1 1308 151 DEFINING A RESEARCH AGENDA TO ADDRESS THE CONVERGING EPIDEMICS OF TUBERCULOSIS AND DIABETES: PART 2: UNDERLYING BIOLOGIC MECHANISMS. THERE IS GROWING INTEREST IN THE RE-EMERGING INTERACTION BETWEEN TYPE 2 DIABETES (DM) AND TB, BUT THE UNDERLYING BIOLOGIC MECHANISMS ARE POORLY UNDERSTOOD DESPITE THEIR POSSIBLE IMPLICATIONS IN CLINICAL MANAGEMENT. EXPERTS IN EPIDEMIOLOGIC, PUBLIC HEALTH, BASIC SCIENCE, AND CLINICAL STUDIES RECENTLY CONVENED AND IDENTIFIED RESEARCH PRIORITIES FOR ELUCIDATING THE UNDERLYING MECHANISMS FOR THE CO-OCCURRENCE OF TB AND DM. WE IDENTIFIED GAPS IN CURRENT KNOWLEDGE OF ALTERED IMMUNITY IN PATIENTS WITH DM DURING TB, WHERE MOST STUDIES SUGGEST AN UNDERPERFORMING INNATE IMMUNITY, BUT EXAGGERATED ADAPTIVE IMMUNITY TO MYCOBACTERIUM TUBERCULOSIS. VARIOUS MOLECULAR MECHANISMS AND PATHWAYS MAY UNDERLIE THESE OBSERVATIONS IN THE DM HOST. THESE INCLUDE SIGNALING INDUCED BY EXCESS ADVANCED GLYCATION END PRODUCTS AND THEIR RECEPTOR, HIGHER LEVELS OF REACTIVE OXIDATIVE SPECIES AND OXIDATIVE STRESS, EPIGENETIC CHANGES DUE TO CHRONIC HYPERGLYCEMIA, ALTERED NUCLEAR RECEPTORS, AND/OR DIFFERENCES IN CELL METABOLISM (IMMUNOMETABOLISM). STUDIES IN HUMANS AT DIFFERENT STAGES OF DM (NO DM, PRE-DM, AND DM) OR TB (LATENT OR ACTIVE TB) SHOULD BE COMPLEMENTED WITH FINDINGS IN ANIMAL MODELS, WHICH PROVIDE THE UNIQUE OPPORTUNITY TO STUDY EARLY EVENTS IN THE HOST-PATHOGEN INTERACTION. SUCH STUDIES COULD ALSO HELP IDENTIFY BIOMARKERS THAT WILL COMPLEMENT CLINICAL STUDIES IN ORDER TO TAILOR THE PREVENTION OF TB-DM, OR TO AVOID THE ADVERSE TB TREATMENT OUTCOMES THAT ARE MORE LIKELY IN THESE PATIENTS. SUCH STUDIES WILL ALSO INFORM NEW APPROACHES TO HOST-DIRECTED THERAPIES. 2017 2 3676 38 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018 3 3404 37 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 4 6607 50 TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR DISEASE: GENETIC AND EPIGENETIC LINKS. TYPE 2 DIABETES MELLITUS (DM) IS A COMMON METABOLIC DISORDER PREDISPOSING TO DIABETIC CARDIOMYOPATHY AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (CVD), WHICH COULD LEAD TO HEART FAILURE THROUGH A VARIETY OF MECHANISMS, INCLUDING MYOCARDIAL INFARCTION AND CHRONIC PRESSURE OVERLOAD. PATHOGENETIC MECHANISMS, MAINLY LINKED TO HYPERGLYCEMIA AND CHRONIC SUSTAINED HYPERINSULINEMIA, INCLUDE CHANGES IN METABOLIC PROFILES, INTRACELLULAR SIGNALING PATHWAYS, ENERGY PRODUCTION, REDOX STATUS, INCREASED SUSCEPTIBILITY TO ISCHEMIA, AND EXTRACELLULAR MATRIX REMODELING. THE CLOSE RELATIONSHIP BETWEEN TYPE 2 DM AND CVD HAS LED TO THE COMMON SOIL HYPOTHESIS, POSTULATING THAT BOTH CONDITIONS