1 5720 120 SIRTUINS LINK INFLAMMATION AND METABOLISM. SIRTUINS (SIRT), FIRST DISCOVERED IN YEAST AS NAD+ DEPENDENT EPIGENETIC AND METABOLIC REGULATORS, HAVE COMPARABLE ACTIVITIES IN HUMAN PHYSIOLOGY AND DISEASE. MOUNTING EVIDENCE SUPPORTS THAT THE SEVEN-MEMBER MAMMALIAN SIRTUIN FAMILY (SIRT1-7) GUARD HOMEOSTASIS BY SENSING BIOENERGY NEEDS AND RESPONDING BY MAKING ALTERATIONS IN THE CELL NUTRIENTS. SIRTUINS PLAY A CRITICAL ROLE IN RESTORING HOMEOSTASIS DURING STRESS RESPONSES. INFLAMMATION IS DESIGNED TO "DEFEND AND MEND" AGAINST THE INVADING ORGANISMS. EMERGING EVIDENCE SUPPORTS THAT METABOLISM AND BIOENERGY REPROGRAMMING DIRECT THE SEQUENTIAL COURSE OF INFLAMMATION; FAILURE OF HOMEOSTASIS RETRIEVAL RESULTS IN MANY CHRONIC AND ACUTE INFLAMMATORY DISEASES. ANABOLIC GLYCOLYSIS QUICKLY INDUCED (COMPARED TO OXIDATIVE PHOSPHORYLATION) FOR ROS AND ATP GENERATION IS NEEDED FOR IMMUNE ACTIVATION TO "DEFEND" AGAINST INVADING MICROORGANISMS. LIPOLYSIS/FATTY ACID OXIDATION, ESSENTIAL FOR CELLULAR PROTECTION/HIBERNATION AND CELL SURVIVAL IN ORDER TO "MEND," LEADS TO IMMUNE REPRESSION. ACUTE/CHRONIC INFLAMMATIONS ARE LINKED TO ALTERED GLYCOLYSIS AND FATTY ACID OXIDATION, AT LEAST IN PART, BY NAD+ DEPENDENT FUNCTION OF SIRTUINS. THERAPEUTICALLY TARGETING SIRTUINS MAY PROVIDE A NEW CLASS OF INFLAMMATION AND IMMUNE REGULATORS. THIS REVIEW DISCUSSES HOW SIRTUINS INTEGRATE METABOLISM, BIOENERGETICS, AND IMMUNITY DURING INFLAMMATION AND HOW SIRTUIN-DIRECTED TREATMENT IMPROVES OUTCOME IN CHRONIC INFLAMMATORY DISEASES AND IN THE EXTREME STRESS RESPONSE OF SEPSIS. 2016 2 5410 34 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 3 4037 23 MACROPHAGE IMMUNOMETABOLISM AND INFLAMMAGING: ROLES OF MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, CD38, AND NAD. AGING IS A COMPLEX PROCESS THAT INVOLVES DYSFUNCTION ON MULTIPLE LEVELS, ALL OF WHICH SEEM TO CONVERGE ON INFLAMMATION. MACROPHAGES ARE INTIMATELY INVOLVED IN INITIATING AND RESOLVING INFLAMMATION, AND THEIR DYSREGULATION WITH AGE IS A PRIMARY CONTRIBUTOR TO INFLAMMAGING-A STATE OF CHRONIC, LOW-GRADE INFLAMMATION THAT DEVELOPS DURING AGING. AMONG THE AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES ARE A HEIGHTENED STATE OF BASAL INFLAMMATION AND DIMINISHED OR HYPERACTIVE INFLAMMATORY RESPONSES, WHICH SEEM TO BE DRIVEN BY METABOLIC-DEPENDENT EPIGENETIC CHANGES. IN THIS REVIEW ARTICLE WE PROVIDE A BRIEF OVERVIEW OF MITOCHONDRIAL FUNCTIONS AND AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES, WITH AN EMPHASIS ON HOW THE INFLAMMAGING ENVIRONMENT, SENESCENCE, AND NAD DECLINE CAN AFFECT THEIR METABOLISM, PROMOTE DYSREGULATION, AND CONTRIBUTE TO INFLAMMAGING AND AGE-RELATED PATHOLOGIES. 