1 4534 109 MULTIPLE REGULATIONS OF KEAP1/NRF2 SYSTEM BY DIETARY PHYTOCHEMICALS. KEAP1/NRF2 SYSTEM PLAYS A CRITICAL ROLE ON CELLULAR PROTECTION BY REGULATING MANY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE). THUS, IT MUST WORK CONSTANTLY TO PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) BECAUSE EXCESS ROS ARE ASSOCIATED WITH MANY DISEASES SUCH AS CANCER, CARDIOVASCULAR COMPLICATIONS, INFLAMMATION, AND NEURODEGENERATION. DIETARY PHYTOCHEMICALS WIDELY DISTRIBUTING IN FRUITS AND VEGETABLES HAVE BEEN CONSIDERED TO POSSESS CANCER CHEMOPREVENTIVE POTENTIAL THROUGH THE INDUCTION OF KEAP1/NRF2 SYSTEM-MEDIATED ANTIOXIDANT AND DETOXIFICATION ENZYMES IN A VARIETY OF MANNERS. THE DATA ARE EXTENSIVE AND ARE NOT WELL CLASSIFIED ON THE MOLECULAR MECHANISMS. IN THIS REVIEW, WE FIRST BRIEFLY INTRODUCE THE CURRENT KNOWLEDGE ON KEAP1/NRF2 SYSTEM REGULATION INCLUDING KEAP1-DEPENDENT AND KEAP1-INDEPENDENT CASCADES, AND EPIGENETIC PATHWAY. THEN, WE SUMMARIZE THE MOLECULAR TARGETS OF KEAP1/NRF2 SYSTEM BY DIETARY PHYTOCHEMICALS, AND FINALLY REVIEW THE CROSSTALK BETWEEN KEAP1/NRF2 SYSTEM AND OTHER CELLULAR SIGNALING PATHWAYS TO REGULATE DIVERSE CHRONIC DISEASES BY DIETARY PHYTOCHEMICALS. THESE COMPREHENSIVE DATA WILL HELP US TO UNDERSTAND THE POTENTIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON THE PREVENTION OF CHRONIC DISEASES AND MAINTENANCE OF HUMAN HEALTH. 2016 2 1387 29 DIABETIC GUT MICROBIOTA DYSBIOSIS AS AN INFLAMMAGING AND IMMUNOSENESCENCE CONDITION THAT FOSTERS PROGRESSION OF RETINOPATHY AND NEPHROPATHY. THE INCREASED PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) AND LIFE EXPECTANCY OF DIABETIC PATIENTS FOSTERS THE WORLDWIDE PREVALENCE OF RETINOPATHY AND NEPHROPATHY, TWO MAJOR MICROVASCULAR COMPLICATIONS THAT HAVE BEEN DIFFICULT TO TREAT WITH CONTEMPORARY GLUCOSE-LOWERING MEDICATIONS. THE GUT MICROBIOTA (GM) HAS BECOME A LIVELY FIELD RESEARCH IN THE LAST YEARS; THERE IS A GROWING RECOGNITION THAT ALTERED INTESTINAL MICROBIOTA COMPOSITION AND FUNCTION CAN DIRECTLY IMPACT THE PHENOMENON OF AGEING AND AGE-RELATED DISORDERS. IN FACT, HUMAN GM, ENVISAGED AS A POTENTIAL SOURCE OF NOVEL THERAPEUTICS, STRONGLY MODULATES HOST IMMUNITY AND METABOLISM. IT IS NOW CLEAR THAT GUT DYSBIOSIS AND THEIR PRODUCTS (E.G. P-CRESYL SULFATE, TRIMETHYLAMINE?N?OXIDE) DICTATE A SECRETORY ASSOCIATED SENESCENCE PHENOTYPE AND CHRONIC LOW-GRADE INFLAMMATION, FEATURES SHARED IN THE PHYSIOLOGICAL PROCESS OF AGEING ("INFLAMMAGING") AS WELL AS IN T2DM ("METAFLAMMATION") AND IN ITS MICROVASCULAR COMPLICATIONS. THIS REVIEW PROVIDES AN IN-DEPTH LOOK ON THE CROSSTALK BETWEEN GM, HOST IMMUNITY AND METABOLISM. FURTHER, IT CHARACTERIZES HUMAN GM SIGNATURES OF ELDERLY AND T2DM PATIENTS. FINALLY, A COMPREHENSIVE SCRUTINY OF RECENT MOLECULAR FINDINGS (E.G. EPIGENETIC CHANGES) UNDERLYING CAUSAL RELATIONSHIPS BETWEEN GM DYSBIOSIS AND DIABETIC RETINOPATHY/NEPHROPATHY COMPLICATIONS IS PINPOINTED, WITH THE ULTIMATE GOAL TO UNRAVEL POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS THAT MAY BE EXPLORED, IN A NEAR FUTURE, AS PERSONALIZED DISEASE-MODIFYING THERAPEUTIC APPROACHES. 