1 241 136 ADIPOCYTE, IMMUNE CELLS, AND MIRNA CROSSTALK: A NOVEL REGULATOR OF METABOLIC DYSFUNCTION AND OBESITY. OBESITY IS CHARACTERIZED AS A COMPLEX AND MULTIFACTORIAL EXCESS ACCRETION OF ADIPOSE TISSUE (AT) ACCOMPANIED WITH ALTERATIONS IN THE IMMUNE RESPONSE THAT AFFECTS VIRTUALLY ALL AGE AND SOCIOECONOMIC GROUPS AROUND THE GLOBE. THE ABNORMAL ACCUMULATION OF AT LEADS TO SEVERAL METABOLIC DISEASES, INCLUDING NONALCOHOLIC FATTY LIVER DISORDER (NAFLD), LOW-GRADE INFLAMMATION, TYPE 2 DIABETES MELLITUS (T2DM), CARDIOVASCULAR DISORDERS (CVDS), AND CANCER. AT IS AN ENDOCRINE ORGAN COMPOSED OF ADIPOCYTES AND IMMUNE CELLS, INCLUDING B-CELLS, T-CELLS AND MACROPHAGES. THESE IMMUNE CELLS SECRETE VARIOUS CYTOKINES AND CHEMOKINES AND CROSSTALK WITH ADIPOKINES TO MAINTAIN METABOLIC HOMEOSTASIS AND LOW-GRADE CHRONIC INFLAMMATION. A NOVEL FORM OF ADIPOKINES, MICRORNA (MIRS), IS EXPRESSED IN MANY DEVELOPING PERIPHERAL TISSUES, INCLUDING ATS, T-CELLS, AND MACROPHAGES, AND MODULATES THE IMMUNE RESPONSE. MIRS ARE ESSENTIAL FOR INSULIN RESISTANCE, MAINTAINING THE TUMOR MICROENVIRONMENT, AND OBESITY-ASSOCIATED INFLAMMATION (OAI). THE ABNORMAL REGULATION OF AT, T-CELLS, AND MACROPHAGE MIRS MAY CHANGE THE FUNCTION OF DIFFERENT ORGANS INCLUDING THE PANCREAS, HEART, LIVER, AND SKELETAL MUSCLE. SINCE OBESITY AND INFLAMMATION ARE CLOSELY ASSOCIATED, THE DYSREGULATED EXPRESSION OF MIRS IN INFLAMMATORY ADIPOCYTES, T-CELLS, AND MACROPHAGES SUGGEST THE IMPORTANCE OF MIRS IN OAI. THEREFORE, IN THIS REVIEW ARTICLE, WE HAVE ELABORATED THE ROLE OF MIRS AS EPIGENETIC REGULATORS AFFECTING ADIPOCYTE DIFFERENTIATION, IMMUNE RESPONSE, AT BROWNING, ADIPOGENESIS, LIPID METABOLISM, INSULIN RESISTANCE (IR), GLUCOSE HOMEOSTASIS, OBESITY, AND METABOLIC DISORDERS. FURTHER, WE WILL DISCUSS A SET OF ALTERED MIRS AS NOVEL BIOMARKERS FOR METABOLIC DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR OBESITY. 2021 2 6182 79 THE IMPACT OF ADIPOSE TISSUE-DERIVED MIRNAS IN METABOLIC SYNDROME, OBESITY, AND CANCER. OBESITY IS A MULTIFACTORIAL AND COMPLEX CONDITION THAT IS CHARACTERIZED BY ABNORMAL AND EXCESSIVE WHITE ADIPOSE TISSUE ACCUMULATION, WHICH CAN LEAD TO THE DEVELOPMENT OF METABOLIC DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS, NONALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASES, AND SEVERAL TYPES OF CANCER. OBESITY IS CHARACTERIZED BY EXCESSIVE ADIPOSE TISSUE ACCUMULATION AND ASSOCIATED WITH ALTERATIONS IN IMMUNITY, DISPLAYING A CHRONIC LOW-GRADE INFLAMMATION PROFILE. ADIPOSE TISSUE IS A DYNAMIC AND COMPLEX ENDOCRINE ORGAN COMPOSED NOT ONLY BY ADIPOCYTES, BUT SEVERAL IMMUNOLOGICAL CELLS, WHICH CAN SECRETE