SHARE COMMON GENETIC AND ENVIRONMENTAL FACTORS INFLUENCING THIS ASSOCIATION. HOWEVER, ALTHOUGH THE COMMON RISK FACTORS OF BOTH CVD AND TYPE 2 DM, SUCH AS OBESITY, INSULIN RESISTANCE, DYSLIPIDEMIA, INFLAMMATION, AND THROMBOPHILIA, CAN BE IDENTIFIED IN THE MAJORITY OF AFFECTED PATIENTS, LESS IS KNOWN ABOUT HOW THESE FACTORS INFLUENCE BOTH CONDITIONS, SO THAT EFFORTS ARE STILL NEEDED FOR A MORE COMPREHENSIVE UNDERSTANDING OF THIS RELATIONSHIP. THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL BACKGROUNDS OF BOTH TYPE 2 DM AND CVD HAVE BEEN MORE RECENTLY STUDIED AND UPDATED. HOWEVER, THE UNDERLYING PATHOGENETIC MECHANISMS HAVE SELDOM BEEN INVESTIGATED WITHIN THE BROADER SHARED BACKGROUND, BUT RATHER STUDIED IN THE SPECIFIC CONTEXT OF TYPE 2 DM OR CVD, SEPARATELY. AS THE PRECISE PATHOPHYSIOLOGICAL LINKS BETWEEN TYPE 2 DM AND CVD ARE NOT ENTIRELY UNDERSTOOD AND MANY ASPECTS STILL REQUIRE ELUCIDATION, AN INTEGRATED DESCRIPTION OF THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL INFLUENCES INVOLVED IN THE CONCOMITANT DEVELOPMENT OF BOTH DISEASES IS OF PARAMOUNT IMPORTANCE TO SHED NEW LIGHT ON THE INTERLINKS BETWEEN TYPE 2 DM AND CVD. THIS REVIEW ADDRESSES THE CURRENT KNOWLEDGE OF OVERLAPPING GENETIC AND EPIGENETIC ASPECTS IN TYPE 2 DM AND CVD, INCLUDING MICRORNAS AND LONG NON-CODING RNAS, WHOSE ABNORMAL REGULATION HAS BEEN IMPLICATED IN BOTH DISEASE CONDITIONS, EITHER ETIOLOGICALLY OR AS CAUSE FOR THEIR PROGRESSION. UNDERSTANDING THE LINKS BETWEEN THESE DISORDERS MAY HELP TO DRIVE FUTURE RESEARCH TOWARD AN INTEGRATED PATHOPHYSIOLOGICAL APPROACH AND TO PROVIDE FUTURE DIRECTIONS IN THE FIELD. 2018 5 2190 45 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 6 1360 39 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 7 6034 39 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 8 1385 45 DIABETES IN CHILDHOOD CANCER SURVIVORS: EMERGING CONCEPTS IN PATHOPHYSIOLOGY AND FUTURE DIRECTIONS. WITH ADVANCEMENTS IN CANCER TREATMENT AND SUPPORTIVE CARE, THERE IS A GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS WHO EXPERIENCE A SUBSTANTIAL BURDEN OF COMORBIDITIES RELATED TO HAVING RECEIVED CANCER TREATMENT AT A YOUNG AGE. DESPITE AN OVERALL REDUCTION IN THE INCIDENCE OF MOST CHRONIC HEALTH CONDITIONS IN CHILDHOOD CANCER SURVIVORS OVER THE PAST SEVERAL DECADES, THE CUMULATIVE INCIDENCE OF CERTAIN LATE EFFECTS, IN PARTICULAR DIABETES MELLITUS (DM), HAS INCREASED. THE IMPLICATIONS ARE SIGNIFICANT, BECAUSE DM IS A KEY RISK FACTOR FOR CARDIOVASCULAR DISEASE, A LEADING CAUSE OF PREMATURE DEATH IN CHILDHOOD CANCER SURVIVORS. THE UNDERLYING PATHOPHYSIOLOGY OF DM IN CANCER SURVIVORS