1 3987 159 LONG-TERM PROBIOTIC INTERVENTION MITIGATES MEMORY DYSFUNCTION THROUGH A NOVEL H3K27ME3-BASED MECHANISM IN LEAD-EXPOSED RATS. CHRONIC LEAD EXPOSURE IS ASSOCIATED WITH THE DEVELOPMENT OF NEURODEGENERATIVE DISEASES, CHARACTERIZED BY THE LONG-TERM MEMORY DECLINE. HOWEVER, WHETHER THIS PATHOGENESIS COULD BE PREVENTED THROUGH ADJUSTING GUT MICROBIOTA IS NOT YET UNDERSTOOD. TO ADDRESS THE ISSUE, PREGNANT RATS AND THEIR FEMALE OFFSPRING WERE TREATED WITH LEAD (125 PPM) OR SEPARATELY THE EXTRA PROBIOTICS (10(10) ORGANISMS/RAT/DAY) TILL ADULTHOOD. FOR RESULTS, MEMORY DYSFUNCTION WAS ALLEVIATED BY THE TREATMENT OF MULTISPECIES PROBIOTICS. MEANWHILE, THE GUT MICROBIOTA COMPOSITION WAS PARTIALLY NORMALIZED AGAINST LEAD-EXPOSED RATS, WHICH IN TURN MEDIATED THE MEMORY REPAIRMENT VIA FECAL TRANSPLANTATION TRIALS. IN THE MOLECULAR ASPECT, THE DECREASED H3K27ME3 (TRIMETHYLATION OF HISTONE H3 LYS 27) IN THE ADULT HIPPOCAMPUS WAS RESTORED WITH PROBIOTIC INTERVENTION, AN EPIGENETIC EVENT MEDIATED BY EZH2 (ENHANCER OF ZESTE HOMOLOG 2) AT EARLY DEVELOPMENTAL STAGE. IN A NEURAL CELLULAR MODEL, EZH2 OVEREXPRESSION SHOWED THE SIMILAR RESCUE EFFECT WITH PROBIOTICS, WHEREAS ITS BLOCKADE LED TO THE NEURAL RE-DAMAGES. REGARDING THE GUT-BRAIN INFLAMMATORY MEDIATORS, THE DISRUPTED IL-6 (INTERLEUKIN 6) EXPRESSION WAS RESUMED BY PROBIOTIC TREATMENT. INTRAPERITONEAL INJECTION OF TOCILIZUMAB, AN IL-6 RECEPTOR ANTAGONIST, UPREGULATED THE HIPPOCAMPAL EZH2 LEVEL AND CONSEQUENTLY ALLEVIATED THE MEMORY INJURIES. IN CONCLUSION, RESHAPING GUT MICROBIOTA COULD MITIGATE MEMORY DYSFUNCTION CAUSED BY CHRONIC LEAD EXPOSURE, WHEREIN THE INFLAMMATION-HIPPOCAMPAL EPIGENETIC PATHWAY OF IL-6-EZH2-H3K27ME3, WAS FIRST PROPOSED TO MEDIATE THE STUDIED GUT-BRAIN COMMUNICATION. THESE FINDINGS PROVIDED INSIGHT WITH EPIGENETIC MECHANISMS UNDERLYING A UNIQUE GUT-BRAIN INTERACTION, SHEDDING LIGHT ON THE SAFE AND NON-INVASIVE TREATMENT OF NEURODEGENERATIVE DISORDERS WITH ENVIRONMENTAL ETIOLOGY. 2020 2 2119 35 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 3 6895 30 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 4 5710 35 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 5 1903 44 ENHANCED NEUROINFLAMMATION MEDIATED BY DNA METHYLATION OF THE GLUCOCORTICOID RECEPTOR TRIGGERS COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS SUBJECTED TO MATERNAL SEPARATION DURING THE NEONATAL PERIOD. BACKGROUND: MOUNTING EVIDENCE INDICATES THAT CHILDREN WHO EXPERIENCE ABUSE AND NEGLECT ARE PRONE TO CHRONIC DISEASES AND PREMATURE MORTALITY LATER IN LIFE. ONE MECHANISTIC HYPOTHESIS FOR THIS PHENOMENON IS THAT EARLY LIFE ADVERSITY ALTERS THE EXPRESSION OR FUNCTIONING OF THE GLUCOCORTICOID RECEPTOR (GR) THROUGHOUT