1 5561 141 ROLE OF HISTONE DEACETYLASES IN MONOCYTE FUNCTION IN HEALTH AND CHRONIC INFLAMMATORY DISEASES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF 18 MEMBERS THAT PARTICIPATE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN ADDITION TO HISTONES, SOME HDACS ALSO DEACETYLATE TRANSCRIPTION FACTORS AND SPECIFIC CYTOPLASMIC PROTEINS.MONOCYTES, AS PART OF THE INNATE IMMUNE SYSTEM, MAINTAIN TISSUE HOMEOSTASIS AND HELP FIGHT INFECTIONS AND CANCER. IN THESE CELLS, HDACS ARE INVOLVED IN MULTIPLE PROCESSES INCLUDING PROLIFERATION, MIGRATION, DIFFERENTIATION, INFLAMMATORY RESPONSE, INFECTIONS, AND TUMORIGENESIS. HERE, A SYSTEMATIC DESCRIPTION OF THE ROLE THAT MOST HDACS PLAY IN THESE FUNCTIONS IS REVIEWED. SPECIFICALLY, SOME HDACS INDUCE A PRO-INFLAMMATORY RESPONSE AND PLAY MAJOR ROLES IN HOST DEFENSE. CONVERSELY, OTHER HDACS REPROGRAM MONOCYTES AND MACROPHAGES TOWARDS AN IMMUNOSUPPRESSIVE PHENOTYPE. THE RIGHT BALANCE BETWEEN BOTH TYPES HELPS MONOCYTES TO RESPOND CORRECTLY TO THE DIFFERENT PHYSIOLOGICAL/PATHOLOGICAL STIMULI. HOWEVER, ABERRANT EXPRESSIONS OR ACTIVITIES OF SPECIFIC HDACS ARE ASSOCIATED WITH AUTOIMMUNE DISEASES ALONG WITH OTHER CHRONIC INFLAMMATORY DISEASES, INFECTIONS, OR CANCER.THIS PAPER CRITICALLY REVIEWS THE INTERESTING AND EXTENSIVE KNOWLEDGE REGARDING THE ROLE OF SOME HDACS IN THESE PATHOLOGIES. IT ALSO SHOWS THAT AS YET, VERY LITTLE PROGRESS HAS BEEN MADE TOWARD THE GOAL OF FINDING EFFECTIVE HDAC-TARGETED THERAPIES. HOWEVER, GIVEN THEIR OBVIOUS POTENTIAL, WE CONCLUDE THAT IT IS WORTH THE EFFORT TO DEVELOP MONOCYTE-SPECIFIC DRUGS THAT SELECTIVELY TARGET HDAC SUBTYPES WITH THE AIM OF FINDING EFFECTIVE TREATMENTS FOR DISEASES IN WHICH OUR INNATE IMMUNE SYSTEM IS INVOLVED. 2021 2 5550 43 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013 3 3703 36 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 4 5937 41 TARGETING HISTONE DEACETYLASE ACTIVITY IN RHEUMATOID ARTHRITIS AND ASTHMA AS PROTOTYPES OF INFLAMMATORY DISEASE: SHOULD WE KEEP OUR HATS ON? CELLULAR ACTIVATION, PROLIFERATION AND SURVIVAL IN CHRONIC INFLAMMATORY DISEASES IS REGULATED NOT ONLY BY ENGAGEMENT OF SIGNAL TRANS-DUCTION PATHWAYS THAT MODULATE TRANSCRIPTION FACTORS REQUIRED FOR THESE PROCESSES, BUT ALSO BY EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR ACCESS TO GENE PROMOTER REGIONS. HISTONE ACETYL TRANSFERASES COORDINATE THE RECRUITMENT AND ACTIVATION OF TRANSCRIPTION FACTORS WITH CONFORMATIONAL CHANGES IN HISTONES THAT ALLOW GENE PROMOTER EXPOSURE. HISTONE DEACETYLASES (HDACS) COUNTERACT HISTONE ACETYL TRANSFERASE ACTIVITY THROUGH THE TARGETING OF BOTH HISTONES AS WELL AS NONHISTONE SIGNAL TRANSDUCTION PROTEINS IMPORTANT IN INFLAMMATION. NUMEROUS STUDIES HAVE INDICATED THAT DEPRESSED HDAC ACTIVITY IN PATIENTS WITH INFLAMMATORY AIRWAY DISEASES MAY CONTRIBUTE TO LOCAL PROINFLAMMATORY CYTOKINE