IS MULTIFACTORIAL. DM DEVELOPS AT YOUNGER AGES IN SURVIVORS COMPARED TO CONTROLS, WHICH MAY REFLECT AN "ACCELERATED AGING" PHENOTYPE IN THESE INDIVIDUALS. THE TREATMENT-RELATED EXPOSURES (I.E., CHEMOTHERAPY, RADIATION) THAT INCREASE RISK FOR DM IN CHILDHOOD CANCER SURVIVORS MAY BE MORE THAN ADDITIVE WITH ESTABLISHED DM RISK FACTORS (E.G., OLDER AGE, OBESITY, RACE, AND ETHNICITY). EMERGING RESEARCH ALSO POINTS TO PARALLELS IN CELLULAR PROCESSES IMPLICATED IN AGING- AND CANCER TREATMENT-RELATED DM. STILL, THERE REMAINS MARKED INTER-INDIVIDUAL VARIABILITY REGARDING RISK OF DM THAT IS NOT EXPLAINED BY DEMOGRAPHIC AND THERAPEUTIC RISK FACTORS ALONE. RECENT STUDIES HAVE HIGHLIGHTED THE ROLE OF GERMLINE GENETIC RISK FACTORS AND EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH RISK OF DM IN BOTH THE GENERAL AND ONCOLOGY POPULATIONS. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF RECOGNIZED RISK FACTORS FOR DM IN CHILDHOOD CANCER SURVIVORS TO HELP INFORM TARGETED APPROACHES FOR DISEASE SCREENING, PREVENTION, AND TREATMENT. FURTHERMORE, IT HIGHLIGHTS THE EXISTING SCIENTIFIC GAPS IN UNDERSTANDING THE RELATIVE CONTRIBUTIONS OF INDIVIDUAL THERAPEUTIC EXPOSURES AND THE MECHANISMS BY WHICH THEY EXERT THEIR EFFECTS THAT UNIQUELY PREDISPOSE THIS POPULATION TO DM FOLLOWING CANCER TREATMENT. 2023 9 6204 35 THE INFLUENCE OF EPIGENETICS AND INFLAMMATION ON CARDIOMETABOLIC RISKS. CARDIOMETABOLIC DISEASES INCLUDE METABOLIC SYNDROME, OBESITY, TYPE 2 DIABETES MELLITUS, AND HYPERTENSION. EPIGENETIC MODIFICATIONS PARTICIPATE IN CARDIOMETABOLIC DISEASES THROUGH SEVERAL PATHWAYS, INCLUDING INFLAMMATION, VASCULAR DYSFUNCTION, AND INSULIN RESISTANCE. EPIGENETIC MODIFICATIONS, WHICH ENCOMPASS ALTERATIONS TO GENE EXPRESSION WITHOUT MUTATING THE DNA SEQUENCE, HAVE GAINED MUCH ATTENTION IN RECENT YEARS, SINCE THEY HAVE BEEN CORRELATED WITH CARDIOMETABOLIC DISEASES AND MAY BE TARGETED FOR THERAPEUTIC INTERVENTIONS. EPIGENETIC MODIFICATIONS ARE GREATLY INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS DIET, PHYSICAL ACTIVITY, CIGARETTE SMOKING, AND POLLUTION. SOME MODIFICATIONS ARE HERITABLE, INDICATING THAT THE BIOLOGICAL EXPRESSION OF EPIGENETIC ALTERATIONS MAY BE OBSERVED ACROSS GENERATIONS. MOREOVER, MANY PATIENTS WITH CARDIOMETABOLIC DISEASES PRESENT WITH CHRONIC INFLAMMATION, WHICH CAN BE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS. THE INFLAMMATORY ENVIRONMENT WORSENS THE PROGNOSIS OF CARDIOMETABOLIC DISEASES AND FURTHER INDUCES EPIGENETIC MODIFICATIONS, PREDISPOSING PATIENTS TO THE DEVELOPMENT OF OTHER METABOLISM-ASSOCIATED DISEASES AND COMPLICATIONS. A DEEPER UNDERSTANDING OF INFLAMMATORY