1 4582 145 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 2 4044 28 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 3 5489 27 REVERSING POST-INFECTIOUS EPIGENETIC-MEDIATED IMMUNE SUPPRESSION. THE IMMUNE RESPONSE MUST BALANCE THE PRO-INFLAMMATORY, CELL-MEDIATED CYTOTOXICITY WITH THE ANTI-INFLAMMATORY AND WOUND REPAIR RESPONSE. EPIGENETIC MECHANISMS MEDIATE THIS BALANCE AND LIMIT HOST IMMUNITY FROM INDUCING EXUBERANT COLLATERAL DAMAGE TO HOST TISSUE AFTER SEVERE AND CHRONIC INFECTIONS. HOWEVER, FOLLOWING TREATMENT FOR THESE INFECTIONS, INCLUDING SEPSIS, PNEUMONIA, HEPATITIS B, HEPATITIS C, HIV, TUBERCULOSIS (TB) OR SCHISTOSOMIASIS, DETRIMENTAL EPIGENETIC SCARS PERSIST, AND RESULT IN LONG-LASTING IMMUNE SUPPRESSION. THIS IS HYPOTHESIZED TO BE ONE OF THE CONTRIBUTING MECHANISMS EXPLAINING WHY SURVIVORS OF INFECTION HAVE INCREASED ALL-CAUSE MORTALITY AND INCREASED RATES OF UNRELATED SECONDARY INFECTIONS. THE MECHANISMS THAT INDUCE EPIGENETIC-MEDIATED IMMUNE SUPPRESSION HAVE BEEN DEMONSTRATED IN-VITRO AND IN ANIMAL MODELS. MODULATION OF THE AMP-ACTIVATED PROTEIN KINASE (AMPK)-MAMMALIAN TARGET OF RAPAMYCIN (MTOR), NUCLEAR FACTOR OF ACTIVATED T CELLS (NFAT) OR NUCLEAR RECEPTOR (NR4A) PATHWAYS IS ABLE TO BLOCK OR REVERSE THE DEVELOPMENT OF DETRIMENTAL EPIGENETIC SCARS. SIMILARLY, DRUGS THAT DIRECTLY MODIFY EPIGENETIC ENZYMES, SUCH AS THOSE THAT INHIBIT HISTONE DEACETYLASES (HDAC) INHIBITORS, DNA HYPOMETHYLATING AGENTS OR MODIFIERS OF THE NUCLEOSOME REMODELING AND DNA METHYLATION (NURD) COMPLEX OR POLYCOMB REPRESSIVE COMPLEX (PRC) HAVE DEMONSTRATED CAPACITY TO RESTORE HOST IMMUNITY IN THE SETTING OF CANCER-, LCMV- OR MURINE SEPSIS-INDUCED EPIGENETIC-MEDIATED IMMUNE SUPPRESSION. A THIRD CLINICALLY FEASIBLE STRATEGY FOR REVERSING DETRIMENTAL EPIGENETIC SCARS INCLUDES BIOENGINEERING APPROACHES TO EITHER DIRECTLY REVERSE THE DETRIMENTAL EPIGENETIC MARKS OR TO MODIFY THE EPIGENETIC ENZYMES OR TRANSCRIPTION FACTORS THAT INDUCE DETRIMENTAL EPIGENETIC SCARS. EACH OF THESE APPROACHES, ALONE OR IN COMBINATION, HAVE ABLATED OR REVERSED DETRIMENTAL EPIGENETIC MARKS IN IN-VITRO OR IN ANIMAL MODELS; TRANSLATIONAL STUDIES ARE NOW REQUIRED TO EVALUATE CLINICAL APPLICABILITY. 