1 776 112 CELL- AND TISSUE-SPECIFIC EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC INFLAMMATION IN INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) IS A CHRONIC METABOLIC DISORDER CHARACTERIZED BY HYPERGLYCAEMIA, WHICH CAN CAUSE MICRO- AND MACROVASCULAR COMPLICATIONS. CHRONIC INFLAMMATION MAY BE THE CAUSE AND RESULT OF T2DM, AND ITS RELATED COMPLICATIONS AS AN IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY CYTOKINES CAN AFFECT IMMUNE FUNCTIONS. APART FROM GENETIC CHANGES OCCURRING WITHIN THE BODY RESULTING IN INFLAMMATION IN T2DM, EPIGENETIC MODIFICATIONS CAN MODIFY GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES SUCH AS AN UNHEALTHY DIET, LACK OF EXERCISE AND OBESITY. THE MOST WIDELY STUDIED EPIGENETIC MODIFICATION, DNA METHYLATION (DNAM), REGULATES GENE EXPRESSION AND MAY MANIPULATE INFLAMMATORY GENES TO INCREASE OR DECREASE INFLAMMATION ASSOCIATED WITH T2DM. THIS REVIEW EXPLORES THE STUDIES RELATED TO EPIGENETIC CHANGES, MORE SPECIFICALLY DNAM, ASSOCIATED WITH CHRONIC INFLAMMATION IN T2DM, AT BOTH THE CELL AND TISSUE LEVELS. STUDYING EPIGENETIC ALTERATIONS DURING INFLAMMATORY RESPONSE, AS A RESULT OF GENETIC AND ENVIRONMENTAL SIGNALS, CREATES OPPORTUNITIES FOR THE DEVELOPMENT OF "EARLY DETECTION/RELATIVE RISK" TESTS TO AID IN PREVENTION OF T2DM. UNDERSTANDING INFLAMMATION IN T2DM AT THE GENE LEVEL IN INFLAMMATION-ASSOCIATED CELLS AND TISSUES MAY PROVIDE FURTHER INSIGHT FOR THE DEVELOPMENT OF SPECIFIC THERAPEUTIC TARGETS FOR THE DISORDER. 2018 2 3748 47 INSIGHTS INTO THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING IN DIABETES MELLITUS. BACKGROUND: DIABETES MELLITUS IS A METABOLIC DISORDER THAT IS CHARACTERIZED BY IMPAIRED GLUCOSE TOLERANCE RESULTING FROM DEFECTS IN INSULIN SECRETION, INSULIN ACTION, OR BOTH. EPIGENETIC MODIFICATIONS, WHICH ARE DEFINED AS INHERITED CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN GENE SEQUENCE, ARE INVOLVED IN THE ETIOLOGY OF DIABETES. METHODS: IN THIS REVIEW, WE FOCUSED ON THE ROLE OF DNA METHYLATION AND PROTEIN MISFOLDING AND THEIR CONTRIBUTION TO THE DEVELOPMENT OF BOTH TYPE 1 AND TYPE 2 DIABETES MELLITUS. RESULTS: CHANGES IN DNA METHYLATION IN PARTICULAR ARE HIGHLY ASSOCIATED WITH THE DEVELOPMENT OF DIABETES. PROTEIN FUNCTION IS DEPENDENT ON THEIR PROPER FOLDING IN THE ENDOPLASMIC RETICULUM. DEFECTIVE PROTEIN FOLDING AND CONSEQUENTLY THEIR FUNCTIONS HAVE ALSO BEEN REPORTED TO PLAY A ROLE. EARLY TREATMENT OF DIABETES HAS PROVEN TO BE OF GREAT BENEFIT, AS EVEN TRANSIENT HYPERGLYCEMIA MAY LEAD