1 6763 97 ZINC AND ITS ROLE IN AGE-RELATED INFLAMMATION AND IMMUNE DYSFUNCTION. ZINC IS AN ESSENTIAL MICRONUTRIENT REQUIRED FOR MANY CELLULAR PROCESSES, ESPECIALLY FOR THE NORMAL DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. ZINC HOMEOSTASIS AND SIGNALING ARE CRITICAL IN IMMUNE ACTIVATION, AND AN IMBALANCE IN ZINC HOMEOSTASIS IS ASSOCIATED WITH THE DEVELOPMENT OF CHRONIC DISEASES. ZINC DEFICIENCY CAUSES SIGNIFICANT IMPAIRMENT IN BOTH ADAPTIVE AND INNATE IMMUNE RESPONSES, AND PROMOTES SYSTEMIC INFLAMMATION. THE ELDERLY ARE A POPULATION PARTICULARLY SUSCEPTIBLE TO ZINC DEFICIENCY. NATIONAL SURVEYS INDICATE THAT A SIGNIFICANT PORTION OF THE AGED POPULATION HAS INADEQUATE ZINC INTAKE, AND A DECLINE IN ZINC STATUS IS OBSERVED WITH AGE. THERE ARE REMARKABLE SIMILARITIES BETWEEN THE HALLMARKS OF ZINC DEFICIENCY AND IMMUNOLOGICAL DYSFUNCTION IN AGED INDIVIDUALS. BOTH ZINC DEFICIENCY AND THE AGING PROCESS ARE CHARACTERIZED BY IMPAIRED IMMUNE RESPONSES AND SYSTEMIC LOW GRADE CHRONIC INFLAMMATION. IT HAS BEEN HYPOTHESIZED THAT AGE-RELATED ZINC DEFICIENCY MAY BE AN IMPORTANT FACTOR CONTRIBUTING TO IMMUNE DYSFUNCTION AND CHRONIC INFLAMMATION DURING THE AGING PROCESS. IN THIS REVIEW, WE DISCUSS THE EFFECTS OF ZINC STATUS ON AGING, POTENTIAL MOLECULAR AND EPIGENETIC MECHANISMS CONTRIBUTING TO AGE-RELATED DECLINE IN ZINC STATUS, AND THE ROLE OF ZINC IN AGE-RELATED IMMUNE DYSFUNCTION AND CHRONIC INFLAMMATION. 2012 2 3643 44 INCREASED INFLAMMATORY RESPONSE IN AGED MICE IS ASSOCIATED WITH AGE-RELATED ZINC DEFICIENCY AND ZINC TRANSPORTER DYSREGULATION. AGING IS A COMPLEX PROCESS ASSOCIATED WITH PHYSIOLOGICAL CHANGES IN NUMEROUS ORGAN SYSTEMS. IN PARTICULAR, AGING OF THE IMMUNE SYSTEM IS CHARACTERIZED BY PROGRESSIVE DYSREGULATION OF IMMUNE RESPONSES, RESULTING IN INCREASED SUSCEPTIBILITY TO INFECTIOUS DISEASES, IMPAIRED VACCINATION EFFICACY AND SYSTEMIC LOW-GRADE CHRONIC INFLAMMATION. INCREASING EVIDENCE SUGGEST THAT INTRACELLULAR ZINC HOMEOSTASIS, REGULATED BY ZINC TRANSPORTER EXPRESSION, IS CRITICALLY INVOLVED IN THE SIGNALING AND ACTIVATION OF IMMUNE CELLS. WE HYPOTHESIZE THAT EPIGENETIC ALTERATIONS AND NUTRITIONAL DEFICITS ASSOCIATED WITH AGING MAY LEAD TO ZINC TRANSPORTER DYSREGULATION, RESULTING IN DECREASES IN CELLULAR ZINC LEVELS AND ENHANCED INFLAMMATION WITH AGE. THE GOAL OF THIS STUDY WAS TO EXAMINE THE CONTRIBUTION OF AGE-RELATED ZINC DEFICIENCY AND ZINC TRANSPORTER DYSREGULATION ON THE INFLAMMATORY RESPONSE IN IMMUNE CELLS. THE EFFECTS OF ZINC DEFICIENCY AND AGE ON THE INDUCTION OF INFLAMMATORY RESPONSES WERE DETERMINED USING AN IN VITRO CELL CULTURE SYSTEM AND AN AGED MOUSE MODEL. WE SHOWED THAT ZINC DEFICIENCY, PARTICULARLY THE REDUCTION IN INTRACELLULAR ZINC IN IMMUNE CELLS, WAS ASSOCIATED WITH INCREASED INFLAMMATION WITH AGE. FURTHERMORE, REDUCED ZIP 6 EXPRESSION ENHANCED PROINFLAMMATORY RESPONSE, AND AGE-SPECIFIC ZIP 6 DYSREGULATION CORRELATED WITH AN INCREASE IN ZIP 6 PROMOTER METHYLATION. FURTHERMORE, RESTORING ZINC STATUS VIA DIETARY SUPPLEMENTATION REDUCED AGED-ASSOCIATED INFLAMMATION. OUR DATA SUGGESTED THAT AGE-RELATED EPIGENETIC DYSREGULATION IN ZINC TRANSPORTER EXPRESSION MAY INFLUENCE CELLULAR ZINC LEVELS AND CONTRIBUTE TO INCREASED SUSCEPTIBILITY TO INFLAMMATION WITH AGE. 2013 3 1636 27 DOES AGEING AFFECT ZINC HOMEOSTASIS AND DIETARY REQUIREMENTS? DIETARY INTAKES OF ZINC ARE LOWER IN THE ELDERLY BECAUSE OF REDUCED ENERGY REQUIREMENTS, AND IT IS NOT CLEAR WHETHER AGEING IMPACTS ON ADAPTIVE HOMEOSTATIC MECHANISMS, NAMELY ABSORPTIVE EFFICIENCY AND ENDOGENOUS LOSSES IN THE GI TRACT. PHYSIOLOGICAL