HORMONES, CYTOKINES AND MANY OTHER FACTORS CAPABLE OF REGULATING METABOLIC HOMEOSTASIS AND SEVERAL CRITICAL BIOLOGICAL PATHWAYS. REMARKABLY, ADIPOSE TISSUE IS A MAJOR SOURCE OF CIRCULATING MICRORNAS (MIRNAS), RECENTLY DESCRIBED AS A NOVEL FORM OF ADIPOKINES. SEVERAL ADIPOSE TISSUE-DERIVED MIRNAS ARE DEEPLY ASSOCIATED WITH ADIPOCYTES DIFFERENTIATION AND HAVE BEEN IDENTIFIED WITH AN ESSENTIAL ROLE IN OBESITY-ASSOCIATED INFLAMMATION, INSULIN RESISTANCE, AND TUMOR MICROENVIRONMENT. DURING OBESITY, ADIPOSE TISSUE CAN COMPLETELY CHANGE THE PROFILE OF THE SECRETED MIRNAS, INFLUENCING CIRCULATING MIRNAS AND IMPACTING THE DEVELOPMENT OF DIFFERENT PATHOLOGICAL CONDITIONS, SUCH AS OBESITY, METABOLIC SYNDROME, AND CANCER. IN THIS REVIEW, WE DISCUSS HOW MIRNAS CAN ACT AS EPIGENETIC REGULATORS AFFECTING ADIPOGENESIS, ADIPOCYTE DIFFERENTIATION, LIPID METABOLISM, BROWNING OF THE WHITE ADIPOSE TISSUE, GLUCOSE HOMEOSTASIS, AND INSULIN RESISTANCE, IMPACTING DEEPLY OBESITY AND METABOLIC DISEASES. MOREOVER, WE CHARACTERIZE HOW MIRNAS CAN OFTEN ACT AS ONCOGENIC AND TUMOR SUPPRESSOR MOLECULES, SIGNIFICANTLY MODULATING CANCER ESTABLISHMENT AND PROGRESSION. FURTHERMORE, WE HIGHLIGHT IN THIS MANUSCRIPT HOW ADIPOSE TISSUE-DERIVED MIRNAS CAN FUNCTION AS IMPORTANT NEW THERAPEUTIC TARGETS. 2020 3 6067 47 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 4 2336 34 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 5 3834 47 INVOLVEMENTS OF LONG NONCODING RNAS IN OBESITY-ASSOCIATED INFLAMMATORY DISEASES. OBESITY IS ASSOCIATED WITH CHRONIC LOW-GRADE INFLAMMATION THAT AFFECTS THE PHENOTYPE OF MULTIPLE TISSUES AND THEREFORE IS IMPLICATED IN THE DEVELOPMENT AND PROGRESSION OF SEVERAL AGE-RELATED CHRONIC INFLAMMATORY DISORDERS. IMPORTANTLY, A NEW FAMILY OF NONCODING RNAS, TERMED LONG NONCODING RNAS (LNCRNAS), HAVE BEEN IDENTIFIED AS KEY REGULATORS OF INFLAMMATORY SIGNALLING PATHWAYS THAT CAN MEDIATE BOTH PRETRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL GENE REGULATION. FURTHERMORE, SEVERAL LNCRNAS HAVE BEEN IDENTIFIED, WHICH ARE DIFFERENTIALLY EXPRESSED IN MULTIPLE TISSUE TYPES IN INDIVIDUALS WHO ARE OBESE OR IN PRECLINICAL MODELS OF OBESITY. IN THIS REVIEW, WE EXAMINE THE EVIDENCE FOR THE ROLE OF SEVERAL OF THE MOST WELL-STUDIED LNCRNAS IN THE REGULATION OF INFLAMMATORY PATHWAYS ASSOCIATED WITH OBESITY. WE HIGHLIGHT THE EVIDENCE FOR THEIR DIFFERENTIAL EXPRESSION IN THE OBESE STATE AND IN AGE-RELATED CONDITIONS INCLUDING INSULIN RESISTANCE, TYPE 2 DIABETES (T2D), SARCOPENIA, OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS, WHERE OBESITY PLAYS A SIGNIFICANT ROLE. DETERMINING THE EXPRESSION AND FUNCTIONAL ROLE OF LNCRNAS IN MEDIATING OBESITY-ASSOCIATED CHRONIC INFLAMMATION WILL ADVANCE OUR UNDERSTANDING OF THE EPIGENETIC REGULATORY PATHWAYS THAT UNDERLIE AGE-RELATED INFLAMMATORY DISEASES AND MAY ALSO ULTIMATELY IDENTIFY NEW TARGETS FOR THERAPEUTIC INTERVENTION. 