2021 4 2950 27 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003 5 4386 28 MITOCHONDRIAL STRESS INDUCED BY CONTINUOUS STIMULATION UNDER HYPOXIA RAPIDLY DRIVES T CELL EXHAUSTION. CANCER AND CHRONIC INFECTIONS INDUCE T CELL EXHAUSTION, A HYPOFUNCTIONAL FATE CARRYING DISTINCT EPIGENETIC, TRANSCRIPTOMIC AND METABOLIC CHARACTERISTICS. HOWEVER, DRIVERS OF EXHAUSTION REMAIN POORLY UNDERSTOOD. AS INTRATUMORAL EXHAUSTED T CELLS EXPERIENCE SEVERE HYPOXIA, WE HYPOTHESIZED THAT METABOLIC STRESS ALTERS THEIR RESPONSES TO OTHER SIGNALS, SPECIFICALLY, PERSISTENT ANTIGENIC STIMULATION. IN VITRO, ALTHOUGH CD8(+) T CELLS EXPERIENCING CONTINUOUS STIMULATION OR HYPOXIA ALONE DIFFERENTIATED INTO FUNCTIONAL EFFECTORS, THE COMBINATION RAPIDLY DROVE T CELL DYSFUNCTION CONSISTENT WITH EXHAUSTION. CONTINUOUS STIMULATION PROMOTED BLIMP-1-MEDIATED REPRESSION OF PGC-1ALPHA-DEPENDENT MITOCHONDRIAL REPROGRAMMING, RENDERING CELLS POORLY RESPONSIVE TO HYPOXIA. LOSS OF MITOCHONDRIAL FUNCTION GENERATED INTOLERABLE LEVELS OF REACTIVE OXYGEN SPECIES (ROS), SUFFICIENT TO PROMOTE EXHAUSTED-LIKE STATES, IN PART THROUGH PHOSPHATASE INHIBITION AND THE CONSEQUENT ACTIVITY OF NUCLEAR FACTOR OF ACTIVATED T CELLS. REDUCING T CELL-INTRINSIC ROS AND LOWERING TUMOR HYPOXIA LIMITED T CELL EXHAUSTION, SYNERGIZING WITH IMMUNOTHERAPY. THUS, IMMUNOLOGIC AND METABOLIC SIGNALING ARE INTRINSICALLY LINKED: THROUGH MITIGATION OF METABOLIC STRESS, T CELL DIFFERENTIATION CAN BE ALTERED TO PROMOTE MORE FUNCTIONAL CELLULAR FATES. 2021 6 593 41 BET PROTEIN INHIBITION REGULATES CYTOKINE PRODUCTION AND PROMOTES NEUROPROTECTION AFTER SPINAL CORD INJURY. BACKGROUND: SPINAL CORD INJURY (SCI) USUALLY CAUSES A DEVASTATING LIFELONG DISABILITY FOR PATIENTS. AFTER A TRAUMATIC LESION, DISRUPTION OF THE BLOOD-SPINAL CORD BARRIER INDUCES THE INFILTRATION OF MACROPHAGES INTO THE LESION SITE AND THE ACTIVATION OF RESIDENT GLIAL CELLS, WHICH RELEASE CYTOKINES AND CHEMOKINES. THESE EVENTS RESULT IN A PERSISTENT INFLAMMATION, WHICH HAS BOTH DETRIMENTAL AND BENEFICIAL EFFECTS, BUT EVENTUALLY LIMITS FUNCTIONAL RECOVERY AND CONTRIBUTES TO THE APPEARANCE OF NEUROPATHIC PAIN. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE THE EXPRESSION OF INFLAMMATORY GENES BY INTERACTING WITH ACETYLATED LYSINE RESIDUES. WHILE BET INHIBITORS ARE A PROMISING THERAPEUTIC STRATEGY FOR CANCER, LITTLE IS KNOWN ABOUT THEIR IMPLICATION AFTER SCI. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY ROLE OF BET INHIBITORS IN THIS PATHOLOGIC CONDITION. METHODS: WE EVALUATED THE EFFECTIVENESS OF THE BET INHIBITOR JQ1 TO MODIFY MACROPHAGE REACTIVITY IN VITRO AND TO MODULATE INFLAMMATION IN A SCI MICE MODEL. WE ANALYZED THE EFFECTS OF BET INHIBITION IN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PRODUCTION IN VITRO AND IN VIVO. WE DETERMINED THE EFFECTIVENESS