1 620 268 BIOCHEMISTRY AND MOLECULAR BIOLOGY OF GELATINASE B OR MATRIX METALLOPROTEINASE-9 (MMP-9): THE NEXT DECADE. RESEARCH ON MATRIX METALLOPROTEINASES (MMPS) AND IN PARTICULAR ON GELATINASE B, ALIAS MMP-9, HAS GROWN EXPONENTIALLY IN THE DECADE 2003-2012. STRUCTURAL DETAILS ABOUT FLEXIBILITY OF MMP-9 MONOMERS, TOGETHER WITH GLYCOSYLATION, OLIGOMERIZATION, HETEROGENEITY AND INSTABILITY OF THE WILDTYPE ENZYME EXPLAIN WHY CRYSTALLOGRAPHY EXPERIMENTS HAVE NOT YET BEEN SUCCESSFUL FOR THE INTACT ENZYME. MMP-9 MAY BE VIEWED AS A MULTIDOMAIN ENZYME IN WHICH THE HEMOPEXIN, THE O-GLYCOSYLATED AND THE CATALYTIC DOMAINS YIELD SUPPORT FOR ATTACHMENT, ARTICULATION AND CATALYSIS, RESPECTIVELY. THE STEPWISE PROTEOLYTIC ACTIVATION OF THE INACTIVE ZYMOGEN INTO A CATALYTICALLY ACTIVE FORM BECOMES GRADUALLY BETTER UNDERSTOOD. PRIMING OF ACTIVATION BY MMP-3 MAY BE EXECUTED BY MEPRINS THAT DESTABILIZE THE INTERACTION OF THE AMINOTERMINUS WITH THE THIRD FIBRONECTIN REPEAT. ALTERNATIVELY, AUTOCATALYTIC ACTIVATION MAY OCCUR IN THE PRESENCE OF MOLECULES THAT TIGHTLY BIND TO THE CATALYTIC SITE AND THAT PUSH THE CYSTEIN RESIDUE IN THE PRODOMAIN AWAY FROM THE CATALYTIC ZINC ION. THANKS TO THE DEVELOPMENT OF DEGRADOMICS TECHNOLOGIES, SUBSTRATE REPERTOIRES OF MMP-9 HAVE BEEN DEFINED, BUT IT REMAINS A CHALLENGE TO DETERMINE AND PROVE WHICH SUBSTRATES ARE BIOLOGICALLY RELEVANT. THE SUBSTRATE REPERTOIRE HAS BEEN ENLARGED FROM EXTRACELLULAR TO MEMBRANE-BOUND AND EFFICIENT INTRACELLULAR SUBSTRATES, SUCH AS CRYSTALLINS, TUBULINS AND ACTINS. BIOLOGICAL STUDIES OF MMP-9 HAVE TUNED THE FIELD FROM BEING PRIMARILY CANCER-ORIENTED TOWARDS VASCULAR AND INFLAMMATORY RESEARCH. IN TUMOR BIOLOGY, IT HAS BEEN INCREASINGLY APPRECIATED THAT MMP-9 FROM INFLAMMATORY CELLS, PARTICULARLY NEUTROPHILS, CO-DETERMINES PROGNOSIS AND OUTCOME. ASIDE FROM THE CATALYTIC FUNCTIONS EXECUTED BY AMINOTERMINAL DOMAINS OF MMP-9, THE CARBOXYTERMINAL HEMOPEXIN (PEX) DOMAIN OF GELATINASE B EXERTS NON-CATALYTIC ANTI-APOPTOTIC SIGNALING EFFECTS. THE RECOGNITION THAT GELATINASE B IS INDUCED BY MANY PRO-INFLAMMATORY CYTOKINES, WHEREAS ITS INHIBITORS ARE INCREASED BY ANTI-INFLAMMATORY CYTOKINES, HAS GENERATED INTEREST TO TARGET MMP-9 IN ACUTE LETHAL CONDITIONS, SUCH AS BACTERIAL MENINGITIS, SEPSIS AND ENDOTOXIN SHOCK, AND IN ACUTE EXACERBATIONS OF CHRONIC DISEASES. PREVIOUSLY DESCRIBED TRANSCRIPTIONAL REGULATION OF MMP-9 IS COMPLEMENTED BY EPIGENETIC CHECKPOINTS, INCLUDING HISTONE MODIFICATIONS AND MICRORNAS. BECAUSE ACTIVATION OF PROMMP-9 MAY BE EXECUTED BY OTHER MMPS, THE THERAPEUTIC DOGMA THAT MMP INHIBITORS NEED TO BE HIGHLY SELECTIVE MAY BE KEYED DOWN FOR THE TREATMENT OF LIFE-THREATENING CONDITIONS. WHEN INFLAMMATION AND MMP-9 FULFILL BENEFICIAL FUNCTIONS TO CLEAR DAMAGING PROTEIN COMPLEXES, SUCH AS IN SYSTEMIC AUTOIMMUNE DISEASES, THERAPEUTIC MMP INHIBITION HAS TO BE AVOIDED. IN MMP9 GENE KNOCKOUT MICE, SPECIFIC SPONTANEOUS PHENOTYPES EMERGED WITH EFFECTS ON THE SKELETAL, REPRODUCTIVE AND NERVOUS SYSTEMS. THESE FINDINGS NOT ONLY HAVE CLINICAL CORRELATES IN BONE GROWTH AND FERTILITY, BUT ALSO STIMULATE RESEARCH ON THE ROLES OF MMPS AND MMP-9 IN ENDOCRINOLOGY, IMMUNOLOGY AND THE NEUROSCIENCES. MMP9-DEFICIENT MICE ARE VALUABLE TOOLS TO DEFINE MMP-9 SUBSTRATES IN