PRODUCTION AND DIMINISH PATIENT RESPONSES TO CORTICOSTEROID TREATMENT. RECENT OBSERVATIONS THAT HDAC ACTIVITY IS DEPRESSED IN RHEUMATOID ARTHRITIS PATIENT SYNOVIAL TISSUE HAVE PREDICTED THAT STRATEGIES RESTORING HDAC FUNCTION MAY BE THERAPEUTIC IN THIS DISEASE AS WELL. PHARMACOLOGICAL INHIBITORS OF HDAC ACTIVITY, HOWEVER, HAVE DEMONSTRATED POTENT THERAPEUTIC EFFECTS IN ANIMAL MODELS OF ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE PRESENT REVIEW WE ASSESS AND RECONCILE THESE OUTWARDLY PARADOXICAL STUDY RESULTS TO PROVIDE A WORKING MODEL FOR HOW ALTERATIONS IN HDAC ACTIVITY MAY CONTRIBUTE TO PATHOLOGY IN RHEUMATOID ARTHRITIS, AND HIGHLIGHT KEY QUESTIONS TO BE ANSWERED IN THE PRECLINICAL EVALUATION OF COMPOUNDS MODULATING THESE ENZYMES. 2008 5 2070 33 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 6 2493 47 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 7 2036 29 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 8 2344 38 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 9 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 10 4738 42 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 11 2303 40 EPIGENETIC REGULATION OF CANNABINOID-MEDIATED ATTENUATION OF INFLAMMATION AND ITS IMPACT ON THE USE OF CANNABINOIDS TO TREAT AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION IS CONSIDERED TO BE A SILENT KILLER BECAUSE IT IS THE UNDERLYING CAUSE OF A WIDE RANGE OF CLINICAL DISORDERS, FROM CARDIOVASCULAR TO NEUROLOGICAL DISEASES, AND FROM CANCER TO OBESITY. IN ADDITION, THERE ARE OVER 80 DIFFERENT TYPES OF DEBILITATING AUTOIMMUNE DISEASES FOR WHICH THERE ARE NO CURE. CURRENTLY, THE DRUGS THAT ARE AVAILABLE TO SUPPRESS CHRONIC INFLAMMATION ARE EITHER INEFFECTIVE OR OVERTLY SUPPRESS THE INFLAMMATION, THEREBY CAUSING INCREASED SUSCEPTIBILITY TO INFECTIONS AND CANCER. THUS, THE DEVELOPMENT OF A NEW CLASS OF DRUGS THAT CAN SUPPRESS CHRONIC INFLAMMATION IS IMPERATIVE. CANNABINOIDS ARE A GROUP OF COMPOUNDS PRODUCED IN THE BODY (ENDOCANNABINOIDS) OR FOUND IN CANNABIS (PHYTOCANNABINOIDS) THAT ACT THROUGH CANNABINOID RECEPTORS AND VARIOUS OTHER RECEPTORS EXPRESSED WIDELY IN THE BRAIN AND IMMUNE SYSTEM. IN THE LAST DECADE, CANNABINOIDS HAVE BEEN WELL ESTABLISHED EXPERIMENTALLY TO MEDIATE ANTI-INFLAMMATORY PROPERTIES. RESEARCH HAS SHOWN THAT THEY SUPPRESS INFLAMMATION THROUGH MULTIPLE PATHWAYS, INCLUDING APOPTOSIS AND INDUCING IMMUNOSUPPRESSIVE T REGULATORY CELLS (TREGS) AND MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS). INTERESTINGLY, CANNABINOIDS ALSO MEDIATE EPIGENETIC ALTERATIONS IN GENES THAT REGULATE INFLAMMATION. IN THE CURRENT REVIEW, WE HIGHLIGHT HOW THE EPIGENETIC MODULATIONS CAUSED BY CANNABINOIDS LEAD TO THE SUPPRESSION OF INFLAMMATION AND HELP IDENTIFY NOVEL PATHWAYS THAT CAN BE USED TO TARGET AUTOIMMUNE DISEASES. 