OF BET INHIBITION IN TISSUE SPARING, INFLAMMATION, NEURONAL PROTECTION, AND BEHAVIORAL OUTCOME AFTER SCI. RESULTS: WE HAVE FOUND THAT THE BET INHIBITOR JQ1 REDUCED THE LEVELS OF PRO-INFLAMMATORY MEDIATORS AND INCREASED THE EXPRESSION OF ANTI-INFLAMMATORY CYTOKINES. A PROLONGED TREATMENT WITH JQ1 ALSO DECREASED REACTIVITY OF MICROGLIA/MACROPHAGES, ENHANCED NEUROPROTECTION AND FUNCTIONAL RECOVERY, AND ACUTELY REDUCED NEUROPATHIC PAIN AFTER SCI. CONCLUSIONS: BET PROTEIN INHIBITION IS AN EFFECTIVE TREATMENT TO REGULATE CYTOKINE PRODUCTION AND PROMOTE NEUROPROTECTION AFTER SCI. THESE NOVEL RESULTS DEMONSTRATE FOR THE FIRST TIME THAT TARGETING BET PROTEINS IS AN ENCOURAGING APPROACH FOR SCI REPAIR AND A POTENTIAL STRATEGY TO TREAT OTHER INFLAMMATORY PATHOLOGIES. 2019 7 1383 39 DIABETES AND ITS CARDIOVASCULAR COMPLICATIONS: POTENTIAL ROLE OF THE ACETYLTRANSFERASE P300. DIABETES HAS BEEN SHOWN TO ACCELERATE VASCULAR SENESCENCE, WHICH IS ASSOCIATED WITH CHRONIC INFLAMMATION AND OXIDATIVE STRESS, BOTH IMPLICATED IN THE DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION. THIS CONDITION REPRESENTS THE INITIAL ALTERATION LINKING DIABETES TO RELATED CARDIOVASCULAR (CV) COMPLICATIONS. RECENTLY, IT HAS BEEN HYPOTHESISED THAT THE ACETYLTRANSFERASE, P300, MAY CONTRIBUTE TO ESTABLISHING AN EARLY VASCULAR SENESCENT PHENOTYPE, PLAYING A RELEVANT ROLE IN DIABETES-ASSOCIATED INFLAMMATION AND OXIDATIVE STRESS, WHICH DRIVE ENDOTHELIAL DYSFUNCTION. SPECIFICALLY, P300 CAN MODULATE VASCULAR INFLAMMATION THROUGH EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTORS ACETYLATION. INDEED, IT REGULATES THE INFLAMMATORY PATHWAY BY INTERACTING WITH NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS P65 SUBUNIT (NF-KAPPAB P65) OR BY INDUCING ITS ACETYLATION, SUGGESTING A CRUCIAL ROLE OF P300 AS A BRIDGE BETWEEN NF-KAPPAB P65 AND THE TRANSCRIPTIONAL MACHINERY. ADDITIONALLY, P300-MEDIATED EPIGENETIC MODIFICATIONS COULD BE UPSTREAM OF THE ACTIVATION OF INFLAMMATORY CYTOKINES, AND THEY MAY INDUCE OXIDATIVE STRESS BY AFFECTING THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). BECAUSE SEVERAL IN VITRO AND IN VIVO STUDIES SHED LIGHT ON THE POTENTIAL USE OF ACETYLTRANSFERASE INHIBITORS, A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE ROLE OF P300 IN DIABETIC VASCULAR DYSFUNCTION COULD HELP IN FINDING NEW STRATEGIES FOR THE CLINICAL MANAGEMENT OF CV DISEASES RELATED TO DIABETES. 