2019 3 1233 29 CROSSTALK BETWEEN KIDNEY AND LIVER IN NON-ALCOHOLIC FATTY LIVER DISEASE: MECHANISMS AND THERAPEUTIC APPROACHES. LIVER AND KIDNEY ARE VITAL ORGANS THAT MAINTAIN HOMEOSTASIS AND INJURY TO EITHER OF THEM TRIGGERS PATHOGENIC PATHWAYS AFFECTING THE OTHER. FOR EXAMPLE, NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) PROMOTES THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD), VICE VERSA ACUTE KIDNEY INJURY (AKI) ENDORSES THE INDUCTION AND PROGRESSION OF LIVER DYSFUNCTION. PROGRESS IN CLINICAL AND BASIC RESEARCH SUGGEST A ROLE OF EXCESSIVE FRUCTOSE INTAKE, INSULIN RESISTANCE, INFLAMMATORY CYTOKINES PRODUCTION, ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM, REDOX IMBALANCE, AND THEIR IMPACT ON EPIGENETIC REGULATION OF GENE EXPRESSION IN THIS CONTEXT. RECENT DEVELOPMENTS IN EXPERIMENTAL AND CLINICAL RESEARCH HAVE IDENTIFIED SEVERAL BIOCHEMICAL AND MOLECULAR PATHWAYS FOR AKI-LIVER INTERACTION, INCLUDING ALTERED LIVER ENZYMES PROFILE, METABOLIC ACIDOSIS, OXIDATIVE STRESS, ACTIVATION OF INFLAMMATORY AND REGULATED CELL DEATH PATHWAYS. THIS REVIEW FOCUSES ON THE CURRENT PRECLINICAL AND CLINICAL FINDINGS ON KIDNEY-LIVER CROSSTALK IN NAFLD-CKD AND AKI-LIVER DYSFUNCTION SETTINGS AND HIGHLIGHTS POTENTIAL MOLECULAR MECHANISMS AND THERAPEUTIC TARGETS. 2022 4 5726 22 SKIN WELL-BEING IN DIABETES: ROLE OF MACROPHAGES. MACROPHAGES ARE KEY PLAYERS IN WOUND HEALING- ALONG WITH MEDIATING THE ACUTE INFLAMMATORY RESPONSE, MACROPHAGES ACTIVATE CUTANEOUS EPITHELIAL CELLS AND PROMOTE TISSUE REPAIR. DIABETES COMPLICATIONS, INCLUDING DIABETIC CHRONIC WOUNDS, ARE ACCOMPANIED BY PERSISTENT INFLAMMATION AND MACROPHAGE MALFUNCTION. SEVERAL STUDIES INDICATE THAT HYPERGLYCEMIA INDUCES VARIOUS ALTERATIONS THAT AFFECT MACROPHAGE FUNCTION IN WOUND HEALING INCLUDING EPIGENETIC CHANGES, IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY MODULATORS, AND INSENSITIVITY TO PROLIFERATIVE STIMULI. IN THIS REVIEW, WE BRIEFLY SUMMARIZE RECENT STUDIES REGARDING THOSE ALTERATIONS AND THEIR IMPLICATIONS ON SKIN WELL-BEING IN DIABETES. 2020 5 241 31 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 6 6053 18 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 7 3920 20 LINKING IMMUNITY, EPIGENETICS, AND CANCER IN INFLAMMATORY BOWEL DISEASE. MOST OF WHAT IS KNOWN ABOUT THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (IBD) PERTAINS TO COMPLEX INTERPLAY BETWEEN HOST GENETICS, IMMUNITY, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS PLAY PIVOTAL ROLES IN INTESTINAL IMMUNITY AND MUCOSAL