2021 12 2532 38 EPIGENETICS IN ATHEROSCLEROSIS AND INFLAMMATION. ATHEROSCLEROSIS IS A MULTIFACTORIAL DISEASE WITH A SEVERE BURDEN ON WESTERN SOCIETY. RECENT INSIGHTS INTO THE PATHOGENESIS OF ATHEROSCLEROSIS UNDERSCORE THE IMPORTANCE OF CHRONIC INFLAMMATION IN BOTH THE INITIATION AND PROGRESSION OF VASCULAR REMODELLING. EXPRESSION OF IMMUNOREGULATORY MOLECULES BY VASCULAR WALL COMPONENTS WITHIN THE ATHEROSCLEROTIC LESIONS IS ACCORDINGLY THOUGHT TO CONTRIBUTE TO THE ONGOING INFLAMMATORY PROCESS. BESIDES GENE REGULATORY PROTEINS (TRANSCRIPTION FACTORS), EPIGENETIC MECHANISMS ALSO PLAY AN ESSENTIAL AND FUNDAMENTAL ROLE IN THE TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION. THESE EPIGENETIC MECHANISMS CHANGE THE ACCESSIBILITY OF CHROMATIN BY DNA METHYLATION AND HISTONE MODIFICATIONS. EPIGENETIC MODULATORS ARE THUS CRITICALLY INVOLVED IN THE REGULATION OF VASCULAR, IMMUNE AND TISSUE-SPECIFIC GENE EXPRESSION WITHIN THE ATHEROSCLEROTIC LESION. IMPORTANTLY, EPIGENETIC PROCESSES ARE REVERSIBLE AND MAY PROVIDE AN EXCELLENT THERAPEUTIC TARGET. THE CONCEPT OF EPIGENETIC REGULATION IS GRADUALLY BEING RECOGNIZED AS AN IMPORTANT FACTOR IN THE PATHOGENESIS OF ATHEROSCLEROSIS. RECENT RESEARCH PROVIDES AN ESSENTIAL LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME. IN THIS REVIEW WE THEREFORE DISCUSS THE BASIS OF EPIGENETIC REGULATION - AND THE CONTRIBUTION THEREOF IN THE REGULATION OF INFLAMMATORY PROCESSES IN GENERAL AND DURING ATHEROSCLEROSIS IN PARTICULAR. MOREOVER WE HIGHLIGHT POTENTIAL THERAPEUTIC INTERVENTIONS BASED ON EPIGENETIC MECHANISMS. 2010 13 4200 45 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 6533 40 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 15 3197 33 HDAC INHIBITORS: TARGETS FOR TUMOR THERAPY, IMMUNE MODULATION AND LUNG DISEASES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT PLAY A KEY ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELING CHROMATIN. INHIBITION OF HDACS IS A PROSPECTIVE THERAPEUTIC APPROACH FOR REVERSING EPIGENETIC ALTERATION IN SEVERAL DISEASES. IN PRECLINICAL RESEARCH, NUMEROUS TYPES OF HDAC INHIBITORS WERE DISCOVERED TO EXHIBIT POWERFUL AND SELECTIVE ANTICANCER PROPERTIES. HOWEVER, SUCH RESEARCH HAS REVEALED THAT THE EFFECTS OF HDAC INHIBITORS MAY BE FAR BROADER AND MORE INTRICATE THAN PREVIOUSLY THOUGHT. THIS REVIEW WILL PROVIDE INSIGHT INTO THE HDAC INHIBITORS AND THEIR MECHANISM OF ACTION WITH SPECIAL EMPHASIS ON THE SIGNIFICANCE OF HDAC INHIBITORS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. NANOCARRIER-MEDIATED HDAC INHIBITOR DELIVERY AND NEW APPROACHES FOR TARGETING HDACS ARE ALSO DISCUSSED. 