2023 8 3184 22 HARNESSING METABOLISM OF HEPATIC MACROPHAGES TO AID LIVER REGENERATION. LIVER REGENERATION IS A DYNAMIC AND REGULATED PROCESS THAT INVOLVES INFLAMMATION, GRANULATION, AND TISSUE REMODELING. HEPATIC MACROPHAGES, ABUNDANTLY DISTRIBUTED IN THE LIVER, ARE ESSENTIAL COMPONENTS THAT ACTIVELY PARTICIPATE IN EACH STEP TO ORCHESTRATE LIVER REGENERATION. IN THE HOMEOSTATIC LIVER, RESIDENT MACROPHAGES (KUPFFER CELLS) ACQUIRE A TOLEROGENIC PHENOTYPE AND CONTRIBUTE TO IMMUNOLOGICAL TOLERANCE. FOLLOWING TOXICITY-INDUCED DAMAGE OR PHYSICAL RESECTION, KUPFFER CELLS AS WELL AS MONOCYTE-DERIVED MACROPHAGES CAN BE ACTIVATED AND PROMOTE AN INFLAMMATORY PROCESS THAT SUPPORTS THE SURVIVAL AND ACTIVATION OF HEPATIC MYOFIBROBLASTS AND THUS PROMOTES SCAR TISSUE FORMATION. SUBSEQUENTLY, THESE MACROPHAGES, IN TURN, EXHIBIT THE ANTI-INFLAMMATORY EFFECTS CRITICAL TO EXTRACELLULAR MATRIX REMODELING DURING THE RESOLUTION STAGE. HOWEVER, CONTINUOUS DAMAGE-INDUCED CHRONIC INFLAMMATION GENERALLY LEADS TO HEPATIC MACROPHAGE DYSFUNCTION, WHICH EXACERBATES HEPATOCELLULAR INJURY AND TRIGGERS FURTHER LIVER FIBROSIS AND EVEN CIRRHOSIS. EMERGING MACROPHAGE-TARGETING STRATEGIES HAVE SHOWN EFFICACY IN BOTH PRECLINICAL AND CLINICAL STUDIES. INCREASING EVIDENCE INDICATES THAT METABOLIC REWIRING PROVIDES SUBSTRATES FOR EPIGENETIC MODIFICATION, WHICH ENDOWS MONOCYTES/MACROPHAGES WITH PROLONGED "INNATE IMMUNE MEMORY". THEREFORE, IT IS REASONABLE TO CONCEIVE NOVEL THERAPEUTIC STRATEGIES FOR METABOLICALLY REPROGRAMMING MACROPHAGES AND THUS MEDIATE A HOMEOSTATIC OR REPARATIVE PROCESS FOR HEPATIC INFLAMMATION MANAGEMENT AND LIVER REGENERATION. 2023 9 6502 21 TRAINED IMMUNITY: LONG-TERM ADAPTATION IN INNATE IMMUNE RESPONSES. ADAPTIVE IMMUNE RESPONSES ARE CHARACTERIZED BY ANTIGEN SPECIFICITY AND INDUCTION OF LIFELONG IMMUNOLOGIC MEMORY. RECENTLY, IT HAS BEEN REPORTED THAT INNATE IMMUNE CELLS CAN ALSO BUILD IMMUNE MEMORY CHARACTERISTICS-A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY DESCRIBES THE PERSISTENT HYPERRESPONSIVE PHENOTYPE THAT INNATE IMMUNE CELLS CAN DEVELOP AFTER BRIEF STIMULATION. PATHOGENIC STIMULI SUCH AS MICROORGANISMS, AND ALSO ENDOGENOUS MOLECULES INCLUDING URIC ACID, OXIDIZED LDL (LOW-DENSITY LIPOPROTEIN), AND CATECHOLAMINES, ARE CAPABLE OF INDUCING MEMORY IN MONOCYTES AND MACROPHAGES. WHILE TRAINED IMMUNITY PROVIDES FAVORABLE CROSS-PROTECTION IN THE CONTEXT OF INFECTIOUS DISEASES, THE HEIGHTENED IMMUNE RESPONSE CAN BE MALADAPTIVE IN DISEASES DRIVEN BY CHRONIC SYSTEMIC INFLAMMATION, SUCH AS ATHEROSCLEROSIS. TRAINED IMMUNITY IS MAINTAINED BY DISTINCT EPIGENETIC AND METABOLIC