TO PATHOLOGICAL EFFECTS AND COMPLICATIONS LATER ON. THIS HAS BEEN EXPLAINED BY THE THEORY OF THE DEVELOPMENT OF A METABOLIC MEMORY IN DIABETES. THE BASIS FOR THIS METABOLIC MEMORY WAS ATTRIBUTED TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, NON-ENZYMATIC GLYCATION OF PROTEINS AND IMPORTANTLY, EPIGENETIC CHANGES. THIS HIGHLIGHTS THE IMPORTANCE OF LINKING NEW THERAPEUTICS TARGETING EPIGENETIC MECHANISMS WITH TRADITIONAL ANTIDIABETIC DRUGS. CONCLUSION: ALTHOUGH NEW DATA IS EVOLVING ON THE RELATION BETWEEN DNA METHYLATION, PROTEIN MISFOLDING, AND THE ETIOLOGY OF DIABETES, MORE STUDIES ARE REQUIRED FOR DEVELOPING NEW RELEVANT DIAGNOSTICS AND THERAPEUTICS. 2019 3 2163 37 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 4 6067 44 THE DIABETES MELLITUS-ATHEROSCLEROSIS CONNECTION: THE ROLE OF LIPID AND GLUCOSE METABOLISM AND CHRONIC INFLAMMATION. DIABETES MELLITUS COMPRISES A GROUP OF CARBOHYDRATE METABOLISM DISORDERS THAT SHARE A COMMON MAIN FEATURE OF CHRONIC HYPERGLYCEMIA THAT RESULTS FROM DEFECTS OF INSULIN SECRETION, INSULIN ACTION, OR BOTH. INSULIN IS AN IMPORTANT ANABOLIC HORMONE, AND ITS DEFICIENCY LEADS TO VARIOUS METABOLIC ABNORMALITIES IN PROTEINS, LIPIDS, AND CARBOHYDRATES. ATHEROSCLEROSIS DEVELOPS AS A RESULT OF A MULTISTEP PROCESS ULTIMATELY LEADING TO CARDIOVASCULAR DISEASE ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. ALTERATION OF LIPID METABOLISM IS A RISK FACTOR AND CHARACTERISTIC FEATURE OF ATHEROSCLEROSIS. POSSIBLE LINKS BETWEEN THE TWO CHRONIC DISORDERS DEPENDING ON ALTERED METABOLIC PATHWAYS HAVE BEEN INVESTIGATED IN NUMEROUS STUDIES. IT WAS SHOWN THAT BOTH TYPES OF DIABETES MELLITUS CAN ACTUALLY INDUCE ATHEROSCLEROSIS DEVELOPMENT OR FURTHER ACCELERATE ITS PROGRESSION. ELEVATED GLUCOSE LEVEL, DYSLIPIDEMIA, AND OTHER METABOLIC ALTERATIONS THAT ACCOMPANY THE DISEASE DEVELOPMENT ARE TIGHTLY INVOLVED IN THE PATHOGENESIS OF ATHEROSCLEROSIS AT ALMOST EVERY STEP OF THE ATHEROGENIC PROCESS. CHRONIC INFLAMMATION IS CURRENTLY CONSIDERED AS ONE OF THE KEY FACTORS IN ATHEROSCLEROSIS DEVELOPMENT AND IS PRESENT STARTING FROM THE EARLIEST STAGES OF THE PATHOLOGY INITIATION. IT MAY ALSO BE REGARDED AS ONE OF THE POSSIBLE LINKS BETWEEN ATHEROSCLEROSIS AND DIABETES MELLITUS. HOWEVER, THE DATA AVAILABLE SO FAR DO NOT ALLOW FOR DEVELOPING EFFECTIVE ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES THAT WOULD STOP ATHEROSCLEROTIC LESION PROGRESSION OR INDUCE LESION REDUCTION. IN THIS REVIEW, WE SUMMARIZE THE MAIN ASPECTS OF DIABETES MELLITUS THAT POSSIBLY AFFECT THE ATHEROGENIC PROCESS AND ITS RELATIONSHIP WITH CHRONIC INFLAMMATION. WE ALSO DISCUSS THE ESTABLISHED PATHOPHYSIOLOGICAL FEATURES THAT LINK ATHEROSCLEROSIS AND DIABETES MELLITUS, SUCH AS OXIDATIVE STRESS, ALTERED PROTEIN KINASE SIGNALING, AND THE ROLE OF CERTAIN MIRNA AND EPIGENETIC MODIFICATIONS. 