2021 6 776 44 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 7 6006 47 THE ALTERATIONS IN AND THE ROLE OF THE TH17/TREG BALANCE IN METABOLIC DISEASES. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OF METABOLIC DISEASES. THESE INCLUDE OBESITY, TYPE 2 DIABETES MELLITUS, AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE. THE PROINFLAMMATORY ENVIRONMENT MAINTAINED BY THE INNATE IMMUNITY, INCLUDING MACROPHAGES AND RELATED CYTOKINES, CAN BE INFLUENCED BY ADAPTIVE IMMUNITY. THE FUNCTION OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS IN THIS PROCESS HAS ATTRACTED ATTENTION. THE TH17/TREG BALANCE IS REGULATED BY INFLAMMATORY CYTOKINES AND VARIOUS METABOLIC FACTORS, INCLUDING THOSE ASSOCIATED WITH CELLULAR ENERGY METABOLISM. THE POSSIBLE UNDERLYING MECHANISMS INCLUDE METABOLISM-RELATED SIGNALING PATHWAYS AND EPIGENETIC REGULATION. SEVERAL STUDIES CONDUCTED ON HUMAN AND ANIMAL MODELS HAVE SHOWN MARKED DIFFERENCES IN AND THE IMPORTANT ROLES OF TH17/TREG IN CHRONIC INFLAMMATION ASSOCIATED WITH OBESITY AND METABOLIC DISEASES. MOREOVER, TH17/TREG SEEMS TO BE A BRIDGE LINKING THE GUT MICROBIOTA TO HOST METABOLIC DISORDERS. IN THIS REVIEW, WE HAVE PROVIDED AN OVERVIEW OF THE ALTERATIONS IN AND THE FUNCTIONS OF THE TH17/TREG BALANCE IN METABOLIC DISEASES AND ITS ROLE IN REGULATING IMMUNE RESPONSE-RELATED GLUCOSE AND LIPID METABOLISM. 2021 8 4455 46 MOLECULAR MECHANISMS FOR THE VICIOUS CYCLE BETWEEN INSULIN RESISTANCE AND THE INFLAMMATORY RESPONSE IN OBESITY. THE COMPREHENSIVE ANABOLIC EFFECTS OF INSULIN THROUGHOUT THE BODY, IN ADDITION TO THE CONTROL OF GLYCEMIA, INCLUDE ENSURING LIPID HOMEOSTASIS AND ANTI-INFLAMMATORY MODULATION, ESPECIALLY IN ADIPOSE TISSUE (AT). THE PREVALENCE OF OBESITY, DEFINED AS A BODY MASS INDEX (BMI) >/= 30 KG/M(2), HAS BEEN INCREASING WORLDWIDE ON A PANDEMIC SCALE WITH ACCOMPANYING SYNDEMIC HEALTH PROBLEMS, INCLUDING GLUCOSE INTOLERANCE, INSULIN RESISTANCE (IR), AND DIABETES. IMPAIRED TISSUE SENSITIVITY TO INSULIN OR IR PARADOXICALLY LEADS TO DISEASES WITH AN INFLAMMATORY COMPONENT DESPITE HYPERINSULINEMIA. THEREFORE, AN EXCESS OF VISCERAL AT IN OBESITY INITIATES CHRONIC LOW-GRADE INFLAMMATORY CONDITIONS THAT INTERFERE WITH INSULIN SIGNALING VIA INSULIN RECEPTORS (INSRS). MOREOVER, IN RESPONSE TO IR, HYPERGLYCEMIA ITSELF STIMULATES A PRIMARILY DEFENSIVE INFLAMMATORY RESPONSE ASSOCIATED WITH THE SUBSEQUENT