2022 16 2578 42 EPIGENETICS OF INFLAMMATORY BOWEL DISEASES. INFLAMMATORY BOWEL DISEASES ARE MULTIFACTORIAL, CHRONIC, CONTINUOUS, RELAPSING, AND IMMUNE-MEDIATED DISEASES OF THE GASTROINTESTINAL TRACT. IT HAS BEEN BELIEVED THAT MECHANISMS UNDERLYING INFLAMMATORY BOWEL DISEASES INCLUDE GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS, AND ALTERED IMMUNE RESPONSE TO THE GUT MICROBIOME. THE EPIGENETIC MODULATION TAKES PLACE VIA CHROMATIN MODIFICATIONS, INCLUDING PHOSPHORYLATION, ACETYLATION, METHYLATION, SUMOYLATION, AND UBIQUITINATION. THE METHYLATION LEVELS OF COLONIC TISSUE WERE FOUND WELL CORRELATED TO BLOOD SAMPLES IN INFLAMMATORY BOWEL DISEASES. MOREOVER, THE METHYLATION LEVEL OF SPECIFIC GENES WAS DIFFERENT BETWEEN CROHN'S DISEASE AND ULCERATIVE COLITIS. IT HAS BEEN SHOWN THAT THE ENZYMES AFFECTING HISTONE MODIFICATIONS LIKE HISTONE DEACETYLASES AND HISTONE ACETYLTRANSFERASES DO NOT ACT SOLELY ON HISTONES BUT ALSO AFFECT THE ACETYLATION OF MANY PROTEINS SUCH AS P53 AND STAT3. IT HAS BEEN ALREADY SHOWN THAT A NONSELECTIVE HISTONE DEACETYLASE INHIBITOR, VORINOSTAT (SAHA), WHICH IS CURRENTLY BEING USED IN SEVERAL CANCER TREATMENTS, SHOWED ANTI-INFLAMMATORY ACTIVITIES IN MOUSE MODELS. AMONG EPIGENETIC ALTERATIONS, LONG NON-CODING RNAS AND MICRORNAS PLAY SIGNIFICANT ROLES IN T-CELL MATURATION, DIFFERENTIATION, ACTIVATION, AND SENILITY. THE LONG NON-CODING RNA AND MICRORNA EXPRESSION PROFILES CAN PERFECTLY SEPARATE INFLAMMATORY BOWEL DISEASE PATIENTS FROM HEALTHY CONTROLS AND ARE REMARKED AS BIOMARKERS OF INFLAMMATORY BOWEL DISEASES. OVERALL, MANY STUDIES HAVE SHOWN THAT EPIGENETIC INHIBITORS CAN TARGET SIGNIFICANT SIGNAL PATHWAYS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES, AND THE IMPACT OF EPIGENETIC INHIBITORS IS BEING STUDIED IN CLINICAL TRIALS. IN CONCLUSION, EXPLORING MORE EPIGENETIC PATHWAYS REGARDING INFLAMMATORY BOWEL DISEASE PATHOGENESIS WILL HELP US TO DISCOVER THERAPEUTIC TARGETS AND NEW DRUGS AND AGENTS TARGETING MIRNAS IN INFLAMMATORY BOWEL DISEASES. IN GENERAL, DISCOVERING EPIGENETIC TARGETS COULD IMPROVE THE DIAGNOSIS AND TREATMENT OF INFLAMMATORY BOWEL DISEASES. 2023 17 6395 44 THE ROLE OF THE MEDIATORS OF INFLAMMATION IN CANCER DEVELOPMENT. EPIGENETIC DISORDERS SUCH AS POINT MUTATIONS IN CELLULAR TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS ARE NEEDED TO TRANSFORMATION OF NORMAL CELLS INTO CANCER CELLS. THESE EVENTS RESULT IN ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS, TRIGGERING TO AN INFLAMMATORY RESPONSE WHICH CAN LEAD THE DEVELOPMENT OF CANCER. THE INFLAMMATORY RESPONSE IS A UNIVERSAL DEFENSE MECHANISM ACTIVATED IN RESPONSE TO AN INJURY TISSUE, OF ANY NATURE, THAT INVOLVES BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, THROUGH THE COLLECTIVE ACTION OF A VARIETY OF SOLUBLE MEDIATORS. MANY INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN SEVERAL TYPES OF CANCER, LINKING CHRONIC INFLAMMATION TO TUMORIGENESIS PROCESS. THUS, INFLAMMATORY RESPONSES PLAY DECISIVE ROLES AT DIFFERENT STAGES OF TUMOR DEVELOPMENT, INCLUDING INITIATION, PROMOTION, GROWTH, INVASION, AND METASTASIS, AFFECTING ALSO THE IMMUNE