REQUIREMENTS FOR ZINC ARE UNLIKELY TO CHANGE SIGNIFICANTLY, BUT THERE ARE SEVERAL ATTRIBUTES OF AGEING THAT MAY AFFECT ASPECTS OF ZINC METABOLISM (E.G. CHANGES IN GUT STRUCTURE AND FUNCTION, DISEASE STATES, CHRONIC INFLAMMATION, EPIGENETIC CHANGES IN GENES THAT EXPRESS ZINC-RELATED PROTEINS AND DRUG REGIMENS) THAT ARE WORTHY OF FURTHER INVESTIGATION. THERE IS, AS YET, NO INFORMATION ON THE EFFECTS OF AGEING ON ZINC TRANSPORTERS, AND THERE ARE NO SENSITIVE AND SPECIFIC MEASURES OF ZINC STATUS, THEREFORE DIETARY RECOMMENDATIONS FOR ZINC HAVE BEEN DERIVED FROM FACTORIAL CALCULATIONS USING INFORMATION ON ZINC ABSORPTION AND LOSS, AND ESTIMATES OF DIETARY BIOAVAILABILITY. 2008 4 6765 36 ZINC DEFICIENCY LEADS TO REDUCED INTERLEUKIN-2 PRODUCTION BY ACTIVE GENE SILENCING DUE TO ENHANCED CREMALPHA EXPRESSION IN T CELLS. BACKGROUND & AIMS: THE MICRONUTRIENT ZINC IS ESSENTIAL FOR PROPER IMMUNE FUNCTION. CONSEQUENTLY, ZINC DEFICIENCY LEADS TO IMPAIRED IMMUNE FUNCTION, AS SEEN IN DECREASED SECRETION OF INTERLEUKIN (IL)-2 BY T CELLS. ALTHOUGH THIS ASSOCIATION HAS BEEN KNOWN SINCE THE LATE 1980S, THE UNDERLYING MOLECULAR MECHANISMS ARE STILL UNKNOWN. ZINC DEFICIENCY AND REDUCED IL-2 LEVELS ARE ESPECIALLY FOUND IN THE ELDERLY, WHICH IN TURN ARE PRONE TO CHRONIC DISEASES. HERE, WE DESCRIBE A NEW MOLECULAR LINK BETWEEN ZINC DEFICIENCY AND REDUCED IL-2 EXPRESSION IN T CELLS. METHODS: THE EFFECTS OF ZINC DEFICIENCY WERE FIRST INVESTIGATED IN VITRO IN THE HUMAN T CELL LINES JURKAT AND HUT-78 AND COMPLEMENTED BY IN VIVO DATA FROM ZINC-SUPPLEMENTED PIGS. A SHORT- AND LONG-TERM MODEL FOR ZINC DEFICIENCY WAS ESTABLISHED. ZINC LEVELS WERE DETECTED BY FLOW CYTOMETRY AND EXPRESSION PROFILES WERE INVESTIGATED ON THE MRNA AND PROTEIN LEVEL. RESULTS: THE EXPRESSION OF THE TRANSCRIPTION FACTOR CAMP-RESPONSIVE-ELEMENT MODULATOR ALPHA (CREMALPHA) IS INCREASED DURING ZINC DEFICIENCY IN VITRO, DUE TO INCREASED PROTEIN PHOSPHATASE 2A (PP2A) ACTIVITY, RESULTING IN DECREASED IL-2 PRODUCTION. ADDITIONALLY, ZINC SUPPLEMENTATION IN VIVO REDUCED CREMALPHA LEVELS CAUSING INCREASED IL-2 EXPRESSION. ON EPIGENETIC LEVELS INCREASED CREMALPHA BINDING TO THE IL-2 PROMOTER IS MEDIATED BY HISTONE DEACETYLASE 1 (HDAC1). THE HDAC1 ACTIVITY IS INHIBITED BY ZINC. MOREOVER, DEACETYLATION OF THE ACTIVATING HISTONE MARK H3K9 WAS INCREASED UNDER ZINC DEFICIENCY, RESULTING IN REDUCED IL-2 EXPRESSION. CONCLUSIONS: WITH THE TRANSCRIPTION FACTOR CREMALPHA A MOLECULAR LINK WAS UNCOVERED, CONNECTING ZINC DEFICIENCY WITH REDUCED IL-2 PRODUCTION DUE TO ENHANCED PP2A AND HDAC1 ACTIVITY. 2021 5 6764 43 ZINC DEFICIENCY ENHANCED INFLAMMATORY RESPONSE BY INCREASING IMMUNE CELL ACTIVATION AND INDUCING IL6 PROMOTER DEMETHYLATION. SCOPE: ZINC DEFICIENCY RESULTS IN IMMUNE DYSFUNCTION AND PROMOTES SYSTEMIC INFLAMMATION. THE OBJECTIVE OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF ZINC DEFICIENCY ON CELLULAR IMMUNE ACTIVATION AND EPIGENETIC MECHANISMS THAT PROMOTE INFLAMMATION. THIS WORK IS POTENTIALLY RELEVANT TO THE AGING POPULATION GIVEN THAT AGE-RELATED IMMUNE DEFECTS, INCLUDING CHRONIC INFLAMMATION, COINCIDE WITH DECLINING ZINC STATUS. METHODS AND RESULTS: AN IN VITRO CELL CULTURE SYSTEM AND THE AGED MOUSE MODEL WERE USED TO CHARACTERIZE IMMUNE ACTIVATION AND DNA METHYLATION PROFILES THAT MAY CONTRIBUTE TO THE ENHANCED PROINFLAMMATORY RESPONSE MEDIATED BY ZINC DEFICIENCY. ZINC DEFICIENCY UPREGULATED CELL ACTIVATION MARKERS ICAM1, MHC CLASS II, AND CD86 IN THP1 CELLS, WHICH COINCIDED WITH INCREASED IL1BETA AND IL6 RESPONSES FOLLOWING LPS STIMULATION. A DECREASED ZINC STATUS IN