RELEASE OF NUMEROUS INFLAMMATORY CYTOKINES AND A REAL THREAT OF ORGAN FUNCTION DETERIORATION. IN THIS REVIEW, ALL COMPONENTS OF THIS VICIOUS CYCLE ARE CHARACTERIZED WITH PARTICULAR EMPHASIS ON THE INTERPLAY BETWEEN INSULIN SIGNALING AND BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSES RELATED TO OBESITY. INCREASED VISCERAL AT ACCUMULATION IN OBESITY SHOULD BE CONSIDERED THE MAIN ENVIRONMENTAL FACTOR RESPONSIBLE FOR THE DISRUPTION IN THE EPIGENETIC REGULATORY MECHANISMS IN THE IMMUNE SYSTEM, RESULTING IN AUTOIMMUNITY AND INFLAMMATION. 2023 9 3749 36 INSIGHTS INTO THE ROLE OF PLASMATIC AND EXOSOMAL MICRORNAS IN OXIDATIVE STRESS-RELATED METABOLIC DISEASES. A COMMON DENOMINATOR OF METABOLIC DISEASES, INCLUDING TYPE 2 DIABETES MELLITUS, DYSLIPIDEMIA, AND ATHEROSCLEROSIS, ARE ELEVATED OXIDATIVE STRESS AND CHRONIC INFLAMMATION. THESE COMPLEX, MULTI-FACTORIAL DISEASES ARE CAUSED BY THE DETRIMENTAL INTERACTION BETWEEN THE INDIVIDUAL GENETIC BACKGROUND AND MULTIPLE ENVIRONMENTAL STIMULI. THE CELLS, INCLUDING THE ENDOTHELIAL ONES, ACQUIRE A PREACTIVATED PHENOTYPE AND METABOLIC MEMORY, EXHIBITING INCREASED OXIDATIVE STRESS, INFLAMMATORY GENE EXPRESSION, ENDOTHELIAL VASCULAR ACTIVATION, AND PROTHROMBOTIC EVENTS, LEADING TO VASCULAR COMPLICATIONS. THERE ARE DIFFERENT PATHWAYS INVOLVED IN THE PATHOGENESIS OF METABOLIC DISEASES, AND INCREASED KNOWLEDGE SUGGESTS A ROLE OF THE ACTIVATION OF THE NF-KB PATHWAY AND NLRP3 INFLAMMASOME AS KEY MEDIATORS OF METABOLIC INFLAMMATION. EPIGENETIC-WIDE ASSOCIATED STUDIES PROVIDE NEW INSIGHT INTO THE ROLE OF MICRORNAS IN THE PHENOMENON OF METABOLIC MEMORY AND THE DEVELOPMENT CONSEQUENCES OF VESSEL DAMAGE. IN THIS REVIEW, WE WILL FOCUS ON THE MICRORNAS RELATED TO THE CONTROL OF ANTI-OXIDATIVE ENZYMES, AS WELL AS MICRORNAS RELATED TO THE CONTROL OF MITOCHONDRIAL FUNCTIONS AND INFLAMMATION. THE OBJECTIVE IS THE SEARCH FOR NEW THERAPEUTIC TARGETS TO IMPROVE THE FUNCTIONING OF MITOCHONDRIA AND REDUCE OXIDATIVE STRESS AND INFLAMMATION, DESPITE THE ACQUIRED METABOLIC MEMORY. 2023 10 2343 29 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION IN CARDIOVASCULAR DISEASES. CARDIOVASCULAR DISEASES (CVDS) ARE THE LEADING CAUSE OF HOSPITALIZATION AND DEATH WORLDWIDE, ESPECIALLY IN DEVELOPING COUNTRIES. THE INCREASED PREVALENCE RATE AND MORTALITY DUE TO CVDS, DESPITE THE DEVELOPMENT OF SEVERAL APPROACHES FOR PREVENTION AND TREATMENT, ARE ALARMING TRENDS IN GLOBAL HEALTH. CHRONIC INFLAMMATION AND MACROPHAGE INFILTRATION ARE KEY REGULATORS OF THE INITIATION AND PROGRESSION OF CVDS. RECENT DATA SUGGEST THAT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, POSTTRANSLATIONAL