MECHANISMS AND PERSISTS FOR AT LEAST SEVERAL MONTHS IN VIVO DUE TO REPROGRAMMING OF MYELOID PROGENITOR CELLS. ADDITIONALLY, CERTAIN NONIMMUNE CELLS ARE ALSO FOUND TO EXHIBIT TRAINED IMMUNITY CHARACTERISTICS. THUS, TRAINED IMMUNITY PRESENTS AN EXCITING FRAMEWORK TO DEVELOP NEW APPROACHES TO VACCINATION AND ALSO NOVEL PHARMACOLOGICAL TARGETS IN THE TREATMENT OF INFLAMMATORY DISEASES. 2021 10 3688 41 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 11 3732 21 INNATE IMMUNE MEMORY AND THE HOST RESPONSE TO INFECTION. UNLIKE THE ADAPTIVE IMMUNE SYSTEM, THE INNATE IMMUNE SYSTEM HAS CLASSICALLY BEEN CHARACTERIZED AS BEING DEVOID OF MEMORY FUNCTIONS. HOWEVER, RECENT RESEARCH SHOWS THAT INNATE MYELOID AND LYMPHOID CELLS HAVE THE ABILITY TO RETAIN MEMORY OF PRIOR PATHOGEN EXPOSURE AND BECOME PRIMED TO ELICIT A ROBUST, BROAD-SPECTRUM RESPONSE TO SUBSEQUENT INFECTION. THIS PHENOMENON HAS BEEN TERMED INNATE IMMUNE MEMORY OR TRAINED IMMUNITY. INNATE IMMUNE MEMORY IS INDUCED VIA ACTIVATION OF PATTERN RECOGNITION RECEPTORS AND THE ACTIONS OF CYTOKINES ON HEMATOPOIETIC PROGENITORS AND STEM CELLS IN BONE MARROW AND INNATE LEUKOCYTES IN THE PERIPHERY. THE TRAINED PHENOTYPE IS INDUCED AND SUSTAINED VIA EPIGENETIC MODIFICATIONS THAT REPROGRAM TRANSCRIPTIONAL PATTERNS AND METABOLISM. THESE MODIFICATIONS AUGMENT ANTIMICROBIAL FUNCTIONS, SUCH AS LEUKOCYTE EXPANSION, CHEMOTAXIS, PHAGOCYTOSIS, AND MICROBIAL KILLING, TO FACILITATE AN AUGMENTED HOST RESPONSE TO INFECTION. ALTERNATIVELY, INNATE IMMUNE MEMORY MAY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS AND ALZHEIMER'S DISEASE. 2022 12 1300 25 DEDIFFERENTIATION AND IN VIVO REPROGRAMMING OF COMMITTED CELLS IN WOUND REPAIR (REVIEW). ACCUMULATING EVIDENCE HAS SHOWN THAT CELL DEDIFFERENTIATION OR REPROGRAMMING IS A PIVOTAL PROCEDURE FOR ANIMALS TO DEAL WITH INJURY AND PROMOTE ENDOGENOUS TISSUE REPAIR. TISSUE DAMAGE IS A CRITICAL FACTOR THAT TRIGGERS CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. BY CONTRAST, MICROENVIRONMENTAL CHANGES, INCLUDING THE LOSS OF STEM CELLS, HYPOXIA, CELL SENESCENCE, INFLAMMATION AND IMMUNITY, CAUSED BY TISSUE DAMAGE CAN RETURN CELLS TO AN UNSTABLE STATE. IF THE WOUND PERSISTS IN THE LONG?TERM DUE TO CHRONIC DAMAGE, THEN DEDIFFERENTIATION OR REPROGRAMMING OF THE SURROUNDING CELLS MAY LEAD TO CARCINOGENESIS. IN RECENT YEARS, EXTENSIVE RESEARCH HAS BEEN PERFORMED INVESTIGATING CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO, WHICH CAN HAVE SIGNIFICANT IMPLICATIONS FOR WOUND REPAIR, TREATMENT