2020 4 5719 30 SIRTUINS IN NEURODEGENERATIVE DISEASES: AN UPDATE ON POTENTIAL MECHANISMS. SILENT INFORMATION REGULATOR 2 PROTEINS (SIRTUINS OR SIRTS) ARE A GROUP OF DEACETYLASES (OR DEACYLASES) WHOSE ACTIVITIES ARE DEPENDENT ON AND REGULATED BY NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)). COMPELLING EVIDENCE SUPPORTS THAT SIRTUINS PLAY MAJOR ROLES IN MANY ASPECTS OF PHYSIOLOGY, ESPECIALLY IN PATHWAYS RELATED TO AGING - THE PREDOMINANT AND UNIFYING RISK FACTOR FOR NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE MOLECULAR MECHANISMS UNDERLYING THE PROTECTIVE EFFECTS OF SIRTUINS IN NEURODEGENERATIVE DISEASES, FOCUSING ON PROTEIN HOMEOSTASIS, NEURAL PLASTICITY, MITOCHONDRIAL FUNCTION, AND SUSTAINED CHRONIC INFLAMMATION. WE WILL ALSO EXAMINE THE POTENTIAL AND CHALLENGES OF TARGETING SIRTUIN PATHWAYS TO BLOCK THESE PATHOGENIC PATHWAYS. 2013 5 3965 28 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 6 4488 30 MONOCYTE AND HAEMATOPOIETIC PROGENITOR REPROGRAMMING AS COMMON MECHANISM UNDERLYING CHRONIC INFLAMMATORY AND CARDIOVASCULAR DISEASES. A LARGE NUMBER OF CARDIOVASCULAR EVENTS ARE NOT PREVENTED BY CURRENT THERAPEUTIC REGIMENS. IN SEARCH FOR ADDITIONAL, INNOVATIVE STRATEGIES, IMMUNE CELLS HAVE BEEN RECOGNIZED AS KEY PLAYERS CONTRIBUTING TO ATHEROSCLEROTIC PLAQUE PROGRESSION AND DESTABILIZATION. PARTICULARLY THE ROLE OF INNATE IMMUNE CELLS IS OF MAJOR INTEREST, FOLLOWING THE RECENT PARADIGM SHIFT THAT INNATE IMMUNITY, LONG CONSIDERED TO BE INCAPABLE OF LEARNING, DOES EXHIBIT IMMUNOLOGICAL MEMORY MEDIATED VIA EPIGENETIC REPROGRAMMING. COMPELLING EVIDENCE SHOWS THAT ATHEROSCLEROTIC RISK FACTORS PROMOTE IMMUNE CELL MIGRATION BY PRE-ACTIVATION OF CIRCULATING INNATE IMMUNE CELLS. INNATE IMMUNE CELL ACTIVATION VIA METABOLIC AND EPIGENETIC REPROGRAMMING PERPETUATES A SYSTEMIC LOW-GRADE INFLAMMATORY STATE IN CARDIOVASCULAR DISEASE (CVD) THAT IS ALSO COMMON IN OTHER CHRONIC INFLAMMATORY DISORDERS. THIS OPENS A NEW THERAPEUTIC AREA IN WHICH METABOLIC OR EPIGENETIC MODULATION OF INNATE IMMUNE CELLS MAY RESULT IN DECREASED SYSTEMIC CHRONIC INFLAMMATION, ALLEVIATING CVD, AND ITS CO-MORBIDITIES. 2018 7 1876 30 EMERGING ROLES FOR EPIGENETIC PROGRAMMING IN THE CONTROL OF INFLAMMATORY SIGNALING INTEGRATION IN HEATH AND DISEASE. MACROPHAGES AND DENDRITIC CELLS INITIATE THE INNATE IMMUNE RESPONSE TO INFECTION AND INJURY AND CONTRIBUTE TO INFLAMMATORY SIGNALING TO MAINTAIN THE HOMEOSTASIS OF VARIOUS TISSUES, WHICH INCLUDES RESIDENT MACROPHAGES FOR THE ELIMINATION OF INVADING MICROORGANISMS AND TISSUE DAMAGE. INAPPROPRIATE INFLAMMATORY SIGNALING CAN LEAD TO PERSISTENT INFLAMMATION AND FURTHER DEVELOP INTO AUTOIMMUNE AND INFLAMMATION-ASSOCIATED DISEASES. INFLAMMATORY SIGNALING PATHWAYS HAVE BEEN WELL CHARACTERIZED, BUT HOW THESE SIGNALING PATHWAYS ARE CONVERTED INTO SUSTAINED AND DIVERSE PATTERNS OF EXPRESSION OF CYTOKINES, CHEMOKINES, AND OTHER GENES IN RESPONSE TO ENVIRONMENTAL CHALLENGES IS UNCLEAR. EMERGING EVIDENCE SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN FINELY TUNING THE OUTCOME OF THE HOST INNATE IMMUNE RESPONSE. AN UNDERSTANDING OF EPIGENETIC REGULATION OF INNATE IMMUNE CELL IDENTITY AND FUNCTION WILL ENABLE THE IDENTIFICATION OF THE MECHANISM BETWEEN GENE-SPECIFIC HOST DEFENSES AND INFLAMMATORY DISEASE AND WILL ALSO ALLOW FOR EXPLORATION OF THE PROGRAM OF INNATE IMMUNE MEMORY IN HEALTH AND DISEASE. THIS INFORMATION COULD BE USED TO DEVELOP THERAPEUTIC AGENTS TO ENHANCE THE HOST RESPONSE, PREVENTING CHRONIC INFLAMMATION THROUGH PRESERVING TISSUES AND SIGNALING INTEGRITY. 