VIVO AND TO STUDY THE ROLE OF THIS ENZYME IN ANIMAL MODELS OF INFLAMMATORY, VASCULAR, NEOPLASTIC AND DEGENERATIVE DISEASES. FUTURE CHALLENGES INCLUDE SOLVING THE CRYSTAL STRUCTURE, DEFINITION OF THE FUNCTIONS OF COVALENT OLIGOMERS AND HETEROMERS IN BIOLOGY AND PATHOLOGY, LIFE-IMAGING OF MMP-9 ACTIVITY, SUBSTRATE DETERMINATION IN SITU AND THE STUDY OF INHIBITOR EFFECTS ON FERTILITY, CANCER AND INFLAMMATION AND IN NEUROBIOLOGY AND REGENERATIVE MEDICINE. SUCH STUDIES WILL BETTER DEFINE CONDITIONS IN WHICH INHIBITION OF MMP-9 IS BENEFICIAL OR HAS TO BE AVOIDED. 2013 2 6504 40 TRAINED INNATE IMMUNITY AND ITS IMPLICATIONS FOR MUCOSAL IMMUNITY AND INFLAMMATION. THE LONG-STANDING DOGMA THAT IMMUNOLOGICAL MEMORY IS THE EXCLUSIVE PREROGATIVE OF THE ADAPTIVE IMMUNE SYSTEM HAS BEEN CHALLENGED BY EMERGING EVIDENCE THAT INNATE IMMUNITY CAN ALSO MAINTAIN MEMORY OF PAST EVENTS. SUCH IMMUNOLOGICAL IMPRINTING TAKES TWO FORMS, TRAINED INNATE IMMUNITY AND TOLERANCE. TRAINED IMMUNITY INVOLVES METABOLIC AND EPIGENETIC ADAPTATIONS IN INNATE IMMUNE CELLS AND THEIR PROGENITORS IN THE BONE MARROW UPON EXPOSURE TO CERTAIN MICROBIAL AND/OR INFLAMMATORY STIMULI SO THAT THE "TRAINED" CELLS WOULD BE POISED TO RESPOND MUCH FASTER AND STRONGER TO A SUBSEQUENT CHALLENGE (E.G., A NEW INFECTION THAT IS NOT NECESSARILY THE SAME AS THE EARLIER ONE). CONVERSELY, TOLERANCE LEADS TO ATTENUATED IMMUNE RESPONSES TO SECONDARY STIMULI. THIS REVIEW FOCUSES ON TRAINED IMMUNITY AND DISCUSSES EVIDENCE FOR ITS EXISTENCE FROM LOWER ORGANISMS TO HUMANS, ITS MECHANISTIC UNDERPINNINGS, AND ITS TRANSLATIONAL RAMIFICATIONS. ALTHOUGH TRAINED IMMUNITY CAN BE CONSIDERED AS AN EVOLUTIONARILY CONSERVED BENEFICIAL RESPONSE AGAINST REINFECTIONS, IN THE SETTING OF MODERN SOCIETIES WITH HIGH PREVALENCE OF CHRONIC MUCOSAL AND SYSTEMIC INFLAMMATORY DISEASES, TRAINED IMMUNITY COULD ALSO PROMOTE MALADAPTIVE IMMUNE RESPONSES THAT AGGRAVATE PATHOLOGY. THUS, DEPENDING ON CONTEXT, INNATE IMMUNE MEMORY COULD BE THERAPEUTICALLY MANIPULATED USING DEFINED AGONISTS TO EITHER PROMOTE INNATE IMMUNE RESPONSES (PARTICULARLY USEFUL FOR THE TREATMENT OF INFECTIONS OR CHEMOTHERAPY-INDUCED MYELOSUPPRESSION) OR SUPPRESS EXCESSIVE INFLAMMATION IN INFLAMMATORY AND AUTOIMMUNE DISEASES. 2019 3 6501 32 TRAINED IMMUNITY: LINKING OBESITY AND CARDIOVASCULAR DISEASE ACROSS THE LIFE-COURSE? OBESITY, A CHRONIC INFLAMMATORY DISEASE, IS THE MOST PREVALENT MODIFIABLE RISK FACTOR FOR CARDIOVASCULAR DISEASE. THE MECHANISMS UNDERLYING INFLAMMATION IN OBESITY ARE INCOMPLETELY UNDERSTOOD. RECENT DEVELOPMENTS HAVE CHALLENGED THE DOGMA OF IMMUNOLOGICAL MEMORY OCCURRING EXCLUSIVELY IN THE ADAPTIVE IMMUNE SYSTEM AND SHOW THAT THE INNATE IMMUNE SYSTEM HAS POTENTIAL TO BE REPROGRAMMED. THIS INNATE IMMUNE MEMORY (TRAINED IMMUNITY) IS CHARACTERIZED BY EPIGENETIC AND METABOLIC REPROGRAMMING OF MYELOID CELLS FOLLOWING ENDOGENOUS OR EXOGENOUS STIMULATION, RESULTING IN ENHANCED INFLAMMATION TO SUBSEQUENT STIMULI. TRAINED IMMUNITY PHENOTYPES HAVE NOW BEEN REPORTED FOR OTHER IMMUNE AND NON-IMMUNE CELLS. HERE, WE PROVIDE A NOVEL PERSPECTIVE ON THE PUTATIVE ROLE OF TRAINED IMMUNITY IN MEDIATING THE ADVERSE CARDIOVASCULAR EFFECTS OF OBESITY AND HIGHLIGHT POTENTIAL TRANSLATIONAL PATHWAYS. 