HISTONE MODIFICATIONS, AND RNA MODIFICATIONS, REGULATE CELL DEVELOPMENT, DNA DAMAGE REPAIR, APOPTOSIS, IMMUNITY, CALCIUM SIGNALING, AND AGING IN CARDIOMYOCYTES; AND ARE INVOLVED IN MACROPHAGE POLARIZATION AND CONTRIBUTE SIGNIFICANTLY TO CARDIAC DISEASE DEVELOPMENT. CARDIAC MACROPHAGES NOT ONLY TRIGGER DAMAGING INFLAMMATORY RESPONSES DURING ATHEROSCLEROTIC PLAQUE FORMATION, MYOCARDIAL INJURY, AND HEART FAILURE BUT ARE ALSO INVOLVED IN TISSUE REPAIR, REMODELING, AND REGENERATION. IN THIS REVIEW, WE SUMMARIZE THE KEY EPIGENETIC MODIFICATIONS THAT INFLUENCE MACROPHAGE POLARIZATION AND CONTRIBUTE TO THE PATHOPHYSIOLOGY OF CVDS, AND HIGHLIGHT THEIR POTENTIAL FOR THE DEVELOPMENT OF ADVANCED EPIGENETIC THERAPIES. 2023 11 2168 32 EPIGENETIC MECHANISMS IN MONOCYTES/MACROPHAGES REGULATE INFLAMMATION IN CARDIOMETABOLIC AND VASCULAR DISEASE. CARDIOMETABOLIC AND VASCULAR DISEASE, WITH THEIR ASSOCIATED SECONDARY COMPLICATIONS, ARE THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN WESTERN SOCIETY. CHRONIC INFLAMMATION IS A COMMON THEME THAT UNDERLIES INITIATION AND PROGRESSION OF CARDIOVASCULAR DISEASE. IN THIS REGARD, MONOCYTES/MACROPHAGES ARE KEY PLAYERS IN THE DEVELOPMENT OF A CHRONIC INFLAMMATORY STATE. OVER THE PAST DECADE, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND POSTTRANSLATIONAL HISTONE PROCESSING, HAVE EMERGED AS IMPORTANT REGULATORS OF IMMUNE CELL PHENOTYPES. ACCUMULATING STUDIES REVEAL THE IMPORTANCE OF EPIGENETIC ENZYMES IN THE DYNAMIC REGULATION OF KEY SIGNALING PATHWAYS THAT ALTER MONOCYTE/MACROPHAGE PHENOTYPES IN RESPONSE TO ENVIRONMENTAL STIMULI. IN THIS REVIEW, WE HIGHLIGHT THE CURRENT PARADIGMS OF MONOCYTE/MACROPHAGE POLARIZATION AND THE EMERGING ROLE OF EPIGENETIC MODIFICATION IN THE REGULATION OF MONOCYTE/MACROPHAGE PHENOTYPE IN OBESITY, DIABETES MELLITUS, ATHEROSCLEROSIS, AND ABDOMINAL AORTIC ANEURYSMS. 2019 12 3965 32 LONG NONCODING RNAS IN THE METABOLIC CONTROL OF INFLAMMATION AND IMMUNE DISORDERS. THE METABOLIC CONTROL OF IMMUNE CELL DEVELOPMENT AND FUNCTION HAS BEEN SHOWN TO BE CRITICAL FOR THE MAINTENANCE OF IMMUNE HOMEOSTASIS AND IS ALSO INVOLVED IN THE PATHOGENESIS OF IMMUNE DISORDERS. PATHOGENIC INFECTIONS OR CANCERS MAY INDUCE METABOLIC REPROGRAMMING THROUGH DIFFERENT PATHWAYS TO MEET THE ENERGY AND METABOLITE DEMANDS FOR PATHOGEN PROPAGATION OR CANCER PROGRESSION. IN ADDITION, SOME DEREGULATED METABOLITES COULD TRIGGER OR REGULATE IMMUNE RESPONSES, THUS CAUSING CHRONIC INFLAMMATION OR IMMUNE DISORDERS, SUCH AS VIRAL INFECTION, CANCER AND OBESITY. THEREFORE, THE METHODS THROUGH WHICH METABOLISM IS REGULATED AND THE ROLE OF METABOLIC REGULATION IN INFLAMMATION