AND PREVENTION OF CANCER IN THE FUTURE. THE CURRENT REVIEW SUMMARIZES THE MOLECULAR EVENTS THAT ARE KNOWN TO DRIVE CELL DEDIFFERENTIATION DIRECTLY FOLLOWING TISSUE INJURY AND THE EFFECTS OF EPIGENETIC MODIFICATION ON DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. IN ADDITION, THE PRESENT REVIEW EXPLORES THE INTRACELLULAR MECHANISM OF ENDOGENOUS TISSUE REPAIR AND ITS RELATIONSHIP WITH CANCER, WHICH IS ESSENTIAL FOR BALANCING THE RISK BETWEEN TISSUE REPAIR AND MALIGNANT TRANSFORMATION AFTER INJURY. 2022 13 4969 35 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 14 6532 26 TRANSCRIPTIONAL REGULATION OF INFLAMMASOMES. INFLAMMASOMES ARE MULTIMOLECULAR COMPLEXES WITH POTENT INFLAMMATORY ACTIVITY. AS SUCH, THEIR ACTIVITY IS TIGHTLY REGULATED AT THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS. IN THIS REVIEW, WE PRESENT THE TRANSCRIPTIONAL REGULATION OF INFLAMMASOME GENES FROM SENSORS (E.G., NLRP3) TO SUBSTRATES (E.G., IL-1BETA). LINEAGE-DETERMINING TRANSCRIPTION FACTORS SHAPE INFLAMMASOME RESPONSES IN DIFFERENT CELL TYPES WITH PROFOUND CONSEQUENCES ON THE RESPONSIVENESS TO INFLAMMASOME-ACTIVATING STIMULI. PRO-INFLAMMATORY SIGNALS (STERILE OR MICROBIAL) HAVE A KEY TRANSCRIPTIONAL IMPACT ON INFLAMMASOME GENES, WHICH IS LARGELY MEDIATED BY NF-KAPPAB AND THAT TRANSLATES INTO HIGHER ANTIMICROBIAL IMMUNE RESPONSES. FURTHERMORE, DIVERSE INTRINSIC (E.G., CIRCADIAN CLOCK, METABOLITES) OR EXTRINSIC (E.G., XENOBIOTICS) SIGNALS ARE INTEGRATED BY SIGNAL-DEPENDENT TRANSCRIPTION FACTORS AND CHROMATIN STRUCTURE CHANGES TO MODULATE TRANSCRIPTIONALLY INFLAMMASOME RESPONSES. FINALLY, ANTI-INFLAMMATORY SIGNALS (E.G., IL-10) COUNTERBALANCE INFLAMMASOME GENES INDUCTION TO LIMIT DELETERIOUS INFLAMMATION. TRANSCRIPTIONAL REGULATIONS THUS APPEAR AS THE FIRST LINE OF INFLAMMASOME REGULATION TO RAISE THE DEFENSE LEVEL IN FRONT OF STRESS AND INFECTIONS BUT ALSO TO LIMIT EXCESSIVE OR CHRONIC INFLAMMATION. 2020 15 3678 34 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 16 2342 24 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 17 6452 23 THERAPIES TARGETING TRAINED IMMUNE CELLS IN INFLAMMATORY AND AUTOIMMUNE DISEASES. THE CONCEPT OF TRAINED IMMUNITY HAS RECENTLY EMERGED AS A MECHANISM CONTRIBUTING TO SEVERAL IMMUNE MEDIATED INFLAMMATORY CONDITIONS. TRAINED IMMUNITY IS DEFINED BY THE IMMUNOLOGICAL MEMORY DEVELOPED IN INNATE IMMUNE CELLS AFTER A PRIMARY NON-SPECIFIC STIMULUS THAT, IN TURN, PROMOTES A HEIGHTENED INFLAMMATORY RESPONSE UPON A SECONDARY CHALLENGE. THE