2020 5 6335 40 THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS. DIABETES MELLITUS (DM) IS A CHRONIC CONDITION CHARACTERISED BY BETA CELL DYSFUNCTION AND PERSISTENT HYPERGLYCAEMIA. THE DISORDER CAN BE DUE TO THE ABSENCE OF ADEQUATE PANCREATIC INSULIN PRODUCTION OR A WEAK CELLULAR RESPONSE TO INSULIN SIGNALLING. AMONG THE THREE TYPES OF DM, NAMELY, TYPE 1 DM (T1DM), TYPE 2 DM (T2DM), AND GESTATIONAL DM (GDM); T2DM ACCOUNTS FOR ALMOST 90% OF DIABETES CASES WORLDWIDE.EPIGENETIC TRAITS ARE STABLY HERITABLE PHENOTYPES THAT RESULT FROM CERTAIN CHANGES THAT AFFECT GENE FUNCTION WITHOUT ALTERING THE GENE SEQUENCE. WHILE EPIGENETIC TRAITS ARE CONSIDERED REVERSIBLE MODIFICATIONS, THEY CAN BE INHERITED MITOTICALLY AND MEIOTICALLY. IN ADDITION, EPIGENETIC TRAITS CAN RANDOMLY ARISE IN RESPONSE TO ENVIRONMENTAL FACTORS OR CERTAIN GENETIC MUTATIONS OR LESIONS, SUCH AS THOSE AFFECTING THE ENZYMES THAT CATALYSE THE EPIGENETIC MODIFICATION. IN THIS REVIEW, WE FOCUS ON THE ROLE OF DNA METHYLATION, A TYPE OF EPIGENETIC MODIFICATION, IN THE PATHOGENESIS OF T2DM. 2020 6 2336 39 EPIGENETIC REGULATION OF INFLAMMATORY FACTORS IN ADIPOSE TISSUE. OBESITY IS A STRONG RISK FACTOR FOR INSULIN RESISTANCE. CHRONIC LOW-GRADE TISSUE INFLAMMATION AND SYSTEMIC INFLAMMATION HAVE BEEN PROPOSED AS MAJOR MECHANISMS THAT PROMOTE INSULIN RESISTANCE IN OBESITY. ADIPOSE TISSUE HAS BEEN RECOGNIZED AS A NEXUS BETWEEN INFLAMMATION AND METABOLISM, BUT HOW EXACTLY INFLAMMATORY GENE EXPRESSION IS ORCHESTRATED DURING THE DEVELOPMENT OF OBESITY IS NOT WELL UNDERSTOOD. EPIGENETIC MODIFICATIONS ARE DEFINED AS HERITABLE CHANGES IN GENE EXPRESSION AND CELLULAR FUNCTION WITHOUT CHANGES TO THE ORIGINAL DNA SEQUENCE. THE MAJOR EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS, NUCLEOPOSITIONING/REMODELING AND CHROMATIN REORGANIZATION. EPIGENETIC MECHANISMS PROVIDE A CRITICAL LAYER OF GENE REGULATION IN RESPONSE TO ENVIRONMENTAL CHANGES. ACCUMULATING EVIDENCE SUPPORTS THAT EPIGENETICS PLAYS A LARGE ROLE IN THE REGULATION OF INFLAMMATORY GENES IN ADIPOCYTES AND ADIPOSE-RESIDENT IMMUNE CELL TYPES. THIS REVIEW FOCUSES ON THE ASSOCIATION BETWEEN ADIPOSE TISSUE INFLAMMATION IN OBESITY AND MAJOR EPIGENETIC MODIFICATIONS. 