THE COURSE OF LIFE AND THEREBY INCREASES SENSITIVITY TO INFLAMMATORY STIMULATION. AN EXAGGERATED PRO-INFLAMMATORY RESPONSE IS GENERALLY CONSIDERED TO BE A KEY CAUSE OF POSTOPERATIVE COGNITIVE DYSFUNCTION (POCD). THE AIM OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF EARLY LIFE ADVERSITY ON COGNITIVE FUNCTION AND NEUROINFLAMMATION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS AND TO DETERMINE WHETHER SUCH EFFECTS ARE ASSOCIATED WITH THE EPIGENETIC REGULATION OF GR. METHODS: WISTAR RAT PUPS WERE REPEATEDLY SUBJECTED TO INFANT MATERNAL SEPARATION (EARLY LIFE STRESS) FROM POSTNATAL DAYS 2-21. IN ADULTHOOD, THEIR BEHAVIOR AND THE SIGNALING OF HIPPOCAMPAL PRO-INFLAMMATORY FACTORS AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AFTER SEVOFLURANE ANESTHESIA WERE EVALUATED. WE ALSO EXAMINED THE EFFECTS OF MATERNAL SEPARATION (MS) ON THE EXPRESSION OF GR AND THE DNA METHYLATION STATUS OF THE PROMOTER REGION OF EXON 1(7) OF GR AND WHETHER BEHAVIORAL CHANGES AND NEUROINFLAMMATION AFTER ANESTHESIA WERE REVERSIBLE WHEN THE EXPRESSION OF GR WAS INCREASED BY ALTERING DNA METHYLATION. RESULTS: MS INDUCED COGNITIVE DECLINE AFTER SEVOFLURANE INHALATION IN THE MORRIS WATER MAZE AND CONTEXT FEAR CONDITIONING TESTS AND ENHANCED THE RELEASE OF CYTOKINES AND THE ACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING INDUCED BY SEVOFLURANE IN THE HIPPOCAMPUS OF ADULT RATS. BLOCKING NF-KAPPAB SIGNALING BY PYRROLIDINE DITHIOCARBAMATE (PDTC) INHIBITED THE RELEASE OF CYTOKINES. MS ALSO REDUCED THE EXPRESSION OF GR AND UPREGULATED THE METHYLATION LEVELS OF THE PROMOTER REGION OF GR EXON 1(7), AND SUCH EFFECTS WERE REVERSED BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) IN ADULT RATS. MOREOVER, TSA TREATMENT IN ADULT MS RATS INHIBITED THE OVERACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING AND THE RELEASE OF CYTOKINES AND ALLEVIATED COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA. CONCLUSIONS: EARLY LIFE STRESS INDUCES COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA, PERHAPS DUE TO THE ABERRANT METHYLATION OF THE GR GENE PROMOTER, WHICH REDUCES THE EXPRESSION OF THE GR GENE AND FACILITATES EXAGGERATED INFLAMMATORY RESPONSES. 2017 6 2297 33 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 7 706 40 BUTYRATE AND DIETARY SOLUBLE FIBER IMPROVE NEUROINFLAMMATION ASSOCIATED WITH AGING IN MICE. AGING RESULTS IN CHRONIC SYSTEMIC INFLAMMATION THAT CAN ALTER NEUROINFLAMMATION OF THE BRAIN. SPECIFICALLY, MICROGLIA SHIFT TO A PRO-INFLAMMATORY PHENOTYPE PREDISPOSING THEM TO HYPERACTIVATION UPON STIMULATION BY PERIPHERAL IMMUNE SIGNALS. IT IS PROPOSED THAT CERTAIN NUTRIENTS CAN DELAY BRAIN AGING BY PREVENTING OR REVERSING MICROGLIAL