AND IMMUNITY ATTRACT MUCH ATTENTION. EPIGENETIC REGULATION OF INFLAMMATION AND IMMUNITY IS AN EMERGING FIELD. LONG NONCODING RNAS (LNCRNAS) HAVE BEEN WELL DOCUMENTED TO PLAY CRUCIAL ROLES IN MANY BIOLOGICAL PROCESSES THROUGH DIVERSE MECHANISMS, INCLUDING IMMUNE REGULATION AND METABOLIC ALTERNATION. HERE, WE REVIEW THE FUNCTIONS AND MECHANISMS OF LNCRNAS IN THE METABOLIC REGULATION OF INFLAMMATORY IMMUNE DISORDERS, AIMING TO DEEPEN OUR UNDERSTANDING OF THE EPIGENETIC REGULATION OF INFLAMMATION AND IMMUNITY. 2019 13 44 35 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 14 5821 38 STRESS IN OBESITY AND ASSOCIATED METABOLIC AND CARDIOVASCULAR DISORDERS. OBESITY HAS SIGNIFICANT IMPLICATIONS FOR HEALTHCARE, SINCE IT IS A MAJOR RISK FACTOR FOR BOTH TYPE 2 DIABETES AND THE METABOLIC SYNDROME. THIS SYNDROME IS A COMMON AND COMPLEX DISORDER COMBINING OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND INSULIN RESISTANCE. IT IS ASSOCIATED WITH HIGH ATHEROSCLEROTIC CARDIOVASCULAR RISK, WHICH CAN ONLY PARTIALLY BE EXPLAINED BY ITS COMPONENTS. THEREFORE, TO EXPLAIN HOW OBESITY CONTRIBUTES TO THE DEVELOPMENT OF METABOLIC AND CARDIOVASCULAR DISORDERS, MORE AND BETTER INSIGHT IS REQUIRED INTO THE EFFECTS OF PERSONAL AND ENVIRONMENTAL STRESS ON DISEASE PROCESSES. IN THIS PAPER, WE SHOW THAT OBESITY IS A CHRONIC INFLAMMATORY DISEASE, WHICH HAS MANY MOLECULAR MECHANISMS IN COMMON WITH ATHEROSCLEROSIS. FURTHERMORE, WE FOCUS ON THE ROLE OF OXIDATIVE STRESS ASSOCIATED WITH OBESITY IN THE DEVELOPMENT OF THE METABOLIC SYNDROME. WE DISCUSS HOW SEVERAL STRESS CONDITIONS ARE RELATED TO INFLAMMATION AND OXIDATIVE STRESS IN ASSOCIATION WITH OBESITY AND ITS COMPLICATIONS. WE ALSO EMPHASIZE THE RELATION BETWEEN STRESS CONDITIONS AND THE DEREGULATION OF EPIGENETIC CONTROL MECHANISMS BY MEANS OF MICRORNAS AND SHOW HOW THIS IMPAIRMENT FURTHER CONTRIBUTES TO THE DEVELOPMENT OF OBESITY, CLOSING THE VICIOUS CIRCLE. FINALLY, WE DISCUSS THE LIMITATIONS OF CURRENT ANTI-INFLAMMATION AND ANTIOXIDANT THERAPY TO TREAT OBESITY. 2012 15 2178 31 EPIGENETIC MECHANISMS OF MACROPHAGE ACTIVATION IN TYPE 2 DIABETES. THE ALARMING RISE OF OBESITY AND TYPE 2 DIABETES (T2D) HAS PUT A TREMENDOUS STRAIN ON GLOBAL HEALTHCARE SYSTEMS. OVER THE PAST DECADE EXTENSIVE RESEARCH HAS FOCUSED ON THE ROLE OF MACROPHAGES AS KEY MEDIATORS OF INFLAMMATION IN T2D. THE INFLAMMATORY ENVIRONMENT IN THE OBESE ADIPOSE TISSUE AND PANCREATIC BETA-CELL ISLETS CREATES AND PERPETUATES IMBALANCED INFLAMMATORY MACROPHAGE ACTIVATION. CONSEQUENCES OF THIS CHRONIC LOW-GRADE INFLAMMATION INCLUDE INSULIN RESISTANCE IN THE ADIPOSE TISSUE AND PANCREATIC BETA-CELL