HOMEOSTASIS AS WELL AS MEDIATING GENE-ENVIRONMENT INTERACTIONS. IN THIS ARTICLE, WE PROVIDE A HISTORICAL ACCOUNT OF EPIGENETIC RESEARCH EITHER DIRECTLY RELATED OR PERTINENT TO THE PATHOGENESIS AND MANAGEMENT OF IBD. WE FURTHER COLLATE EMERGING EVIDENCE SUPPORTING ROLES FOR EPIGENETIC MECHANISMS IN RELEVANT ASPECTS OF IBD BIOLOGY, INCLUDING DEREGULATED IMMUNITY, HOST-PATHOGEN RECOGNITION AND MUCOSAL INTEGRITY. FINALLY, WE HIGHLIGHT KEY EPIGENETIC MECHANISMS THAT LINK CHRONIC INFLAMMATION TO SPECIFIC IBD COMORBIDITIES, INCLUDING COLITIS-ASSOCIATED CANCER AND DISCUSS THEIR POTENTIAL UTILITY AS NOVEL BIOMARKERS OR PHARMACOLOGIC TARGETS IN IBD THERAPY. 2014 8 4337 33 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION. 2021 9 2342 25 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION AND FUNCTION. MACROPHAGE POLARIZATION REFERS TO DEVELOPMENT OF A SPECIFIC PHENOTYPE IMPORTANT FOR TISSUE HOMEOSTASIS OR HOST DEFENSE IN RESPONSE TO ENVIRONMENTAL CUES. ENVIRONMENTAL FACTORS THAT INDUCE MACROPHAGE POLARIZATION INCLUDE CYTOKINES AND MICROBIAL FACTORS PRODUCED BY PATHOGENS OR COMMENSAL MICROBIOTA. SIGNALING PATHWAYS UTILIZED BY THESE POLARIZING FACTORS HAVE BEEN WELL CHARACTERIZED, BUT IT IS LESS CLEAR HOW SIGNALS ARE CONVERTED INTO COMPLEX AND SUSTAINED PATTERNS OF GENE EXPRESSION, AND HOW MACROPHAGES ARE REPROGRAMMED DURING POLARIZATION TO ALTER THEIR RESPONSES TO SUBSEQUENT ENVIRONMENTAL CHALLENGES. EMERGING EVIDENCE, REVIEWED HERE, SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING AND TRANSMITTING SIGNALS DURING MACROPHAGE POLARIZATION AND REPROGRAMMING. DEEPER UNDERSTANDING OF EPIGENETIC REGULATION OF MACROPHAGE PHENOTYPE WILL ENABLE DEVELOPMENT OF GENE-SPECIFIC THERAPEUTIC APPROACHES TO ENHANCE HOST DEFENSE WHILE PRESERVING TISSUE INTEGRITY AND PREVENTING CHRONIC INFLAMMATORY DISEASES. 2013 10 2361 19 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020 11 3965 29 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 12 3734 29 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 13 4097 23 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022 14 4380 30 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 15 2225 30 EPIGENETIC MODIFICATIONS IN TUMOR-ASSOCIATED MACROPHAGES: A NEW PERSPECTIVE FOR AN OLD FOE. TUMORIGENESIS IS FREQUENTLY ACCOMPANIED BY CHRONIC INFLAMMATION, AND THE TUMOR MICROENVIRONMENT (TME) CAN BE CONSIDERED AN ECOSYSTEM THAT CONSISTS OF TUMOR CELLS, ENDOTHELIOCYTES, FIBROBLASTS, IMMUNE CELLS AND ACELLULAR COMPONENTS SUCH AS EXTRACELLULAR MATRIX. FOR TUMOR CELLS, THEIR SURVIVAL ADVANTAGES ARE DEPENDENT ON BOTH GENETIC AND EPIGENETIC ALTERATIONS, WHILE OTHER CELLS MAINLY PRESENT EPIGENETIC MODIFICATIONS. MACROPHAGES ARE THE MOST PLASTIC TYPE OF IMMUNE CELLS AND UNDERGO DIVERSE EPIGENETIC ALTERATIONS IN THE TME. SOME OF THESE EPIGENETIC