2021 7 6341 31 THE ROLE OF EPIGENETIC MODIFICATIONS IN LATE COMPLICATIONS IN TYPE 1 DIABETES. TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE IN WHICH THE DESTRUCTION OF PANCREATIC BETA CELLS LEADS TO HYPERGLYCEMIA. THE PREVENTION OF HYPERGLYCEMIA IS VERY IMPORTANT TO AVOID OR AT LEAST POSTPONE THE DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS, ALSO KNOWN AS LATE COMPLICATIONS. THESE INCLUDE DIABETIC RETINOPATHY, CHRONIC RENAL FAILURE, DIABETIC NEUROPATHY, AND CARDIOVASCULAR DISEASES. THE IMPACT OF LONG-TERM HYPERGLYCEMIA HAS BEEN SHOWN TO PERSIST LONG AFTER THE NORMALIZATION OF BLOOD GLUCOSE LEVELS, A PHENOMENON KNOWN AS METABOLIC MEMORY. IT IS BELIEVED THAT EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, PLAY AN IMPORTANT ROLE IN METABOLIC MEMORY. THE AIM OF THIS REVIEW IS TO ADDRESS THE IMPACT OF LONG-TERM HYPERGLYCEMIA ON EPIGENETIC MARKS IN LATE COMPLICATIONS OF TYPE 1 DIABETES. 2022 8 2613 44 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 9 4425 50 MOLECULAR BASIS OF AGEING IN CHRONIC METABOLIC DISEASES. AIM: OVER THE LAST DECADES, THE SHIFT IN AGE DISTRIBUTION TOWARDS OLDER AGES AND THE PROGRESSIVE AGEING WHICH HAS OCCURRED IN MOST POPULATIONS HAVE BEEN PARALLELED BY A GLOBAL EPIDEMIC OF OBESITY AND ITS RELATED METABOLIC DISORDERS, PRIMARILY, TYPE 2 DIABETES (T2D). DYSFUNCTION OF THE ADIPOSE TISSUE (AT) IS WIDELY RECOGNIZED AS A SIGNIFICANT HALLMARK OF THE AGEING PROCESS THAT, IN TURN, RESULTS IN SYSTEMIC METABOLIC ALTERATIONS. THESE INCLUDE INSULIN RESISTANCE, ACCUMULATION OF ECTOPIC LIPIDS AND CHRONIC INFLAMMATION, WHICH ARE RESPONSIBLE FOR AN ELEVATED RISK OF OBESITY AND T2D ONSET ASSOCIATED TO AGEING. ON THE OTHER HAND, OBESITY AND T2D, THE PARADIGMS OF AT DYSFUNCTION, SHARE MANY PHYSIOLOGICAL CHARACTERISTICS WITH THE AGEING PROCESS, SUCH AS AN INCREASED BURDEN OF SENESCENT CELLS AND EPIGENETIC ALTERATIONS. THUS, THESE CHRONIC METABOLIC DISORDERS MAY REPRESENT A STATE OF ACCELERATED AGEING. MATERIALS AND METHODS: A MORE PRECISE EXPLANATION OF THE FUNDAMENTAL AGEING MECHANISMS THAT OCCUR IN AT AND A DEEPER UNDERSTANDING OF THEIR ROLE IN THE INTERPLAY BETWEEN ACCELERATED AGEING AND AT DYSFUNCTION CAN BE A FUNDAMENTAL LEAP TOWARDS NOVEL THERAPIES THAT ADDRESS THE CAUSES, NOT JUST THE SYMPTOMS, OF OBESITY AND T2D, UTILIZING STRATEGIES THAT TARGET EITHER SENESCENT CELLS OR DNA METHYLATION. RESULTS: IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE PATHWAYS THAT LEAD TO AT DYSFUNCTION IN THE CHRONOLOGICAL AGEING PROCESS AS WELL AS THE PATHOPHYSIOLOGY OF OBESITY AND T2D, EMPHASIZING THE CRITICAL ROLE OF CELLULAR SENESCENCE AND DNA METHYLATION. CONCLUSION: FINALLY, WE HIGHLIGHT THE NEED FOR FURTHER RESEARCH FOCUSED ON TARGETING THESE MECHANISMS. 