MOST CHARACTERISTIC CHANGES ASSOCIATED TO THIS PROCESS INVOLVE THE REWIRING OF CELL METABOLISM AND EPIGENETIC REPROGRAMMING. UNDER PHYSIOLOGICAL CONDITIONS, THE ROLE OF TRAINED IMMUNE CELLS ENSURES A PROMPT RESPONSE. THIS ACTION IS LIMITED BY EFFECTIVE RESOLUTION OF INFLAMMATION AND TISSUE REPAIR IN ORDER TO RESTORE HOMEOSTASIS. HOWEVER, UNRESTRAINED ACTIVATION OF INNATE IMMUNE CELLS CONTRIBUTES TO THE DEVELOPMENT OF CHRONIC INFLAMMATION AND TISSUE DESTRUCTION THROUGH THE SECRETION OF INFLAMMATORY CYTOKINES, PROTEASES AND GROWTH FACTORS. THEREFORE, INTERVENTIONS AIMED AT REVERSING THE CHANGES INDUCED BY TRAINED IMMUNITY PROVIDE POTENTIAL THERAPEUTIC APPROACHES TO TREAT INFLAMMATORY AND AUTOIMMUNE DISEASES LIKE RHEUMATOID ARTHRITIS (RA). WE REVIEW CELLULAR APPROACHES THAT TARGET METABOLISM AND THE EPIGENETIC REPROGRAMMING OF DENDRITIC CELLS, MACROPHAGES, NATURAL KILLER CELLS, AND OTHER TRAINED CELLS IN THE CONTEXT OF AUTOIMMUNE INFLAMMATORY DISEASES. 2020 18 6494 28 TRAINED IMMUNITY AS A NOVEL THERAPEUTIC STRATEGY. RECENT STUDIES HAVE SHOWN THAT UPON CERTAIN VACCINATIONS OR INFECTIONS HUMAN INNATE IMMUNE CELLS CAN UNDERGO EXTENSIVE METABOLIC AND EPIGENETIC REPROGRAMMING, WHICH RESULTS IN ENHANCED IMMUNE RESPONSES UPON HETEROLOGOUS RE-INFECTION, A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY HAS ALSO BEEN SHOWN TO BE INAPPROPRIATELY ACTIVATED IN INFLAMMATORY DISEASES. THIS PROVIDES THE POTENTIAL FOR IDENTIFYING NOVEL THERAPEUTIC TARGETS: POTENTIATION OF TRAINED IMMUNITY COULD PROTECT FROM SECONDARY INFECTIONS AND REVERSE IMMUNOTOLERANT STATES, WHILE INHIBITION OF TRAINED IMMUNITY MIGHT REDUCE EXCESSIVE IMMUNE ACTIVATION IN CHRONIC INFLAMMATORY CONDITIONS. BY TARGETING SPECIFIC MECHANISMS OF TRAINED IMMUNITY ON EITHER IMMUNOLOGIC, METABOLIC OR EPIGENETIC LEVEL, NOVEL THERAPEUTIC APPROACHES COULD BE DEVELOPED. 2018 19 4453 28 MOLECULAR MECHANISMS AND PATHWAYS AS TARGETS FOR CANCER PREVENTION AND PROGRESSION WITH DIETARY COMPOUNDS. A UNIQUE FEATURE OF BIOACTIVE FOOD INGREDIENTS IS THEIR BROAD ANTIOXIDANT FUNCTION. ANTIOXIDANTS HAVING A WIDE SPECTRUM OF CHEMICAL STRUCTURE AND ACTIVITY BEYOND BASIC NUTRITION; DISPLAY DIFFERENT HEALTH BENEFITS BY THE PREVENTION AND PROGRESSION OF CHRONIC DISEASES. FUNCTIONAL FOOD COMPONENTS ARE CAPABLE OF ENHANCING THE NATURAL ANTIOXIDANT DEFENSE SYSTEM BY SCAVENGING REACTIVE OXYGEN AND NITROGEN SPECIES, PROTECTING AND REPAIRING DNA DAMAGE, AS WELL AS MODULATING THE SIGNAL TRANSDUCTION PATHWAYS AND GENE EXPRESSION. MAJOR PATHWAYS