAIN THE LARGEST CAUSE OF MORBIDITY AND MORTALITY GLOBALLY AND WITHIN THE UNITED STATES. THIS IS MAINLY DUE TO OUR LIMITED UNDERSTANDING OF THE MOLECULAR MECHANISMS THAT UNDERLIE THESE COMPLEX PATHOLOGIES. THE AVAILABLE EVIDENCE INDICATES THAT STUDIES OF EPIGENETICS (TRADITIONALLY DEFINED AS THE HERITABLE CHANGES TO GENE EXPRESSION THAT ARE INDEPENDENT OF CHANGES TO DNA) ARE SIGNIFICANTLY ADVANCING OUR KNOWLEDGE OF THESE INFLAMMATORY CONDITIONS. THIS REVIEW WILL FOCUS ON EPIGENETIC STUDIES OF THREE DISEASES, THAT ARE AMONG THE MOST BURDENSOME GLOBALLY: CARDIOVASCULAR DISEASE, THE NUMBER ONE CAUSE OF DEATHS WORLDWIDE, TYPE 2 DIABETES AND, ALZHEIMER'S DISEASE. THE CURRENT STATUS OF EPIGENETIC RESEARCH, INCLUDING THE ABILITY TO PREDICT DISEASE RISK, AND KEY PATHOPHYSIOLOGICAL DEFECTS ARE DISCUSSED. THE SIGNIFICANCE OF DEFINING THE CONTRIBUTION OF EPIGENETIC DEFECTS TO NONRESOLVING INFLAMMATION AND AGING, EACH ASSOCIATED WITH THESE DISEASES, IS HIGHLIGHTED, AS THESE ARE LIKELY TO PROVIDE NEW INSIGHTS INTO INFLAMMATORY DISEASE PATHOGENESIS. 2019 17 6131 37 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 18 2028 30 EPIGENETIC CHANGES IN DIABETES. DIABETES IS A MULTIFACTORIAL DISEASE WITH NUMEROUS PATHWAYS INFLUENCING ITS PROGRESSION AND RECENT OBSERVATIONS SUGGEST THAT THE COMPLEXITY OF THE DISEASE CANNOT BE ENTIRELY ACCOUNTED FOR BY GENETIC PREDISPOSITION. A COMPELLING ARGUMENT FOR AN EPIGENETIC COMPONENT IS RAPIDLY EMERGING. EPIGENETIC PROCESSES AT THE CHROMATIN TEMPLATE SIGNIFICANTLY SENSITIZE TRANSCRIPTIONAL AND PHENOTYPIC OUTCOMES TO ENVIRONMENTAL SIGNALING INFORMATION INCLUDING METABOLIC STATE, NUTRITIONAL REQUIREMENTS AND HISTORY. EPIGENETIC MECHANISMS IMPACT GENE EXPRESSION THAT COULD PREDISPOSE INDIVIDUALS TO THE DIABETIC PHENOTYPE DURING INTRAUTERINE AND EARLY POSTNATAL DEVELOPMENT, AS WELL AS THROUGHOUT ADULT LIFE. FURTHERMORE, EPIGENETIC CHANGES COULD ACCOUNT FOR THE ACCELERATED RATES OF CHRONIC AND PERSISTENT MICROVASCULAR AND MACROVASCULAR COMPLICATIONS ASSOCIATED WITH DIABETES. EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES IDENTIFIED POOR GLYCEMIC CONTROL AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF DIABETIC COMPLICATIONS AND HIGHLIGHT THE REQUIREMENT FOR EARLY INTERVENTION. EARLY EXPOSURE TO HYPERGLYCEMIA CAN DRIVE THE DEVELOPMENT OF COMPLICATIONS THAT MANIFEST LATE IN THE PROGRESSION OF THE DISEASE AND PERSIST DESPITE IMPROVED GLYCEMIC CONTROL, INDICATING A MEMORY OF THE METABOLIC INSULT. UNDERSTANDING THE MOLECULAR EVENTS THAT UNDERLIE THESE TRANSCRIPTIONAL CHANGES WILL SIGNIFICANTLY CONTRIBUTE TO NOVEL THERAPEUTIC INTERVENTIONS TO PREVENT, REVERSE OR RETARD THE DELETERIOUS EFFECTS OF THE DIABETIC MILIEU. 2013 19 2154 42 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 20 4451 30 MOLECULAR MECHANISMS AND FUNCTIONS OF LNCRNAS IN THE INFLAMMATORY REACTION OF DIABETES MELLITUS. DIABETES IS A CHRONIC INFLAMMATORY STATE, AND SEVERAL STUDIES HAVE SHOWN THAT THE MECHANISMS OF INSULIN RESISTANCE AND ABNORMAL ISLET BETA-CELL FUNCTION IN DIABETES ARE CLOSELY RELATED TO INFLAMMATORY REACTIONS. INFLAMMATION PLAYS A CRITICAL ROLE IN DIABETIC COMPLICATIONS. LONG NONCODING RNAS (LNCRNAS), A NEW AREA OF GENOMIC RESEARCH FOR GENE REGULATION, HAVE COMPLEX BIOLOGICAL FUNCTIONS IN VARIOUS ASPECTS OF CELLULAR BIOLOGICAL ACTIVITY. RECENT STUDIES HAVE SHOWN THAT LNCRNAS ARE ASSOCIATED WITH THE REGULATION OF INFLAMMATORY RESPONSES IN VARIOUS WAYS, INCLUDING AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVELS. THIS PAPER PRESENTS A BRIEF REVIEW OF STUDIES ON THE MECHANISMS OF LNCRNAS IN DIABETIC INFLAMMATION. THE PURPOSE OF THIS ARTICLE IS TO DETERMINE THE ROLE OF LNCRNAS IN THE PROCESS OF DIABETIC INFLAMMATION AND TO PROVIDE NEW STRATEGIES FOR THE USE OF LNCRNAS IN THE TREATMENTS FOR DIABETIC INFLAMMATION. 2021