2017 8 5932 32 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 9 4380 35 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 10 6006 27 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 11 2344 21 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 12 4898 35 OXIDATIVE STRESS INDUCED LUNG CANCER AND COPD: OPPORTUNITIES FOR EPIGENETIC THERAPY. REACTIVE OXYGEN SPECIES (ROS) FORM AS A NATURAL BY-PRODUCT OF THE NORMAL METABOLISM OF OXYGEN AND PLAY IMPORTANT ROLES WITHIN THE CELL. UNDER NORMAL CIRCUMSTANCES THE CELL IS ABLE TO MAINTAIN AN ADEQUATE HOMEOSTASIS BETWEEN THE FORMATION OF ROS AND ITS REMOVAL THROUGH PARTICULAR ENZYMATIC PATHWAYS OR VIA ANTIOXIDANTS. IF HOWEVER, THIS BALANCE IS DISTURBED A SITUATION CALLED OXIDATIVE STRESS OCCURS. CRITICALLY, OXIDATIVE STRESS PLAYS IMPORTANT ROLES IN THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. EPIGENETICS IS A PROCESS WHERE GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT CAUSE ANY DIRECT CHANGES TO THE DNA SEQUENCE ITSELF, AND DISRUPTION OF EPIGENETIC MECHANISMS HAS IMPORTANT IMPLICATIONS IN DISEASE. EVIDENCE IS EMERGING THAT HISTONE DEACETYLASES (HDACS) PLAY DECISIVE ROLES IN REGULATING IMPORTANT CELLULAR OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH SENSING OXIDATIVE STRESS AND THOSE INVOLVED WITH REGULATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HDACS MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. IN THIS REVIEW WE DISCUSS THE CURRENT EVIDENCE LINKING EPIGENETICS AND OXIDATIVE STRESS AND CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER TO ILLUSTRATE THE IMPORTANCE OF EPIGENETICS ON THESE PATHWAYS WITHIN THESE DISEASE SETTINGS. 2009 13 4200 38 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 14 4489 32 MONOCYTE AND MACROPHAGE IMMUNOMETABOLISM IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS CHARACTERIZED BY CHRONIC LOW GRADE INFLAMMATION OF ARTERIES THAT RESULTS IN THE DEVELOPMENT OF LIPID DENSE PLAQUES. CHRONIC INFLAMMATION INDUCED BY WESTERN-TYPE DIET IS ASSOCIATED WITH THE RISK OF DEVELOPING ATHEROSCLEROSIS, AND NEW INSIGHTS SHED LIGHT ON THE IMPORTANCE OF METABOLIC AND FUNCTIONAL REPROGRAMMING IN MONOCYTES AND MACROPHAGES FOR PROGRESSION OF ATHEROSCLEROSIS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF OUR CURRENT UNDERSTANDING INTO HOW THE METABOLIC REPROGRAMMING OF GLUCOSE, CHOLESTEROL, FATTY ACID, AND AMINO ACID METABOLISM IN MACROPHAGES CONTRIBUTES TO INFLAMMATION DURING ATHEROSCLEROSIS. RECENT INSIGHTS SUGGEST THAT TRANSCRIPTIONAL AND EPIGENETIC ADAPTATION WITHIN INNATE IMMUNE CELLS (TERMED TRAINED IMMUNITY) PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ATHEROSCLEROSIS. WE PROPOSE THAT METABOLIC CHANGES INDUCED BY PRO-ATHEROGENIC LIPOPROTEINS PARTLY MEDIATE THESE CHANGES IN TRAINED MACROPHAGES. FINALLY, WE DISCUSS THE POSSIBILITY OF MANIPULATING CELLULAR METABOLISM OF IMMUNE CELLS FOR TARGETED THERAPEUTIC INTERVENTION AGAINST ATHEROSCLEROSIS. 