AGED MICE WAS SIMILARLY ASSOCIATED WITH INCREASED ICAM1 AND IL6 GENE EXPRESSION. REDUCED IL6 PROMOTER METHYLATION WAS OBSERVED IN ZINC-DEFICIENT THP1 CELLS, AS WELL AS IN AGED MICE AND HUMAN LYMPHOBLASTOID CELL LINES DERIVED FROM AGED INDIVIDUALS. CONCLUSION: ZINC DEFICIENCY INDUCED INFLAMMATORY RESPONSE IN PART BY ELICITING ABERRANT IMMUNE CELL ACTIVATION AND ALTERED PROMOTER METHYLATION. OUR RESULTS SUGGESTED POTENTIAL INTERACTIONS BETWEEN ZINC STATUS, EPIGENETICS, AND IMMUNE FUNCTION, AND HOW THEIR DYSREGULATION COULD CONTRIBUTE TO CHRONIC INFLAMMATION. 2015 6 482 23 ARSENITE BINDS TO THE ZINC FINGER MOTIF OF TIP60 HISTONE ACETYLTRANSFERASE AND INDUCES ITS DEGRADATION VIA THE 26S PROTEASOME. ARSENIC IS A UBIQUITOUS ENVIRONMENTAL CONTAMINANT WITH WIDESPREAD PUBLIC HEALTH CONCERN. EPIDEMIOLOGICAL STUDIES HAVE REVEALED THAT CHRONIC HUMAN EXPOSURE TO ARSENIC IN DRINKING WATER IS ASSOCIATED WITH THE PREVALENCE OF SKIN, LUNG, AND BLADDER CANCERS. ABERRANT HISTONE MODIFICATIONS (E.G., METHYLATION, ACETYLATION, AND UBIQUITINATION) WERE PREVIOUSLY FOUND TO BE ACCOMPANIED BY ARSENIC EXPOSURE; THUS, PERTURBATION OF EPIGENETIC PATHWAYS IS THOUGHT TO CONTRIBUTE TO ARSENIC CARCINOGENESIS. ARSENITE IS KNOWN TO INTERACT WITH ZINC FINGER MOTIFS OF PROTEINS, AND ZINC FINGER MOTIF IS PRESENT IN AND INDISPENSABLE FOR THE ENZYMATIC ACTIVITIES OF CRUCIAL HISTONE-MODIFYING ENZYMES ESPECIALLY THE MYST FAMILY OF HISTONE ACETYLTRANSFERASES (E.G., TIP60). HENCE, WE REASONED THAT TRIVALENT ARSENIC MAY TARGET THE ZINC FINGER MOTIF OF THESE ENZYMES, DISTURB THEIR ENZYMATIC ACTIVITIES, AND ALTER HISTONE ACETYLATION. HEREIN, WE FOUND THAT AS(3+) COULD BIND DIRECTLY TO THE ZINC-FINGER MOTIF OF TIP60 IN VITRO AND IN CELLS. IN ADDITION, EXPOSURE TO AS(3+) COULD LEAD TO A DOSE-DEPENDENT DECREASE IN TIP60 PROTEIN LEVEL VIA THE UBIQUITIN-PROTEASOME PATHWAY. THUS, THE RESULTS FROM THE PRESENT STUDY REVEALED, FOR THE FIRST TIME, THAT ARSENITE MAY TARGET CYSTEINE RESIDUES IN THE ZINC-FINGER MOTIF OF THE TIP60 HISTONE ACETYLTRANSFERASE, THEREBY ALTERING THE H4K16AC HISTONE EPIGENETIC MARK. OUR RESULTS ALSO SHED SOME NEW LIGHT ON THE MECHANISMS UNDERLYING THE ARSENIC-INDUCED EPIGENOTOXICITY AND CARCINOGENESIS IN HUMANS. 2017 7 3289 27 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 8 2425 19 EPIGENETIC SILENCING OF IRF1 DYSREGULATES TYPE III INTERFERON RESPONSES TO RESPIRATORY VIRUS INFECTION IN EPITHELIAL TO MESENCHYMAL TRANSITION. CHRONIC OXIDATIVE INJURY PRODUCED BY AIRWAY DISEASE TRIGGERS A TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)-MEDIATED EPIGENETIC REPROGRAMMING KNOWN AS THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). WE OBSERVE THAT EMT SILENCES PROTECTIVE MUCOSAL INTERFERON (IFN)-I AND III PRODUCTION ASSOCIATED WITH ENHANCED RHINOVIRUS (RV) AND RESPIRATORY SYNCYTIAL VIRUS (RSV) REPLICATION. MESENCHYMAL TRANSITIONED CELLS ARE DEFECTIVE IN INDUCIBLE INTERFERON REGULATORY FACTOR 1 (IRF1) EXPRESSION BY OCCLUDING RELA AND IRF3 ACCESS TO THE PROMOTER. IRF1 IS NECESSARY FOR THE EXPRESSION OF TYPE III IFNS (IFNLS 1 AND 2/3). INDUCED BY THE EMT, ZINC FINGER E-BOX BINDING HOMEOBOX 1 (ZEB1) BINDS AND SILENCES IRF1. ECTOPIC ZEB1 IS SUFFICIENT FOR IRF1 SILENCING, WHEREAS ZEB1 KNOCKDOWN PARTIALLY RESTORES IRF1-IFNL UPREGULATION. ZEB1 SILENCES IRF1 THROUGH THE CATALYTIC ACTIVITY OF THE ENHANCER OF ZESTE 2 POLYCOMB REPRESSIVE COMPLEX 2 SUBUNIT (EZH2), FORMING REPRESSIVE H3K27(ME3) MARKS. WE OBSERVE THAT IRF1 EXPRESSION IS MEDIATED BY ZEB1 DE-REPRESSION, AND OUR STUDY DEMONSTRATES HOW AIRWAY REMODELLING/FIBROSIS IS ASSOCIATED WITH A DEFECTIVE MUCOSAL ANTIVIRAL RESPONSE THROUGH ZEB1-INITIATED EPIGENETIC SILENCING. 