2020 10 2491 29 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 11 6200 34 THE INFLAMMATORY EFFECT OF EPIGENETIC FACTORS AND MODIFICATIONS IN TYPE 2 DIABETES. INFLAMMATION HAS A CENTRAL ROLE IN THE ETIOLOGY OF TYPE 2 DIABETES (T2D) AND ITS COMPLICATIONS. BOTH GENETIC AND EPIGENETIC FACTORS HAVE BEEN IMPLICATED IN THE DEVELOPMENT OF T2D-ASSOCIATED INFLAMMATION. EPIGENETIC MECHANISMS REGULATE THE FUNCTION OF SEVERAL COMPONENTS OF THE IMMUNE SYSTEM. DIABETIC CONDITIONS TRIGGER ABERRANT EPIGENETIC ALTERATIONS THAT CONTRIBUTE TO THE PROGRESSION OF INSULIN RESISTANCE AND BETA-CELL DYSFUNCTION BY INDUCTION OF INFLAMMATORY RESPONSES. THUS, TARGETING EPIGENETIC FACTORS AND MODIFICATIONS, AS ONE OF THE UNDERLYING CAUSES OF INFLAMMATION, COULD LEAD TO THE DEVELOPMENT OF NOVEL IMMUNE-BASED STRATEGIES FOR THE TREATMENT OF T2D. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE EPIGENETIC MECHANISMS INVOLVED IN THE PROPAGATION AND PERPETUATION OF CHRONIC INFLAMMATION IN T2D. WE ALSO DISCUSS THE POSSIBLE ANTI-INFLAMMATORY APPROACHES THAT TARGET EPIGENETIC FACTORS FOR THE TREATMENT OF T2D. 2020 12 2190 44 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 13 1974 39 EPIGENETIC ALTERATIONS CAUSED BY NUTRITIONAL STRESS DURING FETAL PROGRAMMING OF THE ENDOCRINE PANCREAS. NUTRITION DURING CRITICAL PERIODS OF DEVELOPMENT IS ONE OF THE PIVOTAL FACTORS IN ESTABLISHING A LIFELONG HEALTHY METABOLISM. DIFFERENT NUTRITIONAL DEFICIENCIES SUCH AS A LOW AVAILABILITY OF PROTEINS IN THE MATERNAL DIET PRODUCE ALTERATIONS IN OFFSPRING THAT INCLUDE CHANGES IN INSULIN AND GLUCOSE METABOLISM, A DECREASE IN THE SIZE AND NUMBER OF CELLS OF PANCREATIC ISLETS OF LANGERHANS, AND PREMATURE AGEING OF THE SECRETORY FUNCTION OF PANCREATIC BETA CELLS. MOREOVER, IT HAS BEEN REPORTED THAT CHRONIC NUTRITIONAL STRESS IS ASSOCIATED WITH EPIGENETIC ALTERATIONS IN MECHANISMS OF GENE REGULATION DURING PANCREATIC DEVELOPMENT AND FUNCTION. THESE ALTERATIONS CAN LEAD TO DYSFUNCTIONAL STATES IN PANCREATIC BETA CELLS, WHICH IN THE LONG RUN ARE RESPONSIBLE FOR THE ONSET OF METABOLIC DISEASES LIKE TYPE 2 DIABETES. THE PRESENT REVIEW SUMMARIZES THE MOST IMPORTANT EVIDENCE IN RELATION TO THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE REGULATION OF GENE EXPRESSION DURING THE INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS IN ANIMAL MODELS. SUCH MECHANISMS INCLUDE DNA METHYLATION AS WELL AS MODIFICATIONS OF HISTONES AND MICRORNAS (MIRNAS). 