MODIFICATIONS MITIGATE AGAINST CANCER PROGRESSION, AND OTHERS ACCELERATE THIS PROCESS. DUE TO THE COMPLEX ROLES OF MACROPHAGES IN THE TME, IT IS URGENT TO UNDERSTAND THEIR EPIGENETIC MODIFICATIONS ASSOCIATED WITH THE TME. HERE, WE MAINLY SUMMARIZE RECENT FINDINGS ON TME-ASSOCIATED EPIGENETIC ALTERATIONS OF TUMOR-ASSOCIATED MACROPHAGES (TAMS), INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS OF HISTONE PROTEINS, CHROMATIN REMODELING, AND NONCODING RNA-MEDIATED EPIGENETIC REGULATION. AT THE END OF THIS REVIEW, WE ALSO DISCUSS THE TRANSLATIONAL POTENTIAL OF THESE EPIGENETIC MODIFICATIONS FOR DEVELOPING NOVEL CANCER THERAPIES TARGETING TAMS. 2022 16 3640 22 INCREASED EXTRACELLULAR MATRIX PROTEIN PRODUCTION IN CHRONIC DIABETIC COMPLICATIONS: IMPLICATIONS OF NON-CODING RNAS. MANAGEMENT OF CHRONIC DIABETIC COMPLICATIONS REMAINS A MAJOR MEDICAL CHALLENGE WORLDWIDE. ONE OF THE CHARACTERISTIC FEATURES OF ALL CHRONIC DIABETIC COMPLICATIONS IS AUGMENTED PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS. SUCH ECM PROTEINS ARE DEPOSITED IN ALL TISSUES AFFECTED BY CHRONIC COMPLICATIONS, ULTIMATELY CAUSING ORGAN DAMAGE AND DYSFUNCTION. A CONTRIBUTING FACTOR TO THIS PATHOGENETIC PROCESS IS GLUCOSE-INDUCED ENDOTHELIAL DAMAGE, WHICH INVOLVES PHENOTYPIC TRANSFORMATION OF ENDOTHELIAL CELLS (ECS). THIS PHENOTYPIC TRANSITION OF ECS, FROM A QUIESCENT STATE TO AN ACTIVATED DYSFUNCTIONAL STATE, CAN BE MEDIATED THROUGH ALTERATIONS IN THE SYNTHESIS OF CELLULAR PROTEINS. IN THIS REVIEW, WE DISCUSSED THE ROLES OF NON-CODING RNAS, SPECIFICALLY MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS), IN SUCH PROCESSES. WE FURTHER OUTLINED OTHER EPIGENETIC MECHANISMS REGULATING THE BIOGENESIS AND/OR FUNCTION OF NON-CODING RNAS. OVERALL, WE BELIEVE THAT BETTER UNDERSTANDING OF SUCH MOLECULAR PROCESSES MAY LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC STRATEGIES IN THE FUTURE. 2019 17 5423 23 REGULATION OF MACROPHAGE ACTIVATION AND DIFFERENTIATION IN ATHEROSCLEROSIS. CHRONIC INFLAMMATION IS A HALLMARK OF ATHEROSCLEROSIS AND MACROPHAGES PLAY A CENTRAL ROLE IN CONTROLLING INFLAMMATION AT ALL STAGES OF ATHEROSCLEROSIS. IN ATHEROSCLEROSIS, MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES ARE CONTINUOUSLY EXPOSED TO CHOLESTEROL, OXIDIZED LIPIDS, CELL DEBRIS, CYTOKINES, AND CHEMOKINES. NOT ONLY DO THESE STIMULI INDUCE A SPECIFIC MACROPHAGE PHENOTYPE, BUT THEY ALSO INTERACT EXTENSIVELY, LEADING TO MACROPHAGE HETEROGENEITY IN ATHEROSCLEROTIC PLAQUES. HEREIN, WE REVIEW THE DIVERSE PHENOTYPES OF MACROPHAGES, THE MECHANISMS UNDERLYING MACROPHAGE ACTIVATION, AND THE CONTRIBUTIONS OF MACROPHAGES TO ATHEROSCLEROSIS IN THIS CONTEXT. WE ALSO SUMMARIZE RECENT STUDIES ON FOAMY MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES IN PLAQUE DURING DISEASE PROGRESSION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC REPROGRAMMING OF MACROPHAGES AND DISCUSS THE EMERGING CONCEPTS OF TARGETING CYTOKINES AND MACROPHAGES TO MODULATE ATHEROSCLEROSIS. 