2017 9 6022 33 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 10 5920 30 TARGETING CHROMATIN REMODELING IN INFLAMMATION AND FIBROSIS. MUCOSAL SURFACES OF THE HUMAN BODY ARE LINED BY A CONTIGUOUS EPITHELIAL CELL SURFACE THAT FORMS A BARRIER TO AEROSOLIZED PATHOGENS. SPECIALIZED PATTERN RECOGNITION RECEPTORS DETECT THE PRESENCE OF VIRAL PATHOGENS AND INITIATE PROTECTIVE HOST RESPONSES BY TRIGGERING ACTIVATION OF THE NUCLEAR FACTOR KAPPAB (NFKAPPAB)/RELA TRANSCRIPTION FACTOR AND FORMATION OF A COMPLEX WITH THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (P-TEFB)/CYCLIN-DEPENDENT KINASE (CDK)9 AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) EPIGENETIC READER. THE RELA.BRD4.P-TEFB COMPLEX PRODUCES ACUTE INFLAMMATION BY REGULATING TRANSCRIPTIONAL ELONGATION, WHICH PRODUCES A RAPID GENOMIC RESPONSE BY INACTIVE GENES MAINTAINED IN AN OPEN CHROMATIN CONFIGURATION ENGAGED WITH HYPOPHOSPHORYLATED RNA POLYMERASE II. WE DESCRIBE RECENT STUDIES THAT HAVE LINKED PROLONGED ACTIVATION OF THE RELA-BRD4 PATHWAY WITH THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT) BY INDUCING A CORE OF EMT COREPRESSORS, STIMULATING SECRETION OF GROWTH FACTORS PROMOTING AIRWAY FIBROSIS. THE MESENCHYMAL STATE PRODUCES REWIRING OF THE KINOME AND REPROGRAMMING OF INNATE RESPONSES TOWARD INFLAMMATION. IN ADDITION, THE CORE REGULATOR ZINC FINGER E-BOX HOMEODOMAIN 1 (ZEB1) SILENCES THE EXPRESSION OF THE INTERFERON RESPONSE FACTOR 1 (IRF1), REQUIRED FOR TYPE III IFN EXPRESSION. THIS EPIGENETIC SILENCING IS MEDIATED BY THE ENHANCER OF ZESTE 2 (EZH2) HISTONE METHYLTRANSFERASE. BECAUSE OF THEIR POTENTIAL APPLICATIONS IN CANCER AND INFLAMMATION, SMALL-MOLECULE INHIBITORS OF NFKAPPAB/RELA, CDK9, BRD4, AND EZH2 HAVE BEEN THE TARGETS OF MEDICINAL CHEMISTRY EFFORTS. WE SUGGEST THAT DISRUPTION OF THE RELA.BRD4.P-TEFB PATHWAY AND EZH2 METHYLTRANSFERASE HAS IMPORTANT IMPLICATIONS FOR REVERSING FIBROSIS AND RESTORING NORMAL MUCOSAL IMMUNITY IN CHRONIC INFLAMMATORY DISEASES. 2017 11 4119 32 MECHANISMS OF CADMIUM CARCINOGENICITY IN THE GASTROINTESTINAL TRACT. CANCER, A SERIOUS PUBLIC HEALTH PROBLEM IN WORLDWIDE, RESULTS FROM AN EXCESSIVE AND UNCONTROLLED PROLIFERATION OF THE BODY CELLS WITHOUT OBVIOUS PHYSIOLOGICAL DEMANDS OF ORGANS. THE GASTROINTESTINAL TRACT, INCLUDING THE ESOPHAGUS, STOMACH AND INTESTINE, IS A UNIQUE ORGAN SYSTEM. IT HAS THE HIGHEST CANCER INCIDENCE AND CANCER- RELATED MORTALITY IN THE BODY AND IS INFLUENCEED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. AMONG THE VARIOUS CHEMICAL ELEMENTS RECOGNIZED IN THE NATURE, SOME OF THEM INCLUDING ZINC, IRON, COBALT, AND COPPER HAVE ESSENTIAL ROLES IN THE VARIOUS BIOCHEMICAL AND PHYSIOLOGICAL PROCESSES, BUT ONLY AT LOW LEVELS AND OTHERS SUCH AS CADMIUM, LEAD, MERCURY, ARSENIC, AND NICKEL ARE CONSIDERED AS THREATS FOR HUMAN HEALTH ESPECIALLY WITH CHRONIC EXPOSURE AT HIGH LEVELS. CADMIUM, AN ENVIRONMENT CONTAMINANT, CANNOT BE DESTROYED IN NATURE. THROUGH IMPAIRMENT OF VITAMIN D METABOLISM IN THE KIDNEY IT CAUSES NEPHROTOXICITY AND SUBSEQUENTLY BONE METABOLISM IMPAIRMENT AND FRAGILITY. THE MAJOR MECHANISMS INVOLVED IN CADMIUM CARCINOGENESIS COULD BE RELATED TO THE SUPPRESSION OF GENE EXPRESSION, INHIBITION OF DNA DAMAGE REPAIR, INHIBITION OF APOPTOSIS, AND INDUCTION OF OXIDATIVE STRESS. IN ADDITION, CADMIUM MAY ACT THROUGH ABERRANT DNA METHYLATION. CADMIUM AFFECTS MULTIPLE CELLULAR PROCESSES, INCLUDING SIGNAL TRANSDUCTION PATHWAYS, CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. DOWN-REGULATION OF METHYLTRANSFERASES ENZYMES AND REDUCTION OF DNA METHYLATION HAVE BEEN STATED AS EPIGENETIC EFFECTS OF CADMIUM. FURTHERMORE, INCREASING INTRACELLULAR FREE CALCIUM ION LEVELS INDUCES NEURONAL APOPTOSIS IN ADDITION TO OTHER DELETERIOUS INFLUENCE ON THE STABILITY OF THE GENOME. 