2015 14 4793 29 NUTRITIONAL FACTORS, DNA METHYLATION, AND RISK OF TYPE 2 DIABETES AND OBESITY: PERSPECTIVES AND CHALLENGES. A HEALTHY DIET IMPROVES LIFE EXPECTANCY AND HELPS TO PREVENT COMMON CHRONIC DISEASES SUCH AS TYPE 2 DIABETES (T2D) AND OBESITY. THE MECHANISMS DRIVING THESE EFFECTS ARE NOT FULLY UNDERSTOOD, BUT ARE LIKELY TO INVOLVE EPIGENETICS. EPIGENETIC MECHANISMS CONTROL GENE EXPRESSION, MAINTAINING THE DNA SEQUENCE, AND THEREFORE THE FULL GENOMIC INFORMATION INHERITED FROM OUR PARENTS, UNCHANGED. AN INTERESTING FEATURE OF EPIGENETIC CHANGES LIES IN THEIR DYNAMIC NATURE AND REVERSIBILITY. ACCORDINGLY, THEY ARE SUSCEPTIBLE TO CORRECTION THROUGH TARGETED INTERVENTIONS. HERE WE WILL REVIEW THE EVIDENCE SUPPORTING A ROLE FOR NUTRITIONAL FACTORS IN MEDIATING METABOLIC DISEASE RISK THROUGH DNA METHYLATION CHANGES. SPECIAL EMPHASIS WILL BE PLACED ON THE POTENTIAL OF USING DNA METHYLATION TRAITS AS BIOMARKERS TO PREDICT RISK OF OBESITY AND T2D AS WELL AS ON THEIR RESPONSE TO DIETARY AND PHARMACOLOGICAL (EPI-DRUG) INTERVENTIONS. 2019 15 6812 35 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 16 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 17 1523 33 DNA METHYLATION CHANGES AND INFLAMMAGING IN AGING-ASSOCIATED DISEASES. AGING AS AN INEVITABLE PHENOMENON IS ASSOCIATED WITH PERVASIVE CHANGES IN PHYSIOLOGICAL FUNCTIONS. THERE IS A RELATIONSHIP BETWEEN AGING AND THE INCREASE OF SEVERAL CHRONIC DISEASES. MOST AGE-RELATED DISORDERS ARE ACCOMPANIED BY AN UNDERLYING CHRONIC INFLAMMATORY STATE, AS DEMONSTRATED BY LOCAL INFILTRATION OF INFLAMMATORY CELLS AND GREATER LEVELS OF PROINFLAMMATORY CYTOKINES IN THE BLOODSTREAM. WITHIN INFLAMMAGING, MANY EPIGENETIC EVENTS, ESPECIALLY DNA METHYLATION, CHANGE. DURING THE AGING PROCESS, DUE TO ABERRATIONS OF DNA METHYLATION, BIOLOGICAL PROCESSES ARE DISRUPTED, LEADING TO THE EMERGENCE OR PROGRESSION OF A VARIETY OF HUMAN DISEASES, INCLUDING CANCER, NEURODEGENERATIVE DISORDERS, CARDIOVASCULAR DISEASE AND DIABETES. THE FOCUS OF THIS REVIEW IS ON DNA METHYLATION, WHICH IS INVOLVED IN INFLAMMAGING-RELATED ACTIVITIES, AND HOW ITS DYSREGULATION LEADS TO HUMAN DISORDERS. 