PROCESSES AND EPIGENETIC MODIFICATIONS IN CARDIOMETABOLIC DISEASES IS NECESSARY TO IMPROVE OUR DIAGNOSTIC CAPABILITIES, PERSONALIZED MEDICINE APPROACHES, AND THE DEVELOPMENT OF TARGETED THERAPEUTIC INTERVENTIONS. FURTHER UNDERSTANDING MAY ALSO ASSIST IN PREDICTING DISEASE OUTCOMES, ESPECIALLY IN CHILDREN AND YOUNG ADULTS. THIS REVIEW DESCRIBES EPIGENETIC MODIFICATIONS AND INFLAMMATORY PROCESSES UNDERLYING CARDIOMETABOLIC DISEASES, AND FURTHER DISCUSSES ADVANCES IN THE RESEARCH FIELD WITH A FOCUS ON SPECIFIC POINTS FOR INTERVENTIONAL THERAPY. 2023 10 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 11 4273 34 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 12 5069 24 PHYSICAL ACTIVITY IN THE PREVENTION OF HUMAN DISEASES: ROLE OF EPIGENETIC MODIFICATIONS. EPIGENETIC MODIFICATION REFERS TO HERITABLE CHANGES IN GENE FUNCTION THAT CANNOT BE EXPLAINED BY ALTERATIONS IN THE DNA SEQUENCE. THE CURRENT LITERATURE CLEARLY DEMONSTRATES THAT THE EPIGENETIC RESPONSE IS HIGHLY DYNAMIC AND INFLUENCED BY DIFFERENT BIOLOGICAL AND ENVIRONMENTAL FACTORS SUCH AS AGING, NUTRIENT AVAILABILITY AND PHYSICAL EXERCISE. AS SUCH, IT IS WELL ACCEPTED THAT PHYSICAL ACTIVITY AND EXERCISE CAN MODULATE GENE EXPRESSION THROUGH EPIGENETIC ALTERNATIONS ALTHOUGH THE TYPE AND DURATION OF EXERCISE ELICITING SPECIFIC EPIGENETIC EFFECTS THAT CAN RESULT IN HEALTH BENEFITS AND PREVENT CHRONIC DISEASES REMAINS TO BE DETERMINED. THIS REVIEW HIGHLIGHTS THE MOST SIGNIFICANT FINDINGS FROM EPIGENETIC STUDIES INVOLVING PHYSICAL ACTIVITY/EXERCISE INTERVENTIONS KNOWN TO BENEFIT CHRONIC DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, CANCER, CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. 2017 13 2163 31 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 14 2570 30 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 15 3848 33 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 16 6183 36 THE IMPACT OF ENVIRONMENTAL FACTORS IN INFLUENCING EPIGENETICS RELATED TO OXIDATIVE STATES IN THE CARDIOVASCULAR SYSTEM. OXIDATIVE STATES EXERT A SIGNIFICANT INFLUENCE ON A WIDE RANGE OF BIOLOGICAL AND MOLECULAR PROCESSES AND FUNCTIONS. WHEN THEIR BALANCE IS SHIFTED TOWARDS ENHANCED AMOUNTS OF FREE RADICALS, PATHOLOGICAL PHENOMENA CAN OCCUR, AS THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IN TISSUE MICROENVIRONMENT OR IN THE SYSTEMIC CIRCULATION CAN BE DETRIMENTAL. EPIDEMIC CHRONIC DISEASES OF WESTERN SOCIETIES, SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND DIABETES CORRELATE WITH THE IMBALANCE OF REDOX HOMEOSTASIS. CURRENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETICS HAVE REVEALED A