DYSFUNCTION. RECENTLY, THE EMERGING FIELD OF EPIGENETICS HAS PROVIDED NEW INSIGHTS INTO THE PATHOGENESIS OF T2D, WHILE ALSO AFFORDING POTENTIAL NEW OPPORTUNITIES FOR TREATMENT. IN MACROPHAGES, EPIGENETIC MECHANISMS ARE INCREASINGLY BEING RECOGNIZED AS CRUCIAL CONTROLLERS OF THEIR PHENOTYPE. HERE, WE FIRST DESCRIBE THE ROLE OF MACROPHAGES IN T2D. THEN WE ELABORATE ON EPIGENETIC MECHANISMS THAT REGULATE MACROPHAGE ACTIVATION, THEREBY FOCUSING ON T2D. NEXT, WE HIGHLIGHT HOW DIABETIC CONDITIONS SUCH AS HYPERLIPIDEMIA AND HYPERGLYCEMIA COULD INDUCE EPIGENETIC CHANGES THAT PROMOTE AN INFLAMMATORY MACROPHAGE PHENOTYPE. IN CONCLUSION WE DISCUSS POSSIBLE THERAPEUTIC INTERVENTIONS BY TARGETING MACROPHAGE EPIGENETICS AND SPECULATE ON FUTURE RESEARCH DIRECTIONS. 2017 16 4043 37 MACROPHAGES IN CHRONIC LIVER FAILURE: DIVERSITY, PLASTICITY AND THERAPEUTIC TARGETING. CHRONIC LIVER INJURY RESULTS IN IMMUNE-DRIVEN PROGRESSIVE FIBROSIS, WITH RISK OF CIRRHOSIS DEVELOPMENT AND IMPACT ON MORBIDITY AND MORTALITY. PERSISTENT LIVER CELL DAMAGE AND DEATH CAUSES IMMUNE CELL ACTIVATION AND INFLAMMATION. PATIENTS WITH ADVANCED CIRRHOSIS ADDITIONALLY EXPERIENCE PATHOLOGICAL BACTERIAL TRANSLOCATION, EXPOSURE TO MICROBIAL PRODUCTS AND CHRONIC ENGAGEMENT OF THE IMMUNE SYSTEM. BACTERIAL INFECTIONS HAVE A HIGH INCIDENCE IN CIRRHOSIS, WITH SPONTANEOUS BACTERIAL PERITONITIS BEING THE MOST COMMON, WHILE THE SUBSEQUENT SYSTEMIC INFLAMMATION, ORGAN FAILURE AND IMMUNE DYSREGULATION INCREASE THE MORTALITY RISK. TISSUE-RESIDENT AND RECRUITED MACROPHAGES PLAY A CENTRAL PART IN THE DEVELOPMENT OF INFLAMMATION AND FIBROSIS PROGRESSION. IN THE LIVER, ADIPOSE TISSUE, PERITONEUM AND INTESTINES, DIVERSE MACROPHAGE POPULATIONS EXHIBIT GREAT PHENOTYPIC AND FUNCTIONAL PLASTICITY DETERMINED BY THEIR ONTOGENY, EPIGENETIC PROGRAMMING AND LOCAL MICROENVIRONMENT. THESE CHANGES CAN, AT DIFFERENT TIMES, PROMOTE OR AMELIORATE DISEASE STATES AND THEREFORE REPRESENT POTENTIAL TARGETS FOR MACROPHAGE-DIRECTED THERAPIES. IN THIS REVIEW, WE DISCUSS THE EVIDENCE FOR MACROPHAGE PHENOTYPIC AND FUNCTIONAL ALTERATIONS IN TISSUE COMPARTMENTS DURING THE DEVELOPMENT AND PROGRESSION OF CHRONIC LIVER FAILURE IN DIFFERENT AETIOLOGIES AND HIGHLIGHT THE POTENTIAL OF MACROPHAGE MODULATION AS A THERAPEUTIC STRATEGY FOR LIVER DISEASE. 