SURVEILLANCE. IMMUNE CELLS THAT INFILTRATE TUMORS ENGAGE IN AN EXTENSIVE AND DYNAMIC CROSSTALK WITH CANCER CELLS, AND SOME OF THE MOLECULAR EVENTS THAT MEDIATE THIS DIALOG HAVE BEEN REVEALED. A RANGE OF INFLAMMATION MEDIATORS, INCLUDING CYTOKINES, CHEMOKINES, FREE RADICALS, PROSTAGLANDINS, GROWTH AND TRANSCRIPTION FACTORS, MICRORNAS, AND ENZYMES AS, CYCLOOXYGENASE AND MATRIX METALLOPROTEINASE, COLLECTIVELY ACTS TO CREATE A FAVORABLE MICROENVIRONMENT FOR THE DEVELOPMENT OF TUMORS. IN THIS REVIEW ARE PRESENTED THE MAIN MEDIATORS OF THE INFLAMMATORY RESPONSE AND DISCUSSED THE LIKELY MECHANISMS THROUGH WHICH, THEY INTERACT WITH EACH OTHER TO CREATE A CONDITION FAVORABLE TO DEVELOPMENT OF CANCER. 2015 18 4278 44 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES. 2021 19 5931 40 TARGETING EPIGENETIC MODIFIERS TO REPROGRAMME MACROPHAGES IN NON-RESOLVING INFLAMMATION-DRIVEN ATHEROSCLEROSIS. EPIGENOMIC AND EPIGENETIC RESEARCH HAS BEEN PROVIDING SEVERAL NEW INSIGHTS INTO A VARIETY OF DISEASES CAUSED BY NON-RESOLVING INFLAMMATION, INCLUDING CARDIOVASCULAR DISEASES. ATHEROSCLEROSIS (AS) HAS LONG BEEN RECOGNIZED AS A CHRONIC INFLAMMATORY DISEASE OF THE ARTERIAL WALLS, CHARACTERIZED BY LOCAL PERSISTENT AND STEPWISE ACCELERATING INFLAMMATION WITHOUT RESOLUTION, ALSO KNOWN AS UNCONTROLLED INFLAMMATION. THE PATHOGENESIS OF AS IS DRIVEN PRIMARILY BY HIGHLY PLASTIC MACROPHAGES VIA THEIR POLARIZATION TO PRO- OR ANTI-INFLAMMATORY PHENOTYPES AS WELL AS OTHER NOVEL SUBTYPES RECENTLY IDENTIFIED BY SINGLE-CELL SEQUENCING. ALTHOUGH EMERGING EVIDENCE HAS INDICATED THE KEY ROLE OF THE EPIGENETIC MACHINERY IN THE REGULATION OF MACROPHAGE PLASTICITY, THE INVESTIGATION OF EPIGENETIC ALTERATIONS AND MODIFIERS IN AS AND RELATED INFLAMMATION IS STILL IN ITS INFANCY. AN INCREASING NUMBER OF THE EPIGENETIC MODIFIERS (E.G. TET2, DNMT3A, HDAC3, HDAC9, JMJD3, KDM4A) HAVE BEEN IDENTIFIED IN EPIGENETIC REMODELLING OF MACROPHAGES THROUGH DNA METHYLATION OR HISTONE MODIFICATIONS (E.G. METHYLATION, ACETYLATION, AND RECENTLY LACTYLATION) IN INFLAMMATION. THESE OR MANY UNEXPLORED MODIFIERS FUNCTION TO DETERMINE OR SWITCH THE DIRECTION OF MACROPHAGE POLARIZATION VIA TRANSCRIPTIONAL REPROGRAMMING OF GENE EXPRESSION AND INTRACELLULAR METABOLIC REWIRING UPON MICROENVIRONMENTAL CUES, THEREBY REPRESENTING A PROMISING TARGET FOR ANTI-INFLAMMATORY THERAPY IN AS. HERE, WE REVIEW UP-TO-DATE FINDINGS INVOLVING THE EPIGENETIC REGULATION OF MACROPHAGES TO SHED LIGHT ON THE MECHANISM OF UNCONTROLLED INFLAMMATION DURING AS ONSET AND PROGRESSION. WE ALSO DISCUSS CURRENT CHALLENGES FOR DEVELOPING AN EFFECTIVE AND SAFE ANTI-AS THERAPY THAT TARGETS THE EPIGENETIC MODIFIERS AND PROPOSE A POTENTIAL ANTI-INFLAMMATORY STRATEGY THAT REPOLARIZES MACROPHAGES FROM PRO- TO ANTI-INFLAMMATORY PHENOTYPES. 2021 20 3921 42 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004