2018 15 5943 38 TARGETING OXIDATIVE STRESS IN CANCER. IMPORTANCE OF THE FIELD: REACTIVE OXYGEN SPECIES (ROS) OCCUR AS NATURAL BY-PRODUCTS OF OXYGEN METABOLISM AND HAVE IMPORTANT CELLULAR FUNCTIONS. NORMALLY, THE CELL IS ABLE TO MAINTAIN AN ADEQUATE BALANCE BETWEEN THE FORMATION AND REMOVAL OF ROS EITHER VIA ANTI-OXIDANTS OR THROUGH THE USE SPECIFIC ENZYMATIC PATHWAYS. HOWEVER, IF THIS BALANCE IS DISTURBED, OXIDATIVE STRESS MAY OCCUR IN THE CELL, A SITUATION LINKED TO THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. AREAS COVERED IN THIS REVIEW: HDACS ARE IMPORTANT REGULATORS OF MANY OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH BOTH SENSING AND COORDINATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HISTONE DEACETYLASES MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. WHAT THE READER WILL GAIN: IN THIS REVIEW WE DISCUSS THE NOTION THAT TARGETING HDACS MAY BE A USEFUL THERAPEUTIC AVENUE IN THE TREATMENT OF OXIDATIVE STRESS IN CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), NSCLC AND HEPATOCELLULAR CARCINOMA (HCC) AS EXAMPLES TO ILLUSTRATE THIS POSSIBILITY. TAKE HOME MESSAGE: EPIGENETIC MECHANISMS MAY BE AN IMPORTANT NEW THERAPEUTIC AVENUE FOR TARGETING OXIDATIVE STRESS IN CANCER. 2010 16 3547 36 IMMUNOMODULATORY ROLE OF NUTRIENTS: HOW CAN PULMONARY DYSFUNCTIONS IMPROVE? NUTRITION IS AN IMPORTANT TOOL THAT CAN BE USED TO MODULATE THE IMMUNE RESPONSE DURING INFECTIOUS DISEASES. IN ADDITION, THROUGH DIET, IMPORTANT SUBSTRATES ARE ACQUIRED FOR THE BIOSYNTHESIS OF REGULATORY MOLECULES IN THE IMMUNE RESPONSE, INFLUENCING THE PROGRESSION AND TREATMENT OF CHRONIC LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN THIS WAY, NUTRITION CAN PROMOTE LUNG HEALTH STATUS. A RANGE OF NUTRIENTS, SUCH AS VITAMINS (A, C, D, AND E), MINERALS (ZINC, SELENIUM, IRON, AND MAGNESIUM), FLAVONOIDS AND FATTY ACIDS, PLAY IMPORTANT ROLES IN REDUCING THE RISK OF PULMONARY CHRONIC DISEASES AND VIRAL INFECTIONS. THROUGH THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS, NUTRIENTS ARE ASSOCIATED WITH BETTER LUNG FUNCTION AND A LOWER RISK OF COMPLICATIONS SINCE THEY CAN DECREASE THE HARMFUL EFFECTS FROM THE IMMUNE SYSTEM DURING THE INFLAMMATORY RESPONSE. IN ADDITION, BIOACTIVE COMPOUNDS CAN EVEN CONTRIBUTE TO EPIGENETIC CHANGES, INCLUDING HISTONE DEACETYLASE (HDAC) MODIFICATIONS THAT INHIBIT THE TRANSCRIPTION OF PROINFLAMMATORY CYTOKINES, WHICH CAN CONTRIBUTE TO THE MAINTENANCE OF HOMEOSTASIS IN THE CONTEXT OF INFECTIONS AND CHRONIC INFLAMMATORY DISEASES. THESE NUTRIENTS ALSO PLAY AN