2021 17 2491 31 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 18 4425 48 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 4801 27 OBESITY AND INSULIN RESISTANCE: ASSOCIATIONS WITH CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS. BACKGROUND: OBESITY IS KNOWN TO BE A MULTIFACTORIAL DISEASE. IN ITS PATHOGENESIS, DIFFERENT FACTORS SUCH AS CHRONIC INFLAMMATION, OXIDATIVE STRESS, INSULIN RESISTANCE, GENETIC FACTORS, ENVIRONMENTAL EFFECTS, VEGETATIVE DISTURBANCE, AND UNBALANCED NUTRITION PLAY A SIGNIFICANT ROLE. METHODOLOGY: THIS STUDY DESCRIBES THE ASSOCIATION OF OBESITY AND INSULIN RESISTANCE WITH CHRONIC INFLAMMATION, GENETIC, AND EPIGENETIC FACTORS. PREVIOUS LITERATURE HAS BEEN REVIEWED TO EXPLAIN THE RELATION OF OBESITY WITH THOSE FACTORS INVOLVED IN CHRONIC LOW-GRADE INFLAMMATION AND INSULIN. RESULTS: OBESITY IS ASSOCIATED WITH A DECREASE IN GHRELIN SECRETION, ELEVATED PLASMA LEPTIN LEVELS, OXIDATIVE STRESS, INCREASED MACROPHAGE PHAGOCYTIC ACTIVITY, AND THE INDUCTION OF PROINFLAMMATORY SYNTHESIS OF CYTOKINES AND INTERFERON-GAMMA. OBESITY IS LINKED TO DECREASED LEVELS OF CYTOCHROME P450 (CYP) ENZYMES AND IMPAIRED DETOXIFICATION PROCESSES. DEFICIENCY OF VITAMINS AND MINERALS CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF OXIDATIVE STRESS AND CHRONIC INFLAMMATION IN OBESITY. THERE IS EVIDENCE OF ASSOCIATIONS BETWEEN A GENETIC PREDISPOSITION TO OBESITY IN CHILDREN WITH ELEVATED LEVELS OF CERTAIN MIRNAS. CONCLUSION: THE PURPOSE OF THE PRESENT REVIEW IS AN ANALYSIS OF THE MULTIPLE FACTORS ASSOCIATED WITH OBESITY. 2021 20 3366 31 HISTONE METHYLATION RELATED THERAPEUTIC CHALLENGE IN CARDIOVASCULAR DISEASES. THE EPIDEMIC OF CARDIOVASCULAR DISEASES (CVDS) IS PREDICTED TO SPREAD RAPIDLY IN ADVANCED COUNTRIES ACCOMPANIED BY THE HIGH PREVALENCE OF RISK FACTORS. IN TERMS OF PATHOGENESIS, THE PATHOPHYSIOLOGY OF CVDS IS FEATURED BY MULTIPLE DISORDERS, INCLUDING VASCULAR INFLAMMATION ACCOMPANIED BY SIMULTANEOUSLY PERTURBED PATHWAYS, SUCH AS CELL DEATH AND ACUTE/CHRONIC INFLAMMATORY REACTIONS. EPIGENETIC ALTERATION IS INVOLVED IN THE REGULATION OF GENOME STABILIZATION AND CELLULAR HOMEOSTASIS. THE ASSOCIATION BETWEEN CVD PROGRESSION AND HISTONE MODIFICATIONS IS WIDELY KNOWN. AMONG THE HISTONE MODIFICATIONS, HISTONE METHYLATION IS A REVERSIBLE PROCESS INVOLVED IN THE DEVELOPMENT AND HOMEOSTASIS OF THE CARDIOVASCULAR SYSTEM. ABNORMAL METHYLATION CAN PROMOTE CVD PROGRESSION. THIS REVIEW DISCUSSES HISTONE METHYLATION AND THE ENZYMES INVOLVED IN THE CARDIOVASCULAR SYSTEM AND DETERMINE THE EFFECTS OF HISTONE METHYLTRANSFERASES AND DEMETHYLASES ON THE PATHOGENESIS OF CVDS. WE WILL FURTHER DEMONSTRATE KEY PROTEINS MEDIATED BY HISTONE METHYLATION IN BLOOD VESSELS AND REVIEW HISTONE METHYLATION-MEDIATED CARDIOMYOCYTES AND CELLULAR FUNCTIONS AND PATHWAYS IN CVDS. FINALLY, WE WILL SUMMARIZE THE ROLE OF INHIBITORS OF HISTONE METHYLATION AND DEMETHYLATION IN CVDS AND ANALYZE THEIR THERAPEUTIC POTENTIAL, BASED ON PREVIOUS STUDIES. 2021