PARALLEL SCENARIO SHOWING THE INFLUENCE OF OXIDATIVE STRESS AS A MAJOR REGULATOR OF EPIGENETIC GENE REGULATION VIA MODIFICATION OF DNA METHYLATION, HISTONES, AND MICRORNAS. THIS HAS PROVIDED BOTH THE BIOLOGICAL LINK AND A POTENTIAL MOLECULAR EXPLANATION BETWEEN OXIDATIVE STRESS AND CARDIOVASCULAR/METABOLIC PHENOMENA. ACCORDINGLY, IN THIS REVIEW, WE WILL PROVIDE CURRENT INSIGHTS ON THE PHYSIOLOGICAL AND PATHOLOGICAL IMPACT OF CHANGES IN OXIDATIVE STATES ON CARDIOVASCULAR DISORDERS, BY SPECIFICALLY FOCUSING ON THE INFLUENCE OF EPIGENETIC REGULATION. A SPECIAL EMPHASIS WILL HIGHLIGHT THE EFFECT ON EPIGENETIC REGULATION OF HUMAN'S CURRENT LIFE HABITS, EXTERNAL AND ENVIRONMENTAL FACTORS, INCLUDING FOOD INTAKE, TOBACCO, AIR POLLUTION, AND ANTIOXIDANT-BASED APPROACHES. ADDITIONALLY, THE STRATEGY TO QUANTIFY OXIDATIVE STATES IN HUMANS IN ORDER TO DETERMINE WHICH BIOLOGICAL MARKER COULD BEST MATCH A SUBJECT'S PROFILE WILL BE DISCUSSED. 2017 17 806 33 CHALLENGES FOR MODELING AND INTERPRETING THE COMPLEX BIOLOGY OF SEVERE INJURY AND INFLAMMATION. HUMAN INJURY IS ASSOCIATED WITH INFLAMMATORY RESPONSES THAT ARE MODULATED BY THE ACUTE AND CHRONIC ACTIVITY OF ENDOGENOUS FACTORS AND EXOGENOUS INTERVENTIONS. A CHARACTERISTIC FEATURE OF CHRONIC, SEVERE INFLAMMATORY STATES IS THE DIMINISHED SIGNAL OUTPUT VARIABILITY OF MANY ORGAN SYSTEMS, INCLUDING INNATE IMMUNE RESPONSIVENESS AND ENDOGENOUS NEURAL AND ENDOCRINE-MEDIATED FUNCTIONS. THE ATTENUATION OF SIGNAL/RESPONSE VARIABILITY AND INTEGRATION OF FEEDBACK CAPACITY MAY CONTRIBUTE TO SYSTEMIC AND TISSUE-SPECIFIC DETERIORATION OF FUNCTION. SOME WELL-INTENTIONED THERAPIES DIRECTED TOWARD SUPPORT OF SYSTEMIC AND TISSUE FUNCTIONS MAY ACTUALLY PROMOTE THE LOSS OF SYSTEM(S) ADAPTABILITY AND CONTRIBUTE TO ADVERSE OUTCOMES IN SEVERELY STRESSED PATIENTS. IN VIVO AND IN SILICO MODELS OF STRESS, INJURY, AND INFECTION HAVE YET TO FULLY DEFINE THE INFLUENCES OF ONGOING STRESSFUL STIMULAE AS WELL AS GENETIC VARIATION AND EPIGENETIC FACTORS IN THE CONTEXT OF AN EVOLVING INFLAMMATORY STATE. EXPERIMENTAL AND HUMAN MODELS INCORPORATING VARIABLE, ANTECEDENT STRESS(ES) AND ALTERED NEUROENDOCRINE RHYTHMS MIGHT APPROXIMATE THE ALTERED ADAPTABILITY IN IMMUNE AND ORGAN FUNCTION RESPONSES. SUCH MODELS MAY ALSO PROVIDE INSIGHTS INTO THE SALIENT MECHANISMS OF RISK AND OUTCOME MORE PRECISELY THAN DO THE CONSTRAINED STUDY CONDITIONS OF CURRENT ANIMAL OR HUMAN MODELS OF SYSTEMIC INFLAMMATION. 2008 18 4425 42 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 19 2028 42 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 20 2154 40 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