IMPORTANT ROLE IN ACTIVATING IMMUNE RESPONSES AGAINST PATHOGENS, WHICH CAN HELP THE IMMUNE SYSTEM DURING INFECTIONS. HERE, WE PROVIDE AN UPDATED OVERVIEW OF THE ROLES PLAYED BY DIETARY FACTORS AND HOW THEY CAN AFFECT RESPIRATORY HEALTH. THEREFORE, WE WILL SHOW THE ANTI-INFLAMMATORY ROLE OF FLAVONOIDS, FATTY ACIDS, VITAMINS AND MICROBIOTA, IMPORTANT FOR THE CONTROL OF CHRONIC INFLAMMATORY DISEASES AND ALLERGIES, IN ADDITION TO THE ANTIVIRAL ROLE OF VITAMINS, FLAVONOIDS, AND MINERALS DURING PULMONARY VIRAL INFECTIONS, ADDRESSING THE MECHANISMS INVOLVED IN EACH FUNCTION. THESE MECHANISMS ARE INTERESTING IN THE DISCUSSION OF PERSPECTIVES ASSOCIATED WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION AND ITS PULMONARY COMPLICATIONS SINCE PATIENTS WITH SEVERE DISEASE HAVE VITAMINS DEFICIENCY, ESPECIALLY VITAMIN D. IN ADDITION, RESEARCHES WITH THE USE OF FLAVONOIDS HAVE BEEN SHOWN TO DECREASE VIRAL REPLICATION IN VITRO. THIS WAY, A FULL UNDERSTANDING OF DIETARY INFLUENCES CAN IMPROVE THE LUNG HEALTH OF PATIENTS. 2021 17 5390 31 REDOX-FIBROSIS: IMPACT OF TGFBETA1 ON ROS GENERATORS, MEDIATORS AND FUNCTIONAL CONSEQUENCES. FIBROSIS IS ONE OF THE MOST PREVALENT FEATURES OF AGE-RELATED DISEASES LIKE OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE, OR CARDIOMYOPATHY AND AFFECTS MILLIONS OF PEOPLE IN ALL COUNTRIES. ALTHOUGH THE UNDERSTANDING ABOUT THE PATHOPHYSIOLOGY OF FIBROSIS HAS IMPROVED A LOT DURING THE RECENT YEARS, A NUMBER OF MECHANISMS STILL REMAIN UNKNOWN. ALTHOUGH TGF-BETA1 SIGNALING, LOSS OF METABOLIC HOMEOSTASIS AND CHRONIC LOW-GRADE INFLAMMATION APPEAR TO PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS, RECENT EVIDENCE INDICATES THAT OXIDATIVE STRESS AND THE ANTIOXIDANT SYSTEM MAY ALSO BE CRUCIAL FOR FIBROSIS DEVELOPMENT AND PERSISTENCE. THESE FINDINGS POINT TO A CONCEPT OF A REDOX-FIBROSIS WHERE THE CELLULAR OXIDANT AND ANTIOXIDANT SYSTEM COULD BE POTENTIAL THERAPEUTIC TARGETS. THE CURRENT REVIEW AIMS TO SUMMARIZE THE EXISTING LINKS BETWEEN TGF-BETA1 SIGNALING, GENERATION AND ACTION OF REACTIVE OXYGEN SPECIES, EXPRESSION OF ANTIOXIDATIVE ENZYMES, AND FUNCTIONAL CONSEQUENCES INCLUDING EPIGENETIC REDOX-MEDIATED RESPONSES DURING FIBROSIS. 2015 18 3734 35 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 19 5409 28 REGULATION OF ACETYLATION STATES BY NUTRIENTS IN THE INHIBITION OF VASCULAR INFLAMMATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS (AS) IS A CHRONIC METABOLIC DISORDER AND PRIMARY CAUSE OF CARDIOVASCULAR DISEASES, RESULTING IN SUBSTANTIAL MORBIDITY AND MORTALITY WORLDWIDE. INITIATED BY ENDOTHELIAL CELL STIMULATION, AS IS CHARACTERIZED BY ARTERIAL INFLAMMATION, LIPID DEPOSITION, FOAM CELL FORMATION, AND PLAQUE DEVELOPMENT. NUTRIENTS SUCH AS CAROTENOIDS, POLYPHENOLS, AND VITAMINS CAN PREVENT THE ATHEROSCLEROTIC PROCESS BY MODULATING INFLAMMATION AND METABOLIC DISORDERS THROUGH THE REGULATION OF GENE ACETYLATION STATES MEDIATED WITH HISTONE