2022 18 44 48 A COMPREHENSIVE REVIEW ON HIGH -FAT DIET-INDUCED DIABETES MELLITUS: AN EPIGENETIC VIEW. MODERN LIFESTYLE, GENETICS, NUTRITIONAL OVERLOAD THROUGH HIGH-FAT DIET ATTRIBUTED PREVALENCE AND DIABETES OUTCOMES WITH VARIOUS COMPLICATIONS PRIMARILY DUE TO OBESITY IN WHICH ENERGY-DENSE DIETS FREQUENTLY AFFECT METABOLIC HEALTH. ONE POSSIBLE ISSUE USUALLY ASSOCIATED WITH ELEVATED CHRONIC FAT INTAKE IS INSULIN RESISTANCE, AND HYPERGLYCEMIA CONSTITUTES AN IMPORTANT FUNCTION IN ALTERING THE CARBOHYDRATES AND LIPIDS METABOLISM. SIMILARLY, IN ASSESSING HUMAN SUSCEPTIBILITY TO WEIGHT GAIN AND OBESITY, GENETIC VARIATIONS PLAY A CENTRAL ROLE, CONTRIBUTING TO KEEN INTEREST IN IDENTIFYING THE POSSIBLE ROLE OF EPIGENETICS AS A MEDIATOR OF GENE-ENVIRONMENTAL INTERACTIONS INFLUENCING THE PRODUCTION OF TYPE 2 DIABETES MELLITUS AND ITS RELATED CONCERNS. EPIGENETIC MODIFICATIONS ASSOCIATED WITH THE ACCEPTANCE OF A SEDENTARY LIFESTYLE AND ENVIRONMENTAL STRESS FACTORS IN RESPONSE TO ENERGY INTAKE AND EXPENDITURE IMBALANCES COMPLEMENT GENETIC ALTERATIONS AND LEAD TO THE PRODUCTION AND ADVANCEMENT OF METABOLIC DISORDERS SUCH AS DIABETES AND OBESITY. METHYLATION OF DNA, HISTONE MODIFICATIONS, AND INCREASES IN THE EXPRESSION OF NON-CODING RNAS CAN RESULT IN REDUCED TRANSCRIPTIONAL ACTIVITY OF KEY BETA-CELL GENES THUS CREATING INSULIN RESISTANCE. EPIGENETICS CONTRIBUTE TO CHANGES IN THE EXPRESSION OF THE UNDERLYING INSULIN RESISTANCE AND INSUFFICIENCY GENE NETWORKS, ALONG WITH LOW-GRADE OBESITY-RELATED INFLAMMATION, INCREASED ROS GENERATION, AND DNA DAMAGE IN MULTIORGANS. THIS REVIEW FOCUSED ON EPIGENETIC MECHANISMS AND METABOLIC REGULATIONS ASSOCIATED WITH HIGH-FAT DIET (HFD)-INDUCED DIABETES MELLITUS. 2022 19 4273 30 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 20 2789 31 FACTORS INFLUENCING EPIGENETIC MECHANISMS: IS THERE A ROLE FOR BARIATRIC SURGERY? EPIGENETICS IS THE INTERACTION BETWEEN THE GENOME AND ENVIRONMENTAL STIMULI CAPABLE OF INFLUENCING GENE EXPRESSION DURING DEVELOPMENT AND AGING. A LARGE NUMBER OF STUDIES HAVE SHOWN THAT METABOLIC DISEASES ARE HIGHLY ASSOCIATED WITH EPIGENETIC ALTERATIONS, SUGGESTING THAT EPIGENETIC FACTORS MAY PLAY A CENTRAL ROLE IN OBESITY. TO INVESTIGATE THESE RELATIONSHIPS, WE FOCUS OUR ATTENTION ON THE MOST COMMON EPIGENETIC MODIFICATIONS THAT OCCUR IN OBESITY, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS OF HISTONES. WE ALSO CONSIDER BARIATRIC SURGERY AS AN EPIGENETIC FACTOR, EVALUATING HOW THE ANATOMIC AND PHYSIOLOGIC MODIFICATIONS INDUCED BY THESE SURGICAL TECHNIQUES CAN CHANGE GENE EXPRESSION. HERE WE DISCUSS THE IMPORTANCE OF EPIGENETIC MECHANISMS IN CHRONIC DISEASE AND CANCER, AND THE ROLE OF EPIGENETIC DISTURBANCES IN OBESITY, WITH A FOCUS ON THE ROLE OF BARIATRIC SURGERY. 2020