AFFECTED BY BIOACTIVE FOOD INGREDIENTS INCLUDE THE PRO-INFLAMMATORY PATHWAYS REGULATED BY NUCLEAR FACTOR KAPPA B (NF-KAPPAB), AS WELL AS THOSE ASSOCIATED WITH CYTOKINES AND CHEMOKINES. THE PRESENT REVIEW SUMMARIZES THE IMPORTANCE OF PLANT BIOACTIVES AND THEIR ROLES IN THE REGULATION OF INFLAMMATORY PATHWAYS. BIOACTIVES INFLUENCE SEVERAL PHYSIOLOGICAL PROCESSES SUCH AS GENE EXPRESSION, CELL CYCLE REGULATION, CELL PROLIFERATION, CELL MIGRATION, ETC., RESULTING IN CANCER PREVENTION. CANCER INITIATION IS ASSOCIATED WITH CHANGES IN METABOLIC PATHWAYS SUCH AS GLUCOSE METABOLISM, AND THE EFFECT OF BIOACTIVES IN NORMALIZING THIS PROCESS HAS BEEN PROVIDED. INITIATION AND PROGRESSION OF INFLAMMATORY BOWEL DISEASES (IBD) WHICH INCREASE THE CHANCES OF DEVELOPING OF COLORECTAL CANCERS CAN BE DOWNREGULATED BY PLANT BIOACTIVES. SEVERAL ASPECTS OF THE POTENTIAL ROLES OF MICRORNAS AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF CANCERS HAVE ALSO BEEN PRESENTED. 2017 20 2067 26 EPIGENETIC CONTROL OF MACROPHAGE SHAPE TRANSITION TOWARDS AN ATYPICAL ELONGATED PHENOTYPE BY HISTONE DEACETYLASE ACTIVITY. INFLAMMATORY CHRONIC PATHOLOGIES ARE COMPLEX PROCESSES CHARACTERIZED BY AN IMBALANCE BETWEEN THE RESOLUTION OF THE INFLAMMATORY PHASE AND THE ESTABLISHMENT OF TISSUE REPAIR. THE MAIN PLAYERS IN THESE INFLAMMATORY PATHOLOGIES ARE BONE MARROW DERIVED MONOCYTES (BMDMS). HOWEVER, HOW MONOCYTE DIFFERENTIATION IS MODULATED TO GIVE RISE TO SPECIFIC MACROPHAGE SUBPOPULATIONS (M1 OR M2) THAT MAY EITHER MAINTAIN THE CHRONIC INFLAMMATORY PROCESS OR LEAD TO WOUND HEALING IS STILL UNCLEAR. CONSIDERING THAT INHIBITORS OF HISTONE DEACETYLASE (HDAC) HAVE AN ANTI-INFLAMMATORY ACTIVITY, WE ASKED WHETHER THIS ENZYME WOULD PLAY A ROLE ON MONOCYTE DIFFERENTIATION INTO M1 OR M2 PHENOTYPE AND IN THE CELL SHAPE TRANSITION THAT FOLLOWS. WE THEN INDUCED MURINE BONE MARROW PROGENITORS INTO MONOCYTE/MACROPHAGE DIFFERENTIATION PATHWAY USING MEDIA CONTAINING GM-CSF AND THE HDAC BLOCKER, TRICHOSTATIN A (TSA). WE FOUND THAT THE PHARMACOLOGICAL INHIBITION OF HDAC ACTIVITY LED TO A SHAPE TRANSITION FROM THE TYPICAL MACROPHAGE PANCAKE-LIKE SHAPE INTO AN ELONGATED MORPHOLOGY, WHICH WAS CORRELATED TO A MIXED M1/M2 PROFILE OF CYTOKINE AND CHEMOKINE SECRETION. OUR RESULTS PRESENT, FOR THE FIRST TIME, THAT HDAC ACTIVITY ACTS AS A REGULATOR OF MACROPHAGE DIFFERENTIATION IN THE ABSENCE OF LYMPHOCYTE STIMULI. WE PROPOSE THAT HDAC ACTIVITY DOWN REGULATES MACROPHAGE PLASTICITY FAVORING THE PRO-INFLAMMATORY PHENOTYPE. 2015