2015 12 3521 32 IKAROS: FROM CHROMATIN ORGANIZATION TO TRANSCRIPTIONAL ELONGATION CONTROL. IKAROS IS A MASTER REGULATOR OF CELL FATE DETERMINATION IN LYMPHOID AND OTHER HEMATOPOIETIC CELLS. THIS TRANSCRIPTION FACTOR ORCHESTRATES THE ASSOCIATION OF EPIGENETIC REGULATORS WITH CHROMATIN, ENSURING THE EXPRESSION PATTERN OF TARGET GENES IN A DEVELOPMENTAL AND LINEAGE-SPECIFIC MANNER. DISRUPTION OF IKAROS FUNCTION HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF ACUTE LYMPHOCYTIC LEUKEMIA, LYMPHOMA, CHRONIC MYELOID LEUKEMIA AND IMMUNE DISORDERS. PARADOXICALLY, WHILE IKAROS HAS BEEN SHOWN TO BE A TUMOR SUPPRESSOR, IT HAS ALSO BEEN IDENTIFIED AS A KEY THERAPEUTIC TARGET IN THE TREATMENT OF VARIOUS FORMS OF HEMATOLOGICAL MALIGNANCIES, INCLUDING MULTIPLE MYELOMA. INDEED, TARGETED PROTEOLYSIS OF IKAROS IS ASSOCIATED WITH DECREASED PROLIFERATION AND INCREASED DEATH OF MALIGNANT CELLS. ALTHOUGH THE MOLECULAR MECHANISMS HAVE NOT BEEN ELUCIDATED, THE EXPRESSION LEVELS OF IKAROS ARE VARIABLE DURING HEMATOPOIESIS AND COULD THEREFORE BE A KEY DETERMINANT IN EXPLAINING HOW ITS ABSENCE CAN HAVE SEEMINGLY OPPOSITE EFFECTS. MECHANISTICALLY, IKAROS COLLABORATES WITH A VARIETY OF PROTEINS AND COMPLEXES CONTROLLING CHROMATIN ORGANIZATION AT GENE REGULATORY REGIONS, INCLUDING THE NUCLEOSOME REMODELING AND DEACETYLASE COMPLEX, AND MAY FACILITATE TRANSCRIPTIONAL REPRESSION OR ACTIVATION OF SPECIFIC GENES. SEVERAL TRANSCRIPTIONAL REGULATORY FUNCTIONS OF IKAROS HAVE BEEN PROPOSED. AN EMERGING MECHANISM OF ACTION INVOLVES THE ABILITY OF IKAROS TO PROMOTE GENE REPRESSION OR ACTIVATION THROUGH ITS INTERACTION WITH THE RNA POLYMERASE II MACHINERY, WHICH INFLUENCES PAUSING AND PRODUCTIVE TRANSCRIPTION AT SPECIFIC GENES. THIS CONTROL APPEARS TO BE INFLUENCED BY IKAROS EXPRESSION LEVELS AND ISOFORM PRODUCTION. IN HERE, WE SUMMARIZE THE CURRENT STATE OF KNOWLEDGE ABOUT THE BIOLOGICAL ROLES AND MECHANISMS BY WHICH IKAROS REGULATES GENE EXPRESSION. WE HIGHLIGHT THE DYNAMIC REGULATION OF THIS FACTOR BY POST-TRANSLATIONAL MODIFICATIONS. FINALLY, POTENTIAL AVENUES TO EXPLAIN HOW IKAROS DESTRUCTION MAY BE FAVORABLE IN THE TREATMENT OF CERTAIN HEMATOLOGICAL MALIGNANCIES ARE ALSO EXPLORED. 2023 13 6766 28 ZINC METALLOPROTEINS IN EPIGENETICS AND THEIR CROSSTALK. MORE THAN HALF A CENTURY AGO, ZINC WAS ESTABLISHED AS AN ESSENTIAL MICRONUTRIENT FOR NORMAL HUMAN PHYSIOLOGY. IN SILICO DATA SUGGEST THAT ABOUT 10% OF THE HUMAN PROTEOME POTENTIALLY BINDS ZINC. MANY PROTEINS WITH ZINC-BINDING DOMAINS (ZBDS) ARE INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, WHICH REGULATE TRANSCRIPTION IN PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. ZINC METALLOPROTEINS IN EPIGENETICS ARE MAINLY ZINC METALLOENZYMES AND ZINC FINGER PROTEINS (ZFPS), WHICH ARE CLASSIFIED INTO WRITERS, ERASERS, READERS, EDITORS, AND FEEDERS. ALTOGETHER, THESE CLASSES OF PROTEINS ENGAGE IN CROSSTALK THAT FUNDAMENTALLY MAINTAINS THE EPIGENOME'S MODUS OPERANDI. CHANGES IN THE EXPRESSION OR FUNCTION OF THESE PROTEINS INDUCED BY ZINC DEFICIENCY OR LOSS OF FUNCTION MUTATIONS IN THEIR ZBDS MAY LEAD TO ABERRANT EPIGENETIC REPROGRAMMING, WHICH MAY WORSEN THE RISK OF NON-COMMUNICABLE CHRONIC DISEASES. THIS REVIEW ATTEMPTS TO ADDRESS ZINC'S ROLE AND ITS PROTEINS IN NATURAL EPIGENETIC PROGRAMMING AND ARTIFICIAL REPROGRAMMING AND BRIEFLY DISCUSSES HOW THE ZBDS IN THESE PROTEINS INTERACT WITH THE CHROMATIN. 