2020 4 6503 26 TRAINED IMMUNITY: REPROGRAMMING INNATE IMMUNITY IN HEALTH AND DISEASE. TRADITIONALLY, THE INNATE AND ADAPTIVE IMMUNE SYSTEMS ARE DIFFERENTIATED BY THEIR SPECIFICITY AND MEMORY CAPACITY. IN RECENT YEARS, HOWEVER, THIS PARADIGM HAS SHIFTED: CELLS OF THE INNATE IMMUNE SYSTEM APPEAR TO BE ABLE TO GAIN MEMORY CHARACTERISTICS AFTER TRANSIENT STIMULATION, RESULTING IN AN ENHANCED RESPONSE UPON SECONDARY CHALLENGE. THIS PHENOMENON HAS BEEN CALLED TRAINED IMMUNITY. TRAINED IMMUNITY IS CHARACTERIZED BY NONSPECIFIC INCREASED RESPONSIVENESS, MEDIATED VIA EXTENSIVE METABOLIC AND EPIGENETIC REPROGRAMMING. TRAINED IMMUNITY EXPLAINS THE HETEROLOGOUS EFFECTS OF VACCINES, WHICH RESULT IN INCREASED PROTECTION AGAINST SECONDARY INFECTIONS. HOWEVER, IN CHRONIC INFLAMMATORY CONDITIONS, TRAINED IMMUNITY CAN INDUCE MALADAPTIVE EFFECTS AND CONTRIBUTE TO HYPERINFLAMMATION AND PROGRESSION OF CARDIOVASCULAR DISEASE, AUTOINFLAMMATORY SYNDROMES, AND NEUROINFLAMMATION. IN THIS REVIEW WE SUMMARIZE THE CURRENT STATE OF THE FIELD OF TRAINED IMMUNITY, ITS MECHANISMS, AND ITS ROLES IN BOTH HEALTH AND DISEASE. 2021 5 6502 31 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 6 6494 33 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 7 3544 32 IMMUNOMETABOLIC CONTROL OF TRAINED IMMUNITY. INNATE IMMUNE CELLS CAN ADOPT LONG-TERM INFLAMMATORY PHENOTYPES FOLLOWING BRIEF ENCOUNTERS WITH EXOGENOUS (MICROBIAL) OR ENDOGENOUS STIMULI. THIS PHENOMENON IS NAMED TRAINED IMMUNITY AND CAN IMPROVE HOST DEFENSE AGAINST (RECURRENT) INFECTIONS. IN CONTRAST, TRAINED IMMUNITY CAN ALSO BE MALADAPTIVE IN THE CONTEXT OF CHRONIC INFLAMMATORY DISORDERS, SUCH AS ATHEROSCLEROSIS. KEY TO FUTURE THERAPEUTIC EXPLOITATION OF THIS MECHANISM IS THOROUGH KNOWLEDGE OF THE MECHANISMS DRIVING TRAINED IMMUNITY, WHICH CAN BE USED AS PHARMACOLOGICAL TARGETS. THESE MECHANISMS INCLUDE PROFOUND CHANGES IN INTRACELLULAR METABOLISM, WHICH ARE CLOSELY INTERTWINED WITH EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE MODIFICATIONS. GLYCOLYSIS, GLUTAMINE REPLENISHMENT OF THE TRICARBOXYLIC ACID CYCLE WITH ACCUMULATION OF FUMARATE, AND THE MEVALONATE PATHWAY HAVE ALL BEEN IDENTIFIED AS CRITICAL PATHWAYS FOR TRAINED IMMUNITY IN MONOCYTES AND MACROPHAGES. IN THIS REVIEW, WE PROVIDE A STATE-OF-THE-ART OVERVIEW OF HOW THESE METABOLIC PATHWAYS INTERACT WITH EPIGENETIC PROGRAMS TO DEVELOP TRAINED IMMUNITY. 2021 8 6376 37 THE ROLE OF NEUTROPHILS IN TRAINED IMMUNITY. THE PRINCIPLE OF TRAINED IMMUNITY REPRESENTS INNATE IMMUNE MEMORY DUE TO SUSTAINED, MAINLY EPIGENETIC, CHANGES TRIGGERED BY ENDOGENOUS OR EXOGENOUS STIMULI IN BONE MARROW (BM) PROGENITORS (CENTRAL TRAINED IMMUNITY) AND THEIR INNATE IMMUNE CELL PROGENY, THEREBY TRIGGERING ELEVATED RESPONSIVENESS AGAINST SECONDARY STIMULI. BM PROGENITORS CAN RESPOND TO MICROBIAL AND STERILE SIGNALS, THEREBY POSSIBLY ACQUIRING TRAINED IMMUNITY-MEDIATED LONG-LASTING ALTERATIONS THAT MAY SHAPE THE FATE AND FUNCTION OF THEIR PROGENY, FOR EXAMPLE, NEUTROPHILS. NEUTROPHILS, THE MOST ABUNDANT INNATE IMMUNE CELL POPULATION, ARE PRODUCED IN THE BM FROM COMMITTED PROGENITOR CELLS IN A PROCESS DESIGNATED GRANULOPOIESIS. NEUTROPHILS ARE THE FIRST RESPONDERS AGAINST INFECTIOUS OR INFLAMMATORY CHALLENGES AND HAVE VERSATILE FUNCTIONS IN IMMUNITY. TOGETHER WITH OTHER INNATE IMMUNE CELLS, NEUTROPHILS ARE EFFECTORS OF PERIPHERAL TRAINED IMMUNITY. HOWEVER, GIVEN THE SHORT LIFETIME OF NEUTROPHILS, THEIR ABILITY TO ACQUIRE IMMUNOLOGICAL MEMORY MAY LIE IN THE CENTRAL TRAINING OF THEIR BM PROGENITORS RESULTING IN GENERATION OF REPROGRAMMED, THAT IS, "TRAINED", NEUTROPHILS. ALTHOUGH TRAINED IMMUNITY MAY HAVE BENEFICIAL EFFECTS IN INFECTION OR CANCER, IT MAY ALSO MEDIATE DETRIMENTAL OUTCOMES IN CHRONIC INFLAMMATION. HERE, WE REVIEW THE EMERGING RESEARCH AREA OF TRAINED IMMUNITY WITH A PARTICULAR EMPHASIS ON THE ROLE OF NEUTROPHILS AND GRANULOPOIESIS. 2023 9 1310 26 DEFINING TRAINED IMMUNITY AND ITS ROLE IN HEALTH AND DISEASE. IMMUNE MEMORY IS A DEFINING FEATURE OF THE ACQUIRED IMMUNE SYSTEM, BUT ACTIVATION OF THE INNATE IMMUNE SYSTEM CAN ALSO RESULT IN ENHANCED RESPONSIVENESS TO SUBSEQUENT TRIGGERS. THIS PROCESS HAS BEEN TERMED 'TRAINED IMMUNITY', A DE FACTO INNATE IMMUNE MEMORY. RESEARCH IN THE PAST DECADE HAS POINTED TO THE BROAD BENEFITS OF TRAINED IMMUNITY FOR HOST DEFENCE BUT HAS ALSO SUGGESTED POTENTIALLY DETRIMENTAL OUTCOMES IN IMMUNE-MEDIATED AND CHRONIC INFLAMMATORY DISEASES. HERE WE DEFINE 'TRAINED IMMUNITY' AS A BIOLOGICAL PROCESS AND DISCUSS THE INNATE STIMULI AND THE EPIGENETIC AND METABOLIC REPROGRAMMING EVENTS THAT SHAPE THE INDUCTION OF TRAINED IMMUNITY. 2020 10 6452 32 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 11 2861 48 FROM TRAINED IMMUNITY IN ALLERGY TO TRAINED IMMUNITY-BASED ALLERGEN VACCINES. INNATE IMMUNE CELLS EXPERIENCE LONG LASTING METABOLIC AND EPIGENETIC CHANGES AFTER AN ENCOUNTER WITH SPECIFIC STIMULI. THIS FACILITATES ENHANCED IMMUNE RESPONSES UPON SECONDARY EXPOSITION TO BOTH THE SAME AND UNRELATED PATHOGENS, A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY-BASED VACCINES (TIBV) ARE VACCINES ABLE TO INDUCE INNATE IMMUNE MEMORY, THUS CONFERRING HETEROLOGOUS PROTECTION AGAINST A BROAD RANGE OF PATHOGENS. WHILE TRAINED IMMUNITY HAS BEEN WELL DOCUMENTED IN THE CONTEXT OF INFECTIONS AND MULTIPLE IMMUNE-MEDIATED DISEASES, THE ROLE OF INNATE IMMUNE MEMORY AND ITS CONTRIBUTION TO THE INITIATION AND MAINTENANCE OF CHRONIC ALLERGIC DISEASES REMAINS POORLY UNDERSTOOD. OVER THE LAST YEARS, DIFFERENT STUDIES ATTEMPTING TO UNCOVER THE ROLE OF TRAINED IMMUNITY IN ALLERGY HAVE EMERGED. EXPOSITION TO ENVIRONMENTAL FACTORS IMPACTING ALLERGY DEVELOPMENT SUCH AS ALLERGENS OR VIRUSES INDUCES THE REPROGRAMMING OF INNATE IMMUNE CELLS TO ACQUIRE A MORE PRO-INFLAMMATORY PHENOTYPE IN THE CONTEXT OF ASTHMA OR FOOD ALLERGY. SEVERAL STUDIES HAVE CONVINCINGLY DEMONSTRATED THAT PREVENTION OF VIRAL INFECTIONS USING TIBV CONTRIBUTES TO REDUCE WHEEZING ATTACKS IN CHILDREN, WHICH REPRESENT A HIGH-RISK FACTOR FOR ASTHMA DEVELOPMENT LATER IN LIFE. INNATE IMMUNE CELLS TRAINED WITH SPECIFIC STIMULI MIGHT ALSO ACQUIRE ANTI-INFLAMMATORY FEATURES AND PROMOTE TOLERANCE, WHICH MAY HAVE IMPORTANT IMPLICATIONS FOR CHRONIC INFLAMMATORY DISEASES SUCH AS ALLERGIES. RECENT FINDINGS SHOWED THAT ALLERGOID-MANNAN CONJUGATES, WHICH ARE NEXT GENERATION VACCINES FOR ALLERGEN-SPECIFIC IMMUNOTHERAPY (AIT), ARE ABLE TO REPROGRAM MONOCYTES INTO TOLEROGENIC DENDRITIC CELLS BY MECHANISMS DEPENDING ON METABOLIC AND EPIGENETIC REWIRING. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS OF TRAINED IMMUNITY IN ALLERGY WILL PAVE THE WAY FOR THE DESIGN OF NOVEL TRAINED IMMUNITY-BASED ALLERGEN VACCINES AS POTENTIAL ALTERNATIVE STRATEGIES FOR THE PREVENTION AND TREATMENT OF ALLERGIC DISEASES. 2023 12 4136 36 MECHANISMS OF MANGANESE-INDUCED NEUROTOXICITY AND THE PURSUIT OF NEUROTHERAPEUTIC STRATEGIES. CHRONIC EXPOSURE TO ELEVATED LEVELS OF MANGANESE VIA OCCUPATIONAL OR ENVIRONMENTAL SETTINGS CAUSES A NEUROLOGICAL DISORDER KNOWN AS MANGANISM, RESEMBLING THE SYMPTOMS OF PARKINSON'S DISEASE, SUCH AS MOTOR DEFICITS AND COGNITIVE IMPAIRMENT. NUMEROUS STUDIES HAVE BEEN CONDUCTED TO CHARACTERIZE MANGANESE'S NEUROTOXICITY MECHANISMS IN SEARCH OF EFFECTIVE THERAPEUTICS, INCLUDING NATURAL AND SYNTHETIC COMPOUNDS TO TREAT MANGANESE TOXICITY. SEVERAL POTENTIAL MOLECULAR TARGETS OF MANGANESE TOXICITY AT THE EPIGENETIC AND TRANSCRIPTIONAL LEVELS HAVE BEEN IDENTIFIED RECENTLY, WHICH MAY CONTRIBUTE TO DEVELOP MORE PRECISE AND EFFECTIVE GENE THERAPIES. THIS REVIEW UPDATES FINDINGS ON MANGANESE-INDUCED NEUROTOXICITY MECHANISMS ON INTRACELLULAR INSULTS SUCH AS OXIDATIVE STRESS, INFLAMMATION, EXCITOTOXICITY, AND MITOPHAGY, AS WELL AS TRANSCRIPTIONAL DYSREGULATIONS INVOLVING YIN YANG 1, RE1-SILENCING TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR EB, AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 THAT COULD BE TARGETS OF MANGANESE NEUROTOXICITY THERAPIES. THIS REVIEW ALSO FEATURES INTRACELLULAR PROTEINS SUCH AS PTEN-INDUCIBLE KINASE 1, PARKIN, SIRTUINS, LEUCINE-RICH REPEAT KINASE 2, AND ALPHA-SYNUCLEIN, WHICH ARE ASSOCIATED WITH MANGANESE-INDUCED DYSREGULATION OF AUTOPHAGY/MITOPHAGY. IN ADDITION, NEWER THERAPEUTIC APPROACHES TO TREAT MANGANESE'S NEUROTOXICITY INCLUDING NATURAL AND SYNTHETIC COMPOUNDS MODULATING EXCITOTOXICITY, AUTOPHAGY, AND MITOPHAGY, WERE REVIEWED. TAKEN TOGETHER, IN-DEPTH MECHANISTIC KNOWLEDGE ACCOMPANIED BY ADVANCES IN GENE AND DRUG DELIVERY STRATEGIES WILL MAKE SIGNIFICANT PROGRESS IN THE DEVELOPMENT OF RELIABLE THERAPEUTIC INTERVENTIONS AGAINST MANGANESE-INDUCED NEUROTOXICITY. 2022 13 6498 33 TRAINED IMMUNITY IN MONOCYTE/MACROPHAGE: NOVEL MECHANISM OF PHYTOCHEMICALS IN THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. ATHEROSCLEROSIS (AS) IS THE PATHOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES (ASCVD), CHARACTERIZED BY PERSISTENT CHRONIC INFLAMMATION IN THE VESSEL WALL, IN WHICH MONOCYTES/MACROPHAGES PLAY A KEY ROLE. IT HAS BEEN REPORTED THAT INNATE IMMUNE SYSTEM CELLS CAN ASSUME A PERSISTENT PROINFLAMMATORY STATE AFTER SHORT STIMULATION WITH ENDOGENOUS ATHEROGENIC STIMULI. THE PATHOGENESIS OF AS CAN BE INFLUENCED BY THIS PERSISTENT HYPERACTIVATION OF THE INNATE IMMUNE SYSTEM, WHICH IS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY HAS ALSO BEEN IMPLICATED AS A KEY PATHOLOGICAL MECHANISM, LEADING TO PERSISTENT CHRONIC INFLAMMATION IN AS. TRAINED IMMUNITY IS MEDIATED VIA EPIGENETIC AND METABOLIC REPROGRAMMING AND OCCURS IN MATURE INNATE IMMUNE CELLS AND THEIR BONE MARROW PROGENITORS. NATURAL PRODUCTS ARE PROMISING CANDIDATES FOR NOVEL PHARMACOLOGICAL AGENTS THAT CAN BE USED TO PREVENT OR TREAT CARDIOVASCULAR DISEASES (CVD). A VARIETY OF NATURAL PRODUCTS AND AGENTS EXHIBITING ANTIATHEROSCLEROTIC ABILITIES HAVE BEEN REPORTED TO POTENTIALLY INTERFERE WITH THE PHARMACOLOGICAL TARGETS OF TRAINED IMMUNITY. THIS REVIEW DESCRIBES IN AS MUCH DETAIL AS POSSIBLE THE MECHANISMS INVOLVED IN TRAINED IMMUNITY AND HOW PHYTOCHEMICALS OF THIS PROCESS INHIBIT AS BY AFFECTING TRAINED MONOCYTES/MACROPHAGES. 2023 14 3734 38 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 15 6497 35 TRAINED IMMUNITY IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. TRAINED IMMUNITY, ALSO KNOWN AS INNATE IMMUNE MEMORY, IS A PERSISTENT HYPER-RESPONSIVE FUNCTIONAL STATE OF INNATE IMMUNE CELLS. ACCUMULATING EVIDENCE IMPLICATES TRAINED IMMUNITY AS AN UNDERLYING MECHANISM OF CHRONIC INFLAMMATION IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. IN THIS CONTEXT, TRAINED IMMUNITY IS INDUCED BY ENDOGENOUS ATHEROSCLEROSIS-PROMOTING FACTORS, SUCH AS MODIFIED LIPOPROTEINS OR HYPERGLYCAEMIA, CAUSING BROAD METABOLIC AND EPIGENETIC REPROGRAMMING OF THE MYELOID CELL COMPARTMENT. IN ADDITION TO TRADITIONAL CARDIOVASCULAR RISK FACTORS, LIFESTYLE FACTORS, INCLUDING UNHEALTHY DIETS, SEDENTARY LIFESTYLE, SLEEP DEPRIVATION AND PSYCHOSOCIAL STRESS, AS WELL AS INFLAMMATORY COMORBIDITIES, HAVE BEEN SHOWN TO ACTIVATE TRAINED IMMUNITY-LIKE MECHANISMS IN BONE MARROW HAEMATOPOIETIC STEM CELLS. IN THIS REVIEW, WE DISCUSS THE MOLECULAR AND CELLULAR MECHANISMS OF TRAINED IMMUNITY, ITS SYSTEMIC REGULATION THROUGH HAEMATOPOIETIC PROGENITOR CELLS IN THE BONE MARROW, AND THE ACTIVATION OF THESE MECHANISMS BY CARDIOVASCULAR DISEASE RISK FACTORS. WE ALSO HIGHLIGHT OTHER TRAINED IMMUNITY FEATURES THAT ARE RELEVANT FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, INCLUDING THE DIVERSE CELL TYPES THAT SHOW MEMORY CHARACTERISTICS AND TRANSGENERATIONAL INHERITANCE OF TRAINED IMMUNITY TRAITS. FINALLY, WE PROPOSE POTENTIAL STRATEGIES FOR THE THERAPEUTIC MODULATION OF TRAINED IMMUNITY TO MANAGE ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. 2023 16 6495 30 TRAINED IMMUNITY AS A POTENTIAL TARGET FOR THERAPEUTIC IMMUNOMODULATION IN DUCHENNE MUSCULAR DYSTROPHY. DYSREGULATED INFLAMMATION INVOLVING INNATE IMMUNE CELLS, PARTICULARLY OF THE MONOCYTE/MACROPHAGE LINEAGE, IS A KEY CONTRIBUTOR TO THE PATHOGENESIS OF DUCHENNE MUSCULAR DYSTROPHY (DMD). TRAINED IMMUNITY IS AN EVOLUTIONARILY ANCIENT PROTECTIVE MECHANISM AGAINST INFECTION, IN WHICH EPIGENETIC AND METABOLIC ALTERATIONS CONFER NON-SPECIFIC HYPERRESPONSIVENESS OF INNATE IMMUNE CELLS TO VARIOUS STIMULI. RECENT WORK IN AN ANIMAL MODEL OF DMD (MDX MICE) HAS SHOWN THAT MACROPHAGES EXHIBIT CARDINAL FEATURES OF TRAINED IMMUNITY, INCLUDING THE PRESENCE OF INNATE IMMUNE SYSTEM "MEMORY". THE LATTER IS REFLECTED BY EPIGENETIC CHANGES AND DURABLE TRANSMISSIBILITY OF THE TRAINED PHENOTYPE TO HEALTHY NON-DYSTROPHIC MICE BY BONE MARROW TRANSPLANTATION. MECHANISTICALLY, IT IS SUGGESTED THAT A TOLL-LIKE RECEPTOR (TLR) 4-REGULATED, MEMORY-LIKE CAPACITY OF INNATE IMMUNITY IS INDUCED AT THE LEVEL OF THE BONE MARROW BY FACTORS RELEASED FROM THE DAMAGED MUSCLES, LEADING TO EXAGGERATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. HERE WE PROPOSE A CONCEPTUAL FRAMEWORK FOR THE INVOLVEMENT OF TRAINED IMMUNITY IN DMD PATHOGENESIS AND ITS POTENTIAL TO SERVE AS A NEW THERAPEUTIC TARGET. 2023 17 6883 31 [RESOLUTION OF INFLAMMATION--PHARMACOLOGICAL ASPECTS]. INFLAMMATION IS A FUNDAMENTAL BIOLOGIC PROCESS EVOLUTIONALLY PRESERVED BY A GERM LINE CODE. THE INTERPLAY OF THE EPIGENETIC WITH THE ENVIRONMENT DIRECTS THE CODE TO TEMPORALLY DISTINCT INFLAMMATORY RESPONSES, WHICH CAN BE ACUTE OR CHRONIC. THE AIM OF THIS STUDY IS TO PRESENT NEW ASPECTS REGARDING THE RESOLUTION OF INFLAMMATION. ACUTE INFLAMMATION NORMALLY RESOLVES BY MECHANISMS STILL SOMEWHAT ELUSIVE. CURRENT EVIDENCE SUGGESTS THAT AN ACTIVE COORDINATED PROGRAM INITIATED THE FIRST FEW HOURS AFTER THE INFLAMMATORY RESPONSE BEGINS AND ITS FAILURE LEAD TO CHRONIC INFLAMMATION. THIS PROCESS IS ESSENTIAL FOR APPROPRIATE HOST RESPONSES, TISSUE PROTECTION AND THE RETURN TO HOMEOSTASIS. PROSTAGLANDINS AND LEUKOTRIENES ARE LIPID MEDIATORS THAT PLAY IMPORTANT ROLES IN HOST DEFENSE AND ACUTE INFLAMMATION. GRANULOCYTES PROMOTE THE SWITCH OF ARACHIDONIC ACID-DERIVED PROSTAGLANDINS AND LEUKOTRIENES TO LIPOXINS, ACTIVE ANTIINFLAMMATORY AND PRO-RESOLUTION MEDIATORS. THE APOPTOSIS OF THE NEUTROPHILS COINCIDES WITH THE BIOSYNTHESIS OF RESOLVINS AND PROTECTINS FROM OMEGA-3 POLYUNSATURATED FATTY ACIDS AND RELEASES ANTI-INFLAMMATORY AND REPARATIVE CYTOKINES. THIS INFORMATION COULD LEAD TO NEW TREATMENTS FOR INFLAMMATORY DISEASES. 2011 18 2617 58 EPIGENOME TARGETING BY PROBIOTIC METABOLITES. BACKGROUND: THE INTESTINAL MICROBIOTA PLAYS AN IMPORTANT ROLE IN IMMUNE DEVELOPMENT AND HOMEOSTASIS. A DISTURBED MICROBIOTA DURING EARLY INFANCY IS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING INFLAMMATORY AND ALLERGIC DISEASES LATER IN LIFE. THE MECHANISMS UNDERLYING THESE EFFECTS ARE POORLY UNDERSTOOD BUT ARE LIKELY TO INVOLVE ALTERATIONS IN MICROBIAL PRODUCTION OF FERMENTATION-DERIVED METABOLITES, WHICH HAVE POTENT IMMUNE MODULATING PROPERTIES AND ARE REQUIRED FOR MAINTENANCE OF HEALTHY MUCOSAL IMMUNE RESPONSES. PROBIOTICS ARE BENEFICIAL BACTERIA THAT HAVE THE CAPACITY TO ALTER THE COMPOSITION OF BACTERIAL SPECIES IN THE INTESTINE THAT CAN IN TURN INFLUENCE THE PRODUCTION OF FERMENTATION-DERIVED METABOLITES. PRINCIPAL AMONG THESE METABOLITES ARE THE SHORT-CHAIN FATTY ACIDS BUTYRATE AND ACETATE THAT HAVE POTENT ANTI-INFLAMMATORY ACTIVITIES IMPORTANT IN REGULATING IMMUNE FUNCTION AT THE INTESTINAL MUCOSAL SURFACE. THEREFORE STRATEGIES AIMED AT RESTORING THE MICROBIOTA PROFILE MAY BE EFFECTIVE IN THE PREVENTION OR TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES. PRESENTATION OF THE HYPOTHESIS: PROBIOTIC BACTERIA HAVE DIVERSE EFFECTS INCLUDING ALTERING MICROBIOTA COMPOSITION, REGULATING EPITHELIAL CELL BARRIER FUNCTION AND MODULATING OF IMMUNE RESPONSES. THE PRECISE MOLECULAR MECHANISMS MEDIATING THESE PROBIOTIC EFFECTS ARE NOT WELL UNDERSTOOD. SHORT-CHAIN FATTY ACIDS SUCH AS BUTYRATE ARE A CLASS OF HISTONE DEACETYLASE INHIBITORS IMPORTANT IN THE EPIGENETIC CONTROL OF HOST CELL RESPONSES. IT IS HYPOTHESIZED THAT THE BIOLOGICAL FUNCTION OF PROBIOTICS MAY BE A RESULT OF EPIGENETIC MODIFICATIONS THAT MAY EXPLAIN THE WIDE RANGE OF EFFECTS OBSERVED. STUDIES DELINEATING THE EFFECTS OF PROBIOTICS ON SHORT-CHAIN FATTY ACID PRODUCTION AND THE EPIGENETIC ACTIONS OF SHORT-CHAIN FATTY ACIDS WILL ASSIST IN UNDERSTANDING THE ASSOCIATION BETWEEN MICROBIOTA AND ALLERGIC OR AUTOIMMUNE DISORDERS. TESTING THE HYPOTHESIS: WE PROPOSE THAT TREATMENT WITH SPECIFIC PROBIOTIC BACTERIA UNDER IN VIVO CONDITIONS WOULD OFFER THE IDEAL CONDITIONS TO EXAMINE THE MICROBIOLOGICAL, IMMUNOLOGICAL AND EPIGENETIC MECHANISMS OF ACTION. ADVANCES IN EPIGENETIC TECHNOLOGY NOW ALLOW INVESTIGATORS TO BETTER UNDERSTAND THE COMPLEX BIOLOGICAL PROPERTIES OF PROBIOTICS AND THEIR METABOLITES. IMPLICATIONS OF THE HYPOTHESIS: DETERMINING THE PRECISE MECHANISMS OF PROBIOTIC ACTION WILL LEAD TO MORE SPECIFIC AND EFFICACIOUS THERAPEUTIC STRATEGIES IN THE PREVENTION OR TREATMENT OF CHRONIC INFLAMMATORY CONDITIONS. 2010 19 601 35 BETA-GLUCAN "TRAINED IMMUNITY" IMMUNOMODULATORY PROPERTIES POTENTIATE TISSUE WOUND MANAGEMENT AND ACCELERATE FITNESS RECOVER. INTRODUCTION: IT IS WELL ESTABLISHED THAT MODERATE PHYSICAL ACTIVITY CAN IMPROVE THE IMMUNE STATUS, RATHER EXCESS OR HIGH-INTENSITY PHYSICAL EXERCISE CAN CAUSE DAMAGE TO THE IMMUNE SYSTEM. IN ADDITION, MUSCLE INJURIES RESULTING FROM INCREASED FREQUENCY AND INTENSITY OF EXERCISES COMPROMISE INNATE IMMUNE ACTIVITY AND MAY DECREASE TISSUE REGENERATION. THUS, BETA-GLUCANS, A NATURAL COMPOUND, MAY REPRESENT AN IMPORTANT SUBSTANCE WITH STRONG IMMUNOMODULATORY PROPERTIES ACTING AS AN IMMUNOSTIMULANT THERAPY KNOWN AS "TRAINED IMMUNITY". THIS IMMUNE STIMULATING THERAPEUTIC IS AN IMMUNOLOGICAL MEMORY PHENOMENON LINKED TO THE INNATE IMMUNE SYSTEM, TRIGGERING CELLULAR CHANGES AT EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL LEVELS, TO REGULATE THE IMMUNE SYSTEM AND RECOVER ITS HOMEOSTASIS WITH CLINICAL BENEFITS. CONCLUSION: THIS NARRATIVE REVIEW WORKS WITH THE CURRENT EVIDENCE REGARDING BETA-GLUCANS AS A POSSIBLE ALTERNATIVE THERAPY FOR WOUND HEALING AND ITS SAFETY AND EFFICACY IN THE TREATMENT OF MUSCLE INJURIES AND PHYSICAL RECOVERY INCLUDING OTHER CHRONIC CONDITIONS AND DISEASES. 2022 20 5469 41 RESOLUTION OF INFLAMMATION AS A NOVEL CHEMOPREVENTIVE STRATEGY. ACUTE INFLAMMATION, A PHYSIOLOGIC RESPONSE TO PROTECT CELLS FROM MICROBIAL INFECTION AND OTHER NOXIOUS STIMULI, IS AUTOMATICALLY TERMINATED BY ENDOGENOUS ANTI-INFLAMMATORY AND PRO-RESOLVING MEDIATORS TO RESTORE HOMEOSTATIC CONDITIONS. HOWEVER, IF TIMELY RESOLUTION OF INFLAMMATION IS FAILED, INFLAMMATION PERSISTS AND CAN PROGRESS TO A CHRONIC INFLAMMATION WHICH HAS LONG BEEN THOUGHT AS A PREDISPOSING FACTOR TO CARCINOGENESIS. EXCESSIVE AND PATHOLOGIC INFLAMMATION CAUSES DNA DAMAGE, GENOMIC INSTABILITY, EPIGENETIC DYSREGULATION, AND ALTERATION OF INTRACELLULAR SIGNALING, ALL OF WHICH ARE INVOLVED IN NEOPLASTIC TRANSFORMATION. TO PREVENT CHRONIC INFLAMMATION AND RESULTING INFLAMMATION-PROMOTED CANCER DEVELOPMENT, UNDERSTANDING THE PROCESS THAT RESOLVES INFLAMMATION IS ESSENTIAL. RESOLUTION OF INFLAMMATION IS AN ACTIVE COORDINATED PROCESS REGULATED BY DISTINCT ANTI-INFLAMMATORY AND PRO-RESOLVING ENDOGENOUS LIPID MEDIATORS, SUCH AS RESOLVINS AND LIPOXINS. THE ROLE OF PRO-INFLAMMATORY SIGNALING IN CARCINOGENESIS HAS BECOME MORE AND MORE EVIDENT AND WELL CHARACTERIZED, BUT THE POTENTIAL ROLE OF PRO-RESOLVING MEDIATORS IN CANCER PREVENTION REMAINS STILL ELUSIVE. IN SEARCHING FOR AN EFFICACIOUS WAY TO PREVENT CHRONIC INFLAMMATION-ASSOCIATED CANCER, THE PRO-RESOLVING SIGNAL TRANSDUCTION PATHWAYS AND THEIR REGULATORS SHOULD BE UNRAVELED. 2013