DEACETYLASES (HDACS). NUTRIENTS CAN REGULATE AS-RELATED EPIGENETIC STATES VIA SIRTUINS (SIRTS) ACTIVATION, SPECIFICALLY SIRT1 AND SIRT3. NUTRIENT-DRIVEN ALTERATIONS IN THE REDOX STATE AND GENE MODULATION IN AS PROGRESSION ARE LINKED TO THEIR PROTEIN DEACETYLATING, ANTI-INFLAMMATORY, AND ANTIOXIDANT PROPERTIES. NUTRIENTS CAN ALSO INHIBIT ADVANCED OXIDATION PROTEIN PRODUCT FORMATION, REDUCING ARTERIAL INTIMA-MEDIA THICKNESS EPIGENETICALLY. NONETHELESS, KNOWLEDGE GAPS REMAIN WHEN IT COMES TO UNDERSTANDING EFFECTIVE AS PREVENTION THROUGH EPIGENETIC REGULATION BY NUTRIENTS. THIS WORK REVIEWS AND CONFIRMS THE UNDERLYING MECHANISMS BY WHICH NUTRIENTS PREVENT ARTERIAL INFLAMMATION AND AS, FOCUSING ON THE EPIGENETIC PATHWAYS THAT MODIFY HISTONES AND NON-HISTONE PROTEINS BY REGULATING REDOX AND ACETYLATION STATES THROUGH HDACS SUCH AS SIRTS. THESE FINDINGS MAY SERVE AS A FOUNDATION FOR DEVELOPING POTENTIAL THERAPEUTIC AGENTS TO PREVENT AS AND CARDIOVASCULAR DISEASES BY EMPLOYING NUTRIENTS BASED ON EPIGENETIC REGULATION. 2023 20 1231 31 CROSSTALK BETWEEN GLUCOSE METABOLISM, LACTATE PRODUCTION AND IMMUNE RESPONSE MODULATION. METABOLITES OF GLYCOLYTIC METABOLISM HAVE BEEN IDENTIFIED AS SIGNALING MOLECULES AND REGULATORS OF GENE EXPRESSION, IN ADDITION TO THEIR BASIC FUNCTION AS MAJOR ENERGY AND BIOSYNTHETIC SOURCE. IMMUNE CELLS REPROGRAM METABOLIC PATHWAYS TO CATER TO ENERGY AND BIOSYNTHESIS DEMANDS UPON ACTIVATION. MOST LYMPHOCYTES, INCLUDING INFLAMMATORY M1 MACROPHAGES, MAINLY SHIFT FROM OXIDATIVE PHOSPHORYLATION TO GLYCOLYSIS, WHEREAS REGULATORY T CELLS AND M2 MACROPHAGES PREFERENTIALLY USE THE TRICARBOXYLIC ACID (TCA) CYCLE AND HAVE REDUCED GLYCOLYSIS. RECENT STUDIES HAVE REVEALED THE "NON-METABOLIC" SIGNALING FUNCTIONS OF INTERMEDIATES OF THE MITOCHONDRIAL PATHWAY AND GLYCOLYSIS. THE ROLES OF CITRATE, SUCCINATE AND ITACONATE IN IMMUNE RESPONSE, INCLUDING POST-TRANSLATIONAL MODIFICATIONS OF PROTEINS AND MACROPHAGES ACTIVATION, HAVE BEEN HIGHLIGHTED. AS AN END PRODUCT OF GLYCOLYSIS, LACTATE HAS RECEIVED CONSIDERABLE INTEREST FROM RESEARCHERS. IN THIS REVIEW, WE SPECIFICALLY FOCUSED ON STUDIES EXPLORING THE INTEGRATION OF LACTATE INTO IMMUNE CELL BIOLOGY AND ASSOCIATED PATHOLOGIES. LACTATE CAN ACT AS A DOUBLE-EDGED SWORD. ON ONE HAND, ACTIVATED IMMUNE CELLS PREFER TO USE LACTATE TO SUPPORT THEIR FUNCTION. ON THE OTHER HAND, ACCUMULATED LACTATE IN THE TISSUE MICROENVIRONMENT ACTS AS A SIGNALING MOLECULE THAT RESTRICTS IMMUNE CELL FUNCTION. RECENTLY, A NOVEL EPIGENETIC CHANGE MEDIATED BY HISTONE LYSINE LACTYLATION HAS BEEN PROPOSED. THE BURGEONING RESEARCHES SUPPORT THE IDEA THAT HISTONE LACTYLATION PARTICIPATES IN DIVERSE CELLULAR EVENTS. THIS REVIEW DESCRIBES GLYCOLYTIC METABOLISM, INCLUDING THE IMMUNOREGULATION OF METABOLITES OF THE TCA CYCLE AND LACTATE. THESE LATEST FINDINGS STRENGTHEN OUR UNDERSTANDING ON TUMOR AND CHRONIC INFLAMMATORY DISEASES AND OFFER POTENTIAL THERAPEUTIC OPTIONS. 2022