2021 14 1398 34 DIET, GUT MICROBIOME AND EPIGENETICS: EMERGING LINKS WITH INFLAMMATORY BOWEL DISEASES AND PROSPECTS FOR MANAGEMENT AND PREVENTION. INFLAMMATORY BOWEL DISEASES (IBD) REPRESENT A GROWING PUBLIC HEALTH CONCERN DUE TO INCREASING INCIDENCE WORLDWIDE. THE CURRENT NOTION ON THE PATHOGENESIS OF IBD IS THAT GENETICALLY SUSCEPTIBLE INDIVIDUALS DEVELOP INTOLERANCE TO DYSREGULATED GUT MICROFLORA (DYSBIOSIS) AND CHRONIC INFLAMMATION DEVELOPS AS A RESULT OF ENVIRONMENTAL TRIGGERS. AMONG THE ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD, DIET PLAYS AN IMPORTANT ROLE IN MODULATING THE GUT MICROBIOME, INFLUENCING EPIGENETIC CHANGES, AND, THEREFORE, COULD BE APPLIED AS A THERAPEUTIC TOOL TO IMPROVE THE DISEASE COURSE. NEVERTHELESS, THE CURRENT DIETARY RECOMMENDATIONS FOR DISEASE PREVENTION AND MANAGEMENT ARE SCARCE AND HAVE WEAK EVIDENCE. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ON THE COMPLEX INTERACTIONS BETWEEN DIET, MICROBIOME AND EPIGENETICS IN IBD. WHEREAS AN OVERABUNDANCE OF CALORIES AND SOME MACRONUTRIENTS INCREASE GUT INFLAMMATION, SEVERAL MICRONUTRIENTS HAVE THE POTENTIAL TO MODULATE IT. IMMUNONUTRITION HAS EMERGED AS A NEW CONCEPT PUTTING FORWARD THE IMPORTANCE OF VITAMINS SUCH AS VITAMINS A, C, E, AND D, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS SUCH AS ZINC, SELENIUM, MANGANESE AND IRON. HOWEVER, WHEN ASSESSED IN CLINICAL TRIALS, SPECIFIC MICRONUTRIENTS EXERTED A LIMITED BENEFIT. BEYOND NUTRIENTS, AN ANTI-INFLAMMATORY DIETARY PATTERN AS A COMPLEX INTERVENTION APPROACH HAS BECOME POPULAR IN RECENT YEARS. HENCE, EXCLUSIVE ENTERAL NUTRITION IN PAEDIATRIC CROHN'S DISEASE IS THE ONLY NUTRITIONAL INTERVENTION CURRENTLY RECOMMENDED AS A FIRST-LINE THERAPY. OTHER NUTRITIONAL INTERVENTIONS OR SPECIFIC DIETS INCLUDING THE SPECIFIC CARBOHYDRATE DIET (SCD), THE LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES, AND POLYOL (FODMAP) DIET AND, MOST RECENTLY, THE MEDITERRANEAN DIET HAVE SHOWN STRONG ANTI-INFLAMMATORY PROPERTIES AND SHOW PROMISE FOR IMPROVING DISEASE SYMPTOMS. MORE WORK IS REQUIRED TO EVALUATE THE ROLE OF INDIVIDUAL FOOD COMPOUNDS AND COMPLEX NUTRITIONAL INTERVENTIONS WITH THE POTENTIAL TO DECREASE INFLAMMATION AS A MEANS OF PREVENTION AND MANAGEMENT OF IBD. 2017 15 3546 41 IMMUNOMODULATORY DIET IN PEDIATRIC AGE. IN THE LAST FEW DECADES, THE IMPORTANCE OF A FUNCTIONING IMMUNE SYSTEM AND HEALTH STATUS HAS BECOME MORE EVIDENT. MULTIPLE FACTORS ARE ABLE TO INFLUENCE THE DEVELOPMENT OF CHRONIC DISEASES AND DIET IS ONE OF THE MOST IMPORTANT ENVIRONMENTAL FACTORS. EVIDENCE DEMONSTRATES THAT DIETARY PATTERNS HIGH IN FAT AND LOW IN FIBER ARE ASSOCIATED WITH THE DEVELOPMENT OF NON-COMMUNICABLE DISEASES. MOREOVER, OPTIMAL NUTRITIONAL STATUS CAN MODULATE IMMUNE MATURATION AND RESPONSE TO INFLAMMATION. DURING INFLAMMATORY CONDITIONS, NUTRITIONAL DEFICIENCIES MAY OCCUR, ESTABLISHING A VICIOUS CIRCLE, CONSEQUENTLY A BALANCED NUTRITIONAL STATUS IS ESSENTIAL TO PREVENT AND COUNTERACT INFECTIONS. DIETARY DIVERSITY CAN PREVENT ALLERGIC DISEASES AND NUTRIENTS SUCH AS DHA, ARGININE, VITAMINS AND TRACE ELEMENTS HAVE AN IMPACT ON PHYSICAL BARRIERS (SUCH AS GUT MUCOSAL BARRIER AND SKIN), ON THE IMMUNE SYSTEM RESPONSE AND ON MICROBIOME MODULATION. PROTEIN DEFICIENCIES CAN COMPROMISE INNATE AND ADAPTIVE IMMUNE FUNCTIONS; ARGININE AVAILABILITY CAN AFFECT THE IMMUNE RESPONSE IN INJURED STATES AND OTHER DISEASE PROCESSES; EPA AND DHA CAN MODULATE BOTH INNATE AND ADAPTIVE IMMUNITY; PREBIOTICS HAVE A BENEFICIAL EFFECT ON THE FUNCTIONING OF THE IMMUNE SYSTEM. ZINC, COPPER, SELENIUM AND IRON ARE INVOLVED IN THE CORRECT DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. VITAMINS D, E, A, B AND C HAVE A ROLE ON IMMUNE SYSTEM THROUGH DIFFERENT MECHANISMS OF ACTION. SINCE A COMPLEX INTERPLAY EXISTS BETWEEN DIET, MICROBIOME AND EPIGENETIC FACTORS WHICH DETERMINE NUTRIENT-INDUCED CHANGES ON THE IMMUNE FUNCTION, THE EFFECT OF EACH SINGLE NUTRIENT MAY BE DIFFICULT TO STUDY. WELL-DESIGNED INTERVENTION STUDIES, INVESTIGATING THE EFFECTS OF WHOLE DIETARY PATTERN, SHOULD BE PERFORMED TO CLARIFY IMPACT OF FOODS ON THE IMMUNE FUNCTION AND DISEASE RISK. 2021 16 2700 34 EXCESS IRON: CONSIDERATIONS RELATED TO DEVELOPMENT AND EARLY GROWTH. WHAT EFFECTS MIGHT ARISE FROM EARLY LIFE EXPOSURES TO HIGH IRON? THIS REVIEW CONSIDERS THE SPECIFIC EFFECTS OF HIGH IRON ON THE BRAIN, STEM CELLS, AND THE PROCESS OF ERYTHROPOIESIS AND IDENTIFIES GAPS IN OUR KNOWLEDGE OF WHAT MOLECULAR DAMAGE MAY BE INCURRED BY OXIDATIVE STRESS THAT IS IMPARTED BY HIGH IRON STATUS IN EARLY LIFE. SPECIFIC AREAS TO ENHANCE RESEARCH ON THIS TOPIC INCLUDE THE FOLLOWING: LONGITUDINAL BEHAVIORAL STUDIES OF CHILDREN TO TEST ASSOCIATIONS BETWEEN IRON EXPOSURES AND MOOD, EMOTION, COGNITION, AND MEMORY; ANIMAL STUDIES TO DETERMINE EPIGENETIC CHANGES THAT REPROGRAM BRAIN DEVELOPMENT AND METABOLIC CHANGES IN EARLY LIFE THAT COULD BE FOLLOWED THROUGH THE LIFE COURSE; AND THE ESTABLISHMENT OF HUMAN EPIGENETIC MARKERS OF IRON EXPOSURES AND OXIDATIVE STRESS THAT COULD BE MONITORED FOR EARLY ORIGINS OF ADULT CHRONIC DISEASES. IN ADDITION, EFFORTS TO UNDERSTAND HOW IRON EXPOSURE INFLUENCES STEM CELL BIOLOGY COULD BE ENHANCED BY ESTABLISHING PLATFORMS TO COLLECT BIOLOGICAL SPECIMENS, INCLUDING UMBILICAL CORD BLOOD AND AMNIOTIC FLUID, TO BE MADE AVAILABLE TO THE RESEARCH COMMUNITY. AT THE MOLECULAR LEVEL, THERE IS A NEED TO BETTER UNDERSTAND STRESS ERYTHROPOIESIS AND CHANGES IN IRON METABOLISM DURING PREGNANCY AND DEVELOPMENT, ESPECIALLY WITH RESPECT TO REGULATORY CONTROL UNDER HIGH IRON CONDITIONS THAT MIGHT PROMOTE INEFFECTIVE ERYTHROPOIESIS AND IRON-LOADING ANEMIA. THESE INVESTIGATIONS SHOULD FOCUS NOT ONLY ON FACTORS SUCH AS HEPCIDIN AND ERYTHROFERRONE BUT SHOULD ALSO INCLUDE NEWLY IDENTIFIED INTERACTIONS BETWEEN TRANSFERRIN RECEPTOR-2 AND THE ERYTHROPOIETIN RECEPTOR. FINALLY, DESPITE OUR UNDERSTANDING THAT SEVERAL KEY MICRONUTRIENTS (E.G., VITAMIN A, COPPER, MANGANESE, AND ZINC) SUPPORT IRON'S FUNCTION IN ERYTHROPOIESIS, HOW THESE NUTRIENTS INTERACT REMAINS, TO OUR KNOWLEDGE, UNKNOWN. IT IS NECESSARY TO CONSIDER MANY FACTORS WHEN FORMULATING RECOMMENDATIONS ON IRON SUPPLEMENTATION. 2017 17 3547 41 IMMUNOMODULATORY ROLE OF NUTRIENTS: HOW CAN PULMONARY DYSFUNCTIONS IMPROVE? NUTRITION IS AN IMPORTANT TOOL THAT CAN BE USED TO MODULATE THE IMMUNE RESPONSE DURING INFECTIOUS DISEASES. IN ADDITION, THROUGH DIET, IMPORTANT SUBSTRATES ARE ACQUIRED FOR THE BIOSYNTHESIS OF REGULATORY MOLECULES IN THE IMMUNE RESPONSE, INFLUENCING THE PROGRESSION AND TREATMENT OF CHRONIC LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN THIS WAY, NUTRITION CAN PROMOTE LUNG HEALTH STATUS. A RANGE OF NUTRIENTS, SUCH AS VITAMINS (A, C, D, AND E), MINERALS (ZINC, SELENIUM, IRON, AND MAGNESIUM), FLAVONOIDS AND FATTY ACIDS, PLAY IMPORTANT ROLES IN REDUCING THE RISK OF PULMONARY CHRONIC DISEASES AND VIRAL INFECTIONS. THROUGH THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS, NUTRIENTS ARE ASSOCIATED WITH BETTER LUNG FUNCTION AND A LOWER RISK OF COMPLICATIONS SINCE THEY CAN DECREASE THE HARMFUL EFFECTS FROM THE IMMUNE SYSTEM DURING THE INFLAMMATORY RESPONSE. IN ADDITION, BIOACTIVE COMPOUNDS CAN EVEN CONTRIBUTE TO EPIGENETIC CHANGES, INCLUDING HISTONE DEACETYLASE (HDAC) MODIFICATIONS THAT INHIBIT THE TRANSCRIPTION OF PROINFLAMMATORY CYTOKINES, WHICH CAN CONTRIBUTE TO THE MAINTENANCE OF HOMEOSTASIS IN THE CONTEXT OF INFECTIONS AND CHRONIC INFLAMMATORY DISEASES. THESE NUTRIENTS ALSO PLAY AN IMPORTANT ROLE IN ACTIVATING IMMUNE RESPONSES AGAINST PATHOGENS, WHICH CAN HELP THE IMMUNE SYSTEM DURING INFECTIONS. HERE, WE PROVIDE AN UPDATED OVERVIEW OF THE ROLES PLAYED BY DIETARY FACTORS AND HOW THEY CAN AFFECT RESPIRATORY HEALTH. THEREFORE, WE WILL SHOW THE ANTI-INFLAMMATORY ROLE OF FLAVONOIDS, FATTY ACIDS, VITAMINS AND MICROBIOTA, IMPORTANT FOR THE CONTROL OF CHRONIC INFLAMMATORY DISEASES AND ALLERGIES, IN ADDITION TO THE ANTIVIRAL ROLE OF VITAMINS, FLAVONOIDS, AND MINERALS DURING PULMONARY VIRAL INFECTIONS, ADDRESSING THE MECHANISMS INVOLVED IN EACH FUNCTION. THESE MECHANISMS ARE INTERESTING IN THE DISCUSSION OF PERSPECTIVES ASSOCIATED WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION AND ITS PULMONARY COMPLICATIONS SINCE PATIENTS WITH SEVERE DISEASE HAVE VITAMINS DEFICIENCY, ESPECIALLY VITAMIN D. IN ADDITION, RESEARCHES WITH THE USE OF FLAVONOIDS HAVE BEEN SHOWN TO DECREASE VIRAL REPLICATION IN VITRO. THIS WAY, A FULL UNDERSTANDING OF DIETARY INFLUENCES CAN IMPROVE THE LUNG HEALTH OF PATIENTS. 2021 18 620 36 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 19 3840 30 IRON DEFICIENCY REPROGRAMS PHOSPHORYLATION SIGNALING AND REDUCES O-GLCNAC PATHWAYS IN NEURONAL CELLS. MICRONUTRIENT SENSING IS CRITICAL FOR CELLULAR GROWTH AND DIFFERENTIATION. DEFICIENCIES IN ESSENTIAL NUTRIENTS SUCH AS IRON STRONGLY AFFECT NEURONAL CELL DEVELOPMENT AND MAY LEAD TO DEFECTS IN NEURONAL FUNCTION THAT CANNOT BE REMEDIED BY SUBSEQUENT IRON SUPPLEMENTATION. TO UNDERSTAND THE ADAPTIVE INTRACELLULAR RESPONSES TO IRON DEFICIENCY IN NEURONAL CELLS, WE DEVELOPED AND UTILIZED A STABLE ISOTOPIC LABELING OF AMINO ACIDS IN CELL CULTURE (SILAC)-BASED QUANTITATIVE PHOSPHOPROTEOMICS WORKFLOW. OUR INTEGRATED APPROACH WAS DESIGNED TO COMPREHENSIVELY ELUCIDATE THE CHANGES IN PHOSPHORYLATION SIGNALING UNDER BOTH ACUTE AND CHRONIC IRON-DEFICIENT CELL MODELS. IN ADDITION, WE ANALYZED THE DIFFERENTIAL CELLULAR RESPONSES BETWEEN IRON DEFICIENCY AND HYPOXIA (OXYGEN-DEPRIVED) IN NEURONAL CELLS. OUR ANALYSIS IDENTIFIED NEARLY 16,000 PHOSPHORYLATION SITES IN HT-22 CELLS, A HIPPOCAMPAL-DERIVED NEURONAL CELL LINE, MORE THAN TEN PERCENT OF WHICH SHOWED AT LEAST 2-FOLD CHANGES IN RESPONSE TO EITHER HYPOXIA OR ACUTE/CHRONIC IRON DEFICIENCY. BIOINFORMATIC ANALYSIS REVEALED THAT IRON DEFICIENCY ALTERED KEY METABOLIC AND EPIGENETIC PATHWAYS INCLUDING THE PHOSPHORYLATION OF PROTEINS INVOLVED IN IRON SEQUESTRATION, GLUTAMATE METABOLISM, AND HISTONE METHYLATION. IN PARTICULAR, IRON DEFICIENCY INCREASED GLUTAMINE-FRUCTOSE-6-PHOSPHATE TRANSAMINASE (GFPT1) PHOSPHORYLATION, WHICH IS A KEY ENZYME IN THE GLUCOSAMINE BIOSYNTHESIS PATHWAY AND A TARGET OF 5' AMP-ACTIVATED PROTEIN KINASE (AMPK), LEADING TO REDUCED GFPT1 ENZYMATIC ACTIVITY AND CONSEQUENTLY LOWER GLOBAL O-GLCNAC MODIFICATION IN NEURONAL CELLS. TAKEN TOGETHER, OUR ANALYSIS OF THE PHOSPHOPROTEOME DYNAMICS IN RESPONSE TO IRON AND OXYGEN DEPRIVATION DEMONSTRATED AN ADAPTIVE CELLULAR RESPONSE BY MOUNTING POST-TRANSLATIONAL MODIFICATIONS THAT ARE CRITICAL FOR INTRACELLULAR SIGNALING AND EPIGENETIC PROGRAMMING IN NEURONAL CELLS. 2021 20 5489 26 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