2021 18 2344 28 EPIGENETIC REGULATION OF MACROPHAGES: FROM HOMEOSTASIS MAINTENANCE TO HOST DEFENSE. MACROPHAGES ARE CRUCIAL MEMBERS OF THE INNATE IMMUNE RESPONSE AND IMPORTANT REGULATORS. THE DIFFERENTIATION AND ACTIVATION OF MACROPHAGES REQUIRE THE TIMELY REGULATION OF GENE EXPRESSION, WHICH DEPENDS ON THE INTERACTION OF A VARIETY OF FACTORS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC MODIFICATIONS. EPIGENETIC CHANGES ALSO GIVE MACROPHAGES THE ABILITY TO SWITCH RAPIDLY BETWEEN CELLULAR PROGRAMS, INDICATING THE ABILITY OF EPIGENETIC MECHANISMS TO AFFECT PHENOTYPE PLASTICITY. IN THIS REVIEW, WE FOCUS ON KEY EPIGENETIC EVENTS ASSOCIATED WITH MACROPHAGE FATE, HIGHLIGHTING EVENTS RELATED TO THE MAINTENANCE OF TISSUE HOMEOSTASIS, RESPONSES TO DIFFERENT STIMULI AND THE FORMATION OF INNATE IMMUNE MEMORY. FURTHER UNDERSTANDING OF THE EPIGENETIC REGULATION OF MACROPHAGES WILL BE HELPFUL FOR MAINTAINING TISSUE INTEGRITY, PREVENTING CHRONIC INFLAMMATORY DISEASES AND DEVELOPING THERAPIES TO ENHANCE HOST DEFENSE. 2020 19 2168 29 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 20 4384 30 MITOCHONDRIAL EPIGENETICS REGULATING INFLAMMATION IN CANCER AND AGING. INFLAMMATION IS A DEFINING FACTOR IN DISEASE PROGRESSION; EPIGENETIC MODIFICATIONS OF THIS FIRST LINE OF DEFENCE PATHWAY CAN AFFECT MANY PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS, LIKE AGING AND TUMORIGENESIS. INFLAMMAGEING, ONE OF THE HALLMARKS OF AGING, REPRESENTS A CHRONIC, LOW KEY BUT A PERSISTENT INFLAMMATORY STATE. OXIDATIVE STRESS, ALTERATIONS IN MITOCHONDRIAL DNA (MTDNA) COPY NUMBER AND MIS-LOCALIZED EXTRA-MITOCHONDRIAL MTDNA ARE SUGGESTED TO DIRECTLY INDUCE VARIOUS IMMUNE RESPONSE PATHWAYS. THIS COULD ULTIMATELY PERTURB CELLULAR HOMEOSTASIS AND LEAD TO PATHOLOGICAL CONSEQUENCES. EPIGENETIC REMODELLING OF MTDNA BY DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF MTDNA BINDING PROTEINS AND REGULATION OF MITOCHONDRIAL GENE EXPRESSION BY NUCLEAR DNA OR MTDNA ENCODED NON-CODING RNAS, ARE SUGGESTED TO DIRECTLY CORRELATE WITH THE ONSET AND PROGRESSION OF VARIOUS TYPES OF CANCER. MITOCHONDRIA ARE ALSO CAPABLE OF REGULATING IMMUNE RESPONSE TO VARIOUS INFECTIONS AND TISSUE DAMAGE BY PRODUCING PRO- OR ANTI-INFLAMMATORY SIGNALS. THIS OCCURS BY ALTERING THE LEVELS OF MITOCHONDRIAL METABOLITES AND REACTIVE OXYGEN SPECIES (ROS) LEVELS. SINCE MITOCHONDRIA ARE KNOWN AS THE GUARDIANS OF THE INFLAMMATORY RESPONSE, IT IS PLAUSIBLE THAT MITOCHONDRIAL EPIGENETICS MIGHT PLAY A PIVOTAL ROLE IN INFLAMMATION. HENCE, THIS REVIEW FOCUSES ON THE INTRICATE DYNAMICS OF EPIGENETIC ALTERATIONS OF INFLAMMATION, WITH EMPHASIS ON MITOCHONDRIA IN CANCER AND AGING. 2022