HYPERACTIVATION. BUTYRATE, A SHORT-CHAIN FATTY ACID (SCFA) PRODUCED PRIMARILY BY BACTERIAL FERMENTATION OF FIBER IN THE COLON, HAS BEEN EXTENSIVELY STUDIED PHARMACOLOGICALLY AS A HISTONE DEACETYLASE INHIBITOR AND SERVES AS AN ATTRACTIVE THERAPEUTIC CANDIDATE, AS BUTYRATE HAS ALSO BEEN SHOWN TO BE ANTI-INFLAMMATORY AND IMPROVE MEMORY IN ANIMAL MODELS. IN THIS STUDY, WE DEMONSTRATE THAT BUTYRATE CAN ATTENUATE PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MICROGLIA IN AGED MICE. IT IS STILL NOT FULLY UNDERSTOOD, HOWEVER, IF AN INCREASE IN BUTYRATE-PRODUCING BACTERIA IN THE GUT AS A CONSEQUENCE OF A DIET HIGH IN SOLUBLE FIBER COULD AFFECT MICROGLIAL ACTIVATION DURING AGING. ADULT AND AGED MICE WERE FED EITHER A 1% CELLULOSE (LOW FIBER) OR 5% INULIN (HIGH FIBER) DIET FOR 4 WEEKS. FINDINGS INDICATE THAT MICE FED INULIN HAD AN ALTERED GUT MICROBIOME AND INCREASED BUTYRATE, ACETATE, AND TOTAL SCFA PRODUCTION. IN ADDITION, HISTOLOGICAL SCORING OF THE DISTAL COLON DEMONSTRATED THAT AGED ANIMALS ON THE LOW FIBER DIET HAD INCREASED INFLAMMATORY INFILTRATE THAT WAS SIGNIFICANTLY REDUCED IN ANIMALS CONSUMING THE HIGH FIBER DIET. FURTHERMORE, GENE EXPRESSION OF INFLAMMATORY MARKERS, EPIGENETIC REGULATORS, AND THE MICROGLIAL SENSORY APPARATUS (I.E., THE SENSOME) WERE ALTERED BY BOTH DIET AND AGE, WITH AGED ANIMALS EXHIBITING A MORE ANTI-INFLAMMATORY MICROGLIAL PROFILE ON THE HIGH FIBER DIET. TAKEN TOGETHER, HIGH FIBER SUPPLEMENTATION IN AGING IS A NON-INVASIVE STRATEGY TO INCREASE BUTYRATE LEVELS, AND THESE DATA SUGGEST THAT AN INCREASE IN BUTYRATE THROUGH ADDED SOLUBLE FIBER SUCH AS INULIN COULD COUNTERBALANCE THE AGE-RELATED MICROBIOTA DYSBIOSIS, POTENTIALLY LEADING TO NEUROLOGICAL BENEFITS. 2018 8 5318 24 PSYCHONEUROENDOCRINE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE: A REVIEW. THERE IS EVIDENCE SUGGESTING THAT IMMUNOSENESCENCE CAN BE ACCELERATED BY EXTERNAL FACTORS SUCH AS CHRONIC STRESS. HERE WE REVIEW POTENTIAL PSYCHONEUROENDOCRINE DETERMINANTS OF PREMATURE AGING OF THE IMMUNE SYSTEM AND DISCUSS AVAILABLE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE. CHRONIC STRESS MAY ACCELERATE VARIOUS FEATURES OF IMMUNOSENESCENCE BY ACTIVATING KEY ALLOSTATIC SYSTEMS, NOTABLY THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THE IMMUNOLOGICAL IMPACT OF SUCH NEUROENDOCRINE DYSREGULATION MAY BE FURTHER AMPLIFIED BY A DRAMATIC DECLINE IN DEHYDROEPIANDROSTERONE (DHEA) LEVELS, ACTING IN PART AS AN ENDOGENOUS GLUCOCORTICOID ANTAGONIST. STRESS-BUFFERING STRATEGIES SHOW BENEFICIAL EFFECTS ON VARIOUS BIOMARKERS IN ELDERLY POPULATIONS. LIKEWISE, SUPPLEMENTATION OF DHEA, MELATONIN OR GROWTH HORMONE HAS YIELDED SIGNIFICANT BENEFICIAL EFFECTS IN A NUMBER OF STUDIES, INCLUDING: INCREASED WELL-BEING, MEMORY PERFORMANCE, BONE MINERAL DENSITY AND IMPROVED IMMUNOCOMPETENCE AS EVIDENCED BY RESULTS OF IN VITRO (T CELL PROLIFERATION, CYTOTOXICITY, CYTOKINE PRODUCTION), AND IN VIVO IMMUNE CHALLENGES. HOWEVER, THE SIDE-EFFECTS OF HORMONAL SUPPLEMENTATION ARE ALSO DISCUSSED. FINALLY, MODERATE EXERCISE VIA THE PROMOTION OF CORTISOL/DHEA BALANCE OR EPIGENETIC MODIFICATIONS, IS ASSOCIATED WITH LOWER SERUM PRO-INFLAMMATORY CYTOKINES, GREATER LYMPHOPROLIFERATIVE RESPONSES AND LOWER COUNTS OF SENESCENT T CELLS. TAKEN TOGETHER, THESE DATA SUGGEST THAT IMMUNE SYSTEM IS PLASTIC AND IMMUNOSENESCENCE CAN BE ATTENUATED PSYCHONEUROENDOCRINE INTERVENTIONS. 2013 9 1362 34 DEVELOPMENTAL EPIGENETIC PROGRAMMING OF ADULT GERM CELL DEATH DISEASE: POLYCOMB PROTEIN EZH2-MIR-101 PATHWAY. AIM: THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE REFERS TO THE CONCEPT THAT EARLY EXPOSURE TO TOXICANTS OR NUTRITIONAL IMBALANCES DURING PERINATAL LIFE INDUCES CHANGES THAT ENHANCE THE RISK OF DEVELOPING NONCOMMUNICABLE DISEASES IN ADULTHOOD. PATIENTS/MATERIALS & METHODS: AN EXPERIMENTAL MODEL WITH AN ADULT CHRONIC GERM CELL DEATH PHENOTYPE RESULTING FROM EXPOSURE TO A XENOESTROGEN WAS USED. RESULTS: A RECIPROCAL NEGATIVE FEEDBACK LOOP INVOLVING DECREASED EZH2 PROTEIN LEVEL AND INCREASED MIR-101 EXPRESSION WAS IDENTIFIED. IN VITRO AND IN VIVO KNOCKDOWN OF EZH2 INDUCED AN APOPTOTIC PROCESS IN GERM CELLS THROUGH INCREASED LEVELS OF APOPTOTIC FACTORS (BIM AND BAD) AND DNA REPAIR ALTERATION VIA TOPOISOMERASE 2B DEREGULATION. THE INCREASED MIR-101 LEVELS WERE OBSERVED IN THE ANIMAL BLOOD, MEANING THAT MIR-101 MAY BE A PART OF A CIRCULATING MARK OF GERM CELL DEATH. CONCLUSION: MIR-101-EZH2 PATHWAY DEREGULATION COULD REPRESENT A NOVEL PATHOPHYSIOLOGICAL EPIGENETIC BASIS FOR ADULT GERM CELL DISEASE WITH ENVIRONMENTAL AND DEVELOPMENTAL ORIGINS. 2016 10 2442 27 EPIGENETIC STABILITY IN THE ADULT MOUSE CORTEX UNDER CONDITIONS OF PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION. HISTONE ACETYLATION IS CONSIDERED A MAJOR EPIGENETIC PROCESS THAT AFFECTS BRAIN DEVELOPMENT AND SYNAPTIC PLASTICITY, AS WELL AS LEARNING AND MEMORY. THE TRANSCRIPTIONAL EFFECTORS AND MORPHOLOGICAL CHANGES RESPONSIBLE FOR PLASTICITY AS A RESULT OF LONG-TERM MODIFICATIONS TO HISTONE ACETYLATION ARE NOT FULLY UNDERSTOOD. TO THIS END, WE PHARMACOLOGICALLY INHIBITED HISTONE DEACETYLATION USING TRICHOSTATIN A IN ADULT (6-MONTH-OLD) MICE AND FOUND SIGNIFICANT INCREASES IN THE LEVELS OF THE ACETYLATED HISTONE MARKS H3LYS9, H3LYS14 AND H4LYS12. HIGH-RESOLUTION TRANSCRIPTOME ANALYSIS OF DIVERSE BRAIN REGIONS UNCOVERED FEW DIFFERENCES IN GENE EXPRESSION BETWEEN TREATED AND CONTROL ANIMALS, NONE OF WHICH WERE PLASTICITY RELATED. INSTEAD, AFTER INCREASED HISTONE ACETYLATION, WE DETECTED A LARGE NUMBER OF NOVEL TRANSCRIPTIONALLY ACTIVE REGIONS, WHICH CORRESPOND TO LONG NON-CODING RNAS (LNCRNAS). WE ALSO SURPRISINGLY FOUND NO SIGNIFICANT CHANGES IN DENDRITIC SPINE PLASTICITY IN LAYERS 1 AND 2/3 OF THE VISUAL CORTEX USING LONG-TERM IN VIVO TWO-PHOTON IMAGING. OUR RESULTS INDICATE THAT CHRONIC PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION CAN BE DECOUPLED FROM GENE EXPRESSION AND INSTEAD, MAY POTENTIALLY EXERT A POST-TRANSCRIPTIONAL EFFECT THROUGH THE DIFFERENTIAL PRODUCTION OF LNCRNAS. 2016 11 5189 31 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE. 2022 12 1823 44 EFFECTS OF EARLY-LIFE STRESS AND HDAC INHIBITION ON MATERNAL BEHAVIOR IN MICE. DESPITE THE WELL-ESTABLISHED FACT THAT MATERNAL CARE PLAYS A PIVOTAL ROLE IN THE OFFSPRING DEVELOPMENT, LITTLE IS KNOWN ABOUT THE EFFECTS OF DISRUPTION OF MATERNAL CARE EARLY IN LIFE ON THE DEVELOPMENT OF THIS BEHAVIOR IN THE OFFSPRING. USING BRIEF REPEATED MATERNAL SEPARATION (45 MIN/DAY ON POSTNATAL DAYS 3-6), WHICH REPRESENTS A MODEL OF EARLY LIFE STRESS, WE FOUND BEHAVIORAL CHANGES IN ADULT FEMALE MICE OFFSPRING. THE DECREASE IN HOME CAGE EXPLORATORY BEHAVIOR (BOTH PUP-DIRECTED AND NONPUP-DIRECTED) WAS REVEALED LATER IN ADULTHOOD WITHOUT CHANGES IN MATERNAL CARE LEVEL. MATERNAL SEPARATION COUPLED WITH PAIN EXPOSURE CAUSED BY SUBCUTANEOUS SALINE INJECTION PROCEDURE HAD A CUMULATIVE RESULTING EFFECT, WHICH WAS MANIFESTED IN THE DECREASED LEVEL OF NURSING ASSOCIATED WITH LICKING-GROOMING IN ADULT FEMALES. THE BEHAVIORAL CHANGES FOUND IN ADULT FEMALE OFFSPRING COULD BE TRIGGERED BY IDENTIFIED CHANGES IN THE BEHAVIOR OF THEIR MOTHERS, WHILE ALTERATIONS OF THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN WERE NOT DETECTED. HISTONE DEACETYLASE INHIBITOR SODIUM VALPROATE WAS USED IN ORDER TO STUDY THE POSSIBILITY OF PREVENTING THE EFFECTS OF EARLY LIFE STRESS THROUGH INVOLVEMENT OF EPIGENETIC MECHANISMS. DESPITE THE INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN CAUSED BY VALPROATE, ITS BEHAVIORAL EFFECTS WERE BARELY DETECTABLE. THESE EFFECTS WERE REFLECTED IN PREVENTION OF THE REDUCTION OF NURSING ASSOCIATED WITH LICKING-GROOMING INDUCED BY MATERNAL SEPARATION, ACCOMPANIED BY PAIN EXPOSURE. THE DATA ARE DISCUSSED IN TERMS OF THE POSSIBLE APPLICATION TO THE STUDIES OF MECHANISMS UNDERLYING LONG-TERM EFFECTS OF HUMAN EARLY LIFE TRAUMA. (PSYCINFO DATABASE RECORD (C) 2019 APA, ALL RIGHTS RESERVED). 2019 13 4093 28 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 14 6564 32 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS. 2021 15 6226 14 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 16 4405 27 MOLECULAR ADAPTATIONS OF THE BLOOD-BRAIN BARRIER PROMOTE STRESS RESILIENCE VS. DEPRESSION. PRECLINICAL AND CLINICAL STUDIES SUGGEST THAT INFLAMMATION AND VASCULAR DYSFUNCTION CONTRIBUTE TO THE PATHOGENESIS OF MAJOR DEPRESSIVE DISORDER (MDD). CHRONIC SOCIAL STRESS ALTERS BLOOD-BRAIN BARRIER (BBB) INTEGRITY THROUGH LOSS OF TIGHT JUNCTION PROTEIN CLAUDIN-5 (CLDN5) IN MALE MICE, PROMOTING PASSAGE OF CIRCULATING PROINFLAMMATORY CYTOKINES AND DEPRESSION-LIKE BEHAVIORS. THIS EFFECT IS PROMINENT WITHIN THE NUCLEUS ACCUMBENS, A BRAIN REGION ASSOCIATED WITH MOOD REGULATION; HOWEVER, THE MECHANISMS INVOLVED ARE UNCLEAR. MOREOVER, COMPENSATORY RESPONSES LEADING TO PROPER BEHAVIORAL STRATEGIES AND ACTIVE RESILIENCE ARE UNKNOWN. HERE WE IDENTIFY ACTIVE MOLECULAR CHANGES WITHIN THE BBB ASSOCIATED WITH STRESS RESILIENCE THAT MIGHT SERVE A PROTECTIVE ROLE FOR THE NEUROVASCULATURE. WE ALSO CONFIRM THE RELEVANCE OF SUCH CHANGES TO HUMAN DEPRESSION AND ANTIDEPRESSANT TREATMENT. WE SHOW THAT PERMISSIVE EPIGENETIC REGULATION OF CLDN5 EXPRESSION AND LOW ENDOTHELIUM EXPRESSION OF REPRESSIVE CLDN5-RELATED TRANSCRIPTION FACTOR FOXO1 ARE ASSOCIATED WITH STRESS RESILIENCE. REGION- AND ENDOTHELIAL CELL-SPECIFIC WHOLE TRANSCRIPTOMIC ANALYSES REVEALED MOLECULAR SIGNATURES ASSOCIATED WITH STRESS VULNERABILITY VS. RESILIENCE. WE IDENTIFIED PROINFLAMMATORY TNFALPHA/NFKAPPAB SIGNALING AND HDAC1 AS MEDIATORS OF STRESS SUSCEPTIBILITY. PHARMACOLOGICAL INHIBITION OF STRESS-INDUCED INCREASE IN HDAC1 ACTIVITY RESCUED CLDN5 EXPRESSION IN THE NAC AND PROMOTED RESILIENCE. IMPORTANTLY, WE CONFIRMED CHANGES IN HDAC1 EXPRESSION IN THE NAC OF DEPRESSED PATIENTS WITHOUT ANTIDEPRESSANT TREATMENT IN LINE WITH CLDN5 LOSS. CONVERSELY, MANY OF THESE DELETERIOUS CLDN5-RELATED MOLECULAR CHANGES WERE REDUCED IN POSTMORTEM NAC FROM ANTIDEPRESSANT-TREATED SUBJECTS. THESE FINDINGS REINFORCE THE IMPORTANCE OF CONSIDERING STRESS-INDUCED NEUROVASCULAR PATHOLOGY IN DEPRESSION AND PROVIDE THERAPEUTIC TARGETS TO TREAT THIS MOOD DISORDER AND PROMOTE RESILIENCE. 2020 17 5894 37 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 18 422 34 ANNEXIN-A1 DEFICIENCY ATTENUATES STRESS-INDUCED TUMOR GROWTH VIA FATTY ACID METABOLISM IN MICE: AN INTEGRATED MULTIPLE OMICS ANALYSIS ON THE STRESS- MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. BACKGROUND: HIGH EMOTIONAL OR PSYCHOPHYSICAL STRESS LEVELS HAVE BEEN CORRELATED WITH AN INCREASED RISK AND PROGRESSION OF VARIOUS DISEASES. HOW STRESS IMPACTS THE GUT MICROBIOTA TO INFLUENCE METABOLISM AND SUBSEQUENT CANCER PROGRESSION IS UNCLEAR. METHODS: FECES AND SERUM SAMPLES FROM BALB/C ANXA1(+/+) AND ANXA1(-/-) MICE WITH OR WITHOUT CHRONIC RESTRAINT STRESS WERE USED FOR 16S RRNA GENE SEQUENCING AND GC-MS METABOLOMICS ANALYSIS TO INVESTIGATE THE EFFECT OF STRESS ON MICROBIOME AND METABOLOMICS DURING STRESS AND BREAST TUMORIGENESIS. BREAST TUMORS SAMPLES FROM STRESSED AND NON-STRESSED MICE WERE USED TO PERFORM WHOLE-GENOME BISULFITE SEQUENCING (WGBS) AND RNASEQ ANALYSIS TO CONSTRUCT THE POTENTIAL NETWORK FROM CANDIDATE HUB GENES. FINALLY, MACHINE LEARNING AND INTEGRATED ANALYSIS WERE USED TO MAP THE AXIS FROM CHRONIC RESTRAINT STRESS TO BREAST CANCER DEVELOPMENT. RESULTS: WE REPORT THAT CHRONIC STRESS PROMOTES BREAST TUMOR GROWTH VIA A STRESS-MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. CHRONIC RESTRAINT STRESS IN MICE ALTERS THE MICROBIOME COMPOSITION AND FATTY ACIDS METABOLISM AND INDUCES AN EPIGENETIC SIGNATURE IN TUMORS XENOGRAFTED AFTER STRESS. SUBSEQUENT MACHINE LEARNING AND SYSTEMIC MODELING ANALYSES IDENTIFIED A SIGNIFICANT CORRELATION AMONG MICROBIOME COMPOSITION, METABOLITES, AND DIFFERENTIALLY METHYLATED REGIONS IN STRESSED TUMORS. MOREOVER, SILENCING ANNEXIN-A1 INHIBITS THE CHANGES IN THE GUT MICROBIOME AND FATTY ACID METABOLISM AFTER STRESS AS WELL AS BASAL AND STRESS-INDUCED TUMOR GROWTH. CONCLUSIONS: THESE DATA SUPPORT A PHYSIOLOGICAL AXIS LINKING THE MICROBIOME AND METABOLITES TO CANCER EPIGENETICS AND INFLAMMATION. THE IDENTIFICATION OF THIS AXIS COULD PROPEL THE NEXT PHASE OF EXPERIMENTAL DISCOVERY IN FURTHER UNDERSTANDING THE UNDERLYING MOLECULAR MECHANISM OF TUMORIGENESIS CAUSED BY PHYSIOLOGICAL STRESS. 2022 19 4391 34 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA. 2023 20 4036 23 MACROPHAGE EPIGENETIC MEMORIES OF EARLY LIFE INJURY DRIVE NEONATAL NOCICEPTIVE PRIMING. THE DEVELOPING PERIPHERAL NERVOUS AND IMMUNE SYSTEMS ARE FUNCTIONALLY DISTINCT FROM ADULTS. THESE SYSTEMS ARE VULNERABLE TO EFFECTS OF EARLY LIFE INJURY WHICH CAN INFLUENCE OUTCOMES RELATED TO NOCICEPTION FOLLOWING SUBSEQUENT INJURY LATER IN LIFE (I.E. "NEONATAL NOCICEPTIVE PRIMING"). THE UNDERPINNINGS OF THIS PHENOMENON ARE LARGELY UNKNOWN, ALTHOUGH MACROPHAGES CAN BE EPIGENETICALLY TRAINED BY INJURY. WE FOUND THAT MACROPHAGES ARE BOTH NECESSARY AND PARTIALLY SUFFICIENT TO DRIVE NEONATAL NOCICEPTIVE PRIMING POSSIBLY DUE TO A LONG-LASTING EPIGENETIC REMODELING OF PERIPHERAL MACROPHAGES. THE P75 NEUROTROPHIC FACTOR RECEPTOR (NTR) WAS OBSERVED TO BE AN IMPORTANT EFFECTOR IN REGULATING NEONATAL NOCICEPTIVE PRIMING. P75NTR MODULATES THE INFLAMMATORY PROFILE AND RESPONSES OF RODENT AND HUMAN MACROPHAGES. THIS "PAIN MEMORY" WAS ABLE TO BE TRANSFERRED TO A NAIVE HOST TO ALTER SEX-SPECIFIC PAIN-RELATED BEHAVIORS. THIS STUDY REVEALS A NOVEL MECHANISM BY WHICH ACUTE